KR102331854B1 - Novel Biomarkers for Diagnosing Skin Aging - Google Patents
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Abstract
Description
본 발명은 피부 노화 및 피부 장벽기능 저하의 지표가 되는 후각 수용체 유전자에 관한 것이다.The present invention relates to an olfactory receptor gene that is an indicator of skin aging and deterioration of skin barrier function.
피부는 표피층, 진피층 및 피하지방층으로 구성되어 있으며, 표피층의 가장 최외각에 위치한 각질층은 낮은 투과성과 물리적인 장벽을 제공함으로써 신체 내부를 외부 환경으로부터 보호하고, 수분 손실을 막으며, 독성 물질, 감염성 미생물, 기계적 자극, 자외선 등에 대한 피부 장벽(Stratum corneum, Skin barrier) 기능을 제공하는 것으로 알려져 있다(Rawlings et al., Dermatologic therapy, 17:43-48, 2004). 이러한 과정에 중요하게 관여하는 필라그린(filaggrin)은 표피 단백질의 일종으로서, 필라그린의 전구체인 프로필라그린(profilaggrin) 형태로 분비된 후 필라그린 단량체(monomer)로 분해되고, 이는 각질층 내에서 케라틴 중간미세섬유를 응집시켜 불용성인 케라틴 기질을 형성한다. 이 기질을 뼈대로 하여 각질세포의 세포막 바로 아래에 각화세포피(cornified cell envelope, CE)가 형성되며, 이는 피부의 장벽기능에 밀접하게 관여하고 있다. 또한, 그 일부에는 세라미드 등이 공유 결합하며, 소수성 구조를 형성함으로써 세포간 지질의 라멜라 구조의 토대를 공급하고, 각층 장벽기능과 피부의 수분유지 기능의 기초를 제공한다(Dale et al., Annals of the New York Academy of Sciences 455(1):330-342, 1985; Senshu et al., Biochemical and biophysical research communications 225(3): 712-719, 1996). 그러나, 자외선(특히 UVB)이나 염증 등에 의한 자극이 가해지면 필라그린과 케라틴의 생성이 현격하게 감소하고, CE가 불완전한 상태로 형성되어 각질 세포나 세포간 지질의 구조에 이상이 생김으로써 각층의 수분유지 기능과 장벽기능의 저하가 나타난다. 이러한 현상은 궁극적으로 피부 거칠음, 피부 건조 등을 수반하는 피부의 노화 증상으로 이어진다(Simonsen et al., Acta Dermato-Venereologica 97(6):797-801, 2017).The skin is composed of the epidermis, dermis, and subcutaneous fat layer, and the stratum corneum, located at the outermost layer of the epidermis, provides low permeability and a physical barrier to protect the inside of the body from the external environment, prevent water loss, toxic substances, and infectious agents. It is known to provide a skin barrier (Stratum corneum, Skin barrier) function against microorganisms, mechanical stimulation, ultraviolet rays, etc. (Rawlings et al., Dermatologic therapy , 17:43-48, 2004). Filaggrin, which is importantly involved in this process, is a kind of epidermal protein, which is secreted in the form of profilagrin, a precursor of filaggrin, and then decomposed into filaggrin monomer, which is keratin in the stratum corneum. Agglomerate the intermediate fibrils to form an insoluble keratin matrix. Using this matrix as a skeleton, a cornified cell envelope (CE) is formed just below the cell membrane of keratinocytes, which is closely involved in the barrier function of the skin. In addition, ceramides are covalently bonded to some of them, and by forming a hydrophobic structure, it provides the basis for the lamellar structure of intercellular lipids, and provides the basis for the barrier function of each layer and the moisture retention function of the skin (Dale et al., Annals). of the New York Academy of Sciences 455(1):330-342, 1985; Senshu et al., Biochemical and biophysical research communications 225(3): 712-719, 1996). However, when stimulation by ultraviolet rays (especially UVB) or inflammation is applied, the production of filaggrin and keratin is remarkably reduced, and CE is formed in an incomplete state, resulting in abnormalities in the structure of keratinocytes or intercellular lipids. Decreased maintenance and barrier function. This phenomenon ultimately leads to skin aging symptoms accompanied by rough skin, dry skin, etc. (Simonsen et al., Acta Dermato-Venereologica 97(6):797-801, 2017).
최근 유전정보를 기반으로 한 개인별 맞춤의료가 보건산업의 새로운 패러다임으로 등장하면서 진단검사와 소비자 직접의뢰(DTC; Direct To Consumer) 검사를 수행하는 기업이 점차 증가하고, 유전자 검사 시장이 2017년 58.2억 달러(약 7.7조원)에서 연평균 10.6%씩 성장하여 2024년에는 117.9억 달러(약 14.3조원) 규모로 성장할 것이라는 전망이 보고되었다(생명공학정책연구센터, 2019). 현재 국내의 DTC 유전자 검사 진단 키트는 테라젠바이오와 아모레퍼시픽의‘아이오페 랩 지노 인덱스’, 마크로젠의‘마이지놈스토리 더플러스’, 바이오니아의‘진투라이프’등 다양한 바이오 업체에서 제작되어 대부분 생체 DNA 분석을 통해 타고난 개인의 유전자 발현 상태를 측정하여 혈당, 혈압, 탈모, 콜레스테롤 등 해당 질병에 대해 얼마나 취약한지를 파악하는 것에 초점이 맞춰져 있으나, 선천적 유전 정보가 아닌 현재의 피부 노화 진행 상태를 반영하는 진단 키트는 전무한 실정이다. 또한 시중의 진단 키트는 여러가지 항목에 대한 유전자를 종합 검사하기 위하여 검체를 피부가 아닌 구강상피세포에서 채취하고 있으므로 피부에서 직접 피부노화 상태를 검사할 수 있는 보완 제품의 필요성이 절실한 실정이다.Recently, as personalized medicine based on genetic information has emerged as a new paradigm in the health industry, the number of companies performing diagnostic tests and direct to consumer (DTC) tests is gradually increasing, and the genetic test market is 5.82 billion won in 2017. It has been reported that it will grow from the dollar (about 7.7 trillion won) at an average annual rate of 10.6% to 11.79 billion dollars (about 14.3 trillion won) in 2024 (Biotechnology Policy Research Center, 2019). Currently, domestic DTC genetic test and diagnostic kits are produced by various bio companies such as Theragen Bio and Amorepacific's 'IOPE Lab Gino Index', Macrogen's 'My Genome Story The Plus', and Bioneer's 'Gene2 Life', and most of them analyze biological DNA. Although the focus is on determining how vulnerable an individual is to the disease, such as blood sugar, blood pressure, hair loss, and cholesterol, by measuring the gene expression state of an individual through is non-existent. In addition, since commercially available diagnostic kits collect samples from oral epithelial cells, not skin, in order to comprehensively test genes for various items, there is an urgent need for complementary products that can directly test skin aging.
한편, 후각 수용체(olfactory receptor)는 후각 상피세포에서 주로 발현되는 것으로 알려져 있다. 공기 중의 냄새분자가 후각상피세포의 세포막에 존재하는 후각 수용체와 결합하면, Golf(olfactory G protein)을 우선적으로 활성화시키고 곧이어 AC3(olfactory-related adenylate cyclase)를 활성화시킨다. 후자는 후각세포 내에서 ATP로부터 cAMP(cyclic AMP)의 생성을 촉진시키고, 칼슘이온 채널을 활성화시켜서 궁극적으로 뇌로 신호를 전달하여 냄새 분자를 인식하도록 하는 작용을 한다(Fleischer et al., Frontiers in Cellular Neuroscience 3:9, 2009). 인간에서는 약 350종의 후각 수용체 아형(isoform)이 발현하는 것으로 보고되었고, 이는 전체 지놈 유전자의 1% 이상에 달하는 큰 유전자군으로서, GPCR 중에서도 가장 거대한 군에 해당되는 유전자로 알려져 있다. 단일 후각수용체가 담당하는 냄새 분자는 약 2-3가지이며, 약 100여 가지 후각 수용체의 조합에 따라 사람은 1만 가지 정도의 냄새(또는 냄새 분자)를 구별할 수 있다(Pluznick et al., Proceedings of the National Academy of Sciences, 106(6):2059-2064, 2009). Meanwhile, it is known that olfactory receptors are mainly expressed in olfactory epithelial cells. When odor molecules in the air bind to olfactory receptors on the cell membrane of olfactory epithelial cells, they preferentially activate Golf (olfactory G protein) and then AC3 (olfactory-related adenylate cyclase). The latter promotes the production of cAMP (cyclic AMP) from ATP in the olfactory cell, activates calcium ion channels, and ultimately transmits a signal to the brain to recognize odor molecules (Fleischer et al., Frontiers in Cellular) (Fleischer et al., Frontiers in Cellular) Neuroscience 3:9, 2009). It has been reported that about 350 olfactory receptor isoforms are expressed in humans, which is a large gene group that accounts for more than 1% of the total genome genes, and is known as the gene corresponding to the largest group among GPCRs. A single olfactory receptor is responsible for about 2-3 odor molecules, and according to a combination of about 100 olfactory receptors, humans can distinguish about 10,000 odors (or odor molecules) (Pluznick et al., Proceedings of the National Academy of Sciences , 106(6):2059-2064, 2009).
최근 연구에 의하면 후각 수용체는 후각 조직 뿐 아니라 피부, 폐, 방광, 대장 등 비후각 조직에서 광범위하게 발현되어 신체의 상태에 따라 발현이 다르게 나타나는 것으로 알려져 있다. 예를 들면 아토피 환자의 피부에서 정상인의 피부보다 OR10G7 유전자의 발현이 더 높게 나타났으며(Tham et al., Journal of Allergy and Clinical Immunology, 143(5):1838-1848. 2019), 천식 환자의 폐조직에서 OR2AG2 유전자의 발현이 정상인의 폐조직보다 낮은 것으로 보고되어 현재 질환의 상태 및 민감성을 예측할 수 있는 마커로 제시되었다(Chakraborty et al., Scientific reports 9(1):1-10, 2019). 또한 정상인 방광에 비하여 방광암 환자의 방광에서 OR10H1 유전자의 발현이 현저하게 높아, 방광암의 조기 진단용 바이오마커로 제시된 바 있으며(Weber, L et al., Frontiers in physiology, 9:456,2018), 대장에서 OR7C1 유전자의 발현이 대장암 환자에서 정상인보다 높게 나타나 대장암 진단을 위한 새로운 마커로 제시되었다(Morita et al., Clinical Cancer Research, 22(13):3298-3309, 2016). 따라서, 후각수용체의 이소성 발현은 단순히 후각을 인지하는 것 이상으로 생리학 및 병리학적 상태를 진단 및 대변할 수 있는 마커로서 역할을 할 수 있다는 사실이 최근 2~3년 사이에 보고되고 있으나, 자외선 및 염증과 같이 피부노화를 일으키는 자극에 대해 표피의 후각수용체의 발현 변화 여부에 대해서는 아직 밝혀진 바가 없다.According to recent studies, olfactory receptors are widely expressed in non-olfactory tissues such as skin, lung, bladder, and colon as well as in olfactory tissues, and it is known that their expression varies depending on the state of the body. For example, the expression of the OR10G7 gene was higher in the skin of atopic patients than in normal skin (Tham et al., Journal of Allergy and Clinical Immunology , 143(5):1838-1848. 2019), and in asthma patients The expression of OR2AG2 gene in lung tissue was reported to be lower than that of normal lung tissue, and it has been suggested as a marker for predicting the current disease state and susceptibility (Chakraborty et al., Scientific reports 9(1):1-10, 2019). . In addition, the expression of the OR10H1 gene in the bladder of bladder cancer patients is significantly higher than that of the normal bladder, which has been suggested as a biomarker for early diagnosis of bladder cancer (Weber, L et al., Frontiers in physiology , 9:456,2018), and in the colon The expression of the OR7C1 gene was higher in colorectal cancer patients than in normal individuals, which was suggested as a new marker for colorectal cancer diagnosis (Morita et al., Clinical Cancer Research , 22(13):3298-3309, 2016). Therefore, the fact that the ectopic expression of olfactory receptors can serve as a marker that can diagnose and represent physiological and pathological conditions beyond simply recognizing the sense of smell has been reported in recent 2-3 years. Whether the expression of olfactory receptors in the epidermis changes in response to stimuli that causes skin aging, such as inflammation, has not yet been clarified.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Numerous papers and patent documents are referenced throughout this specification and their citations are indicated. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to more clearly describe the level of the technical field to which the present invention pertains and the content of the present invention.
본 발명자들은 연령의 증가 또는 다양한 생물학적·비생물학적 스트레스 자극으로 인한 피부 노화의 진행 정도를 정확하게 평가하는 분자 진단 방법을 개발하기 위하여 예의 연구 노력하였다. 그 결과, 피부 각질층의 장벽기능(barrier function) 저하를 야기하는 핵심 노화 인자인 자외선 및 염증 자극이 가해질 경우 특정 후각수용체(lfactory receptor) 유전자의 발현이 유의하게 변화되며, 이들의 발현 수준을 측정할 경우 현재의 피부 노화정도 뿐 아니라 향후 피부 장벽기능이 상실될 유전적 위험성을 높은 신뢰도로 예측할 수 있음을 발견함으로써, 본 발명을 완성하게 되었다.The present inventors made intensive research efforts to develop a molecular diagnostic method that accurately evaluates the progress of skin aging due to an increase in age or various biological and non-biological stress stimuli. As a result, when ultraviolet rays and inflammatory stimuli, which are key aging factors that cause a decrease in the barrier function of the stratum corneum of the skin, are applied, the expression of specific lfactory receptor genes is significantly changed, and their expression levels can be measured. In this case, the present invention was completed by discovering that not only the current degree of skin aging but also the genetic risk of loss of skin barrier function in the future can be predicted with high reliability.
따라서 본 발명의 목적은 피부 노화의 진단용 조성물 및 이를 이용한 피부 노화 진단 방법을 제공하는 데 있다.Accordingly, an object of the present invention is to provide a composition for diagnosing skin aging and a method for diagnosing skin aging using the same.
본 발명의 다른 목적은 피부 장벽기능 증진용 조성물의 스크리닝 방법을 제공하는 데 있다.Another object of the present invention is to provide a method for screening a composition for enhancing skin barrier function.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3, OR7E91P, OR2AE1, OR2W3, OR10A2 및 OR51B2로 구성된 군으로부터 선택되는 하나 이상의 유전자 또는 이들이 인코딩하는 단백질의 발현량을 측정하는 제제를 유효성분으로 포함하는 피부 노화의 진단용 조성물을 제공한다.According to one aspect of the present invention, one or more genes selected from the group consisting of OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3, OR7E91P, OR2AE1, OR2W3, OR10A2 and OR51B2; Provided is a composition for diagnosis of skin aging comprising, as an active ingredient, an agent for measuring the expression level of the protein they encode.
본 발명자들은 연령의 증가 또는 다양한 생물학적·비생물학적 스트레스 자극으로 인한 피부 노화의 진행 정도를 정확하게 평가하는 분자 진단 방법을 개발하기 위하여 예의 연구 노력하였다. 그 결과, 피부 각질층의 장벽기능(barrier function) 저하를 야기하는 핵심 노화 인자인 자외선 및 염증 자극이 가해질 경우 특정 후각수용체(lfactory receptor) 유전자의 발현이 유의하게 변화되며, 이들의 발현 수준을 측정할 경우 현재의 피부 노화정도 뿐 아니라 향후 피부 장벽기능이 상실될 유전적 위험성을 높은 신뢰도로 예측할 수 있음을 발견하였다. The present inventors made intensive research efforts to develop a molecular diagnostic method that accurately evaluates the progress of skin aging due to an increase in age or various biological and non-biological stress stimuli. As a result, when ultraviolet rays and inflammatory stimuli, which are key aging factors that cause a decrease in the barrier function of the stratum corneum of the skin, are applied, the expression of specific lfactory receptor genes is significantly changed, and their expression levels can be measured. In this case, it was found that not only the current degree of skin aging but also the genetic risk of loss of skin barrier function in the future can be predicted with high reliability.
본 명세서에서 용어“진단”은 피부 노화에 대한 개체의 감수성(susceptibility)의 판정, 현재 개체에서 진행된 피부 노화 정도의 판정 및 향후 피부 노화와 관련한 객체의 예후(prognosis)의 판정을 포함한다. 후술하는 실시예에서 보는 바와 같이, 본 발명에서 발굴된 후각수용체 유전자들의 발현은 피부 장벽기능의 표지자인 필라그린(filaggrin) 및 케라틴(keratin)의 발현 변화와 밀접하게 관련되어 있으므로, 용어“피부노화 진단”은“피부 장벽기능의 평가”또는“피부 장벽기능 장애 관련 질환의 진단”과 동일한 의미로 사용된다. As used herein, the term “diagnosis” includes determination of the subject's susceptibility to skin aging, determination of the degree of skin aging that has progressed in the current subject, and determination of the subject's prognosis in relation to skin aging in the future. As shown in the Examples to be described later, the expression of the olfactory receptor genes discovered in the present invention is closely related to changes in the expression of filaggrin and keratin, which are markers of the skin barrier function, so the term “skin aging” Diagnosis” is used in the same sense as “evaluation of skin barrier function” or “diagnosis of diseases related to skin barrier function disorder”.
본 명세서에서 용어“피부 장벽기능 장애(skin barrier dysfunction) 관련 질환”은 피부 표피 조직 또는 이를 구성하는 각질형성세포(keratinocyte)가 필라그린, 케라틴 등의 표피 단백질을 정상적으로 생성하지 못하여 외부의 유해분자 투과(permeation)를 차단하고 내부의 수분 유출을 억제하는 장벽기능을 상실함으로써 유발되는 일련의 질환을 포괄하는 의미이다. 장벽기능의 상실은 예를 들어 표피 세포간 접촉 저하 및 수분 상실로 인한 피부 노화, 병원균의 침투로 인한 다양한 감염성 질환, 아토피 피부염, 접촉성 피부염과 같은 염증성·자가면역 질환 등의 다양한 병적 상태의 원인이 된다. As used herein, the term “skin barrier dysfunction-related disease” means that the skin epidermal tissue or keratinocytes constituting it cannot normally produce epidermal proteins such as filaggrin and keratin, so that external harmful molecules penetrate It is meant to encompass a series of diseases caused by the loss of the barrier function that blocks the permeation and inhibits the outflow of internal water. Loss of barrier function is the cause of various pathological conditions, such as, for example, skin aging due to decreased contact between epidermal cells and loss of moisture, various infectious diseases due to infiltration of pathogens, and inflammatory and autoimmune diseases such as atopic dermatitis and contact dermatitis. becomes this
본 명세서에서 용어“진단용 조성물”은 대상체의 피부노화 정도를 판단하거나 향후 피부노화 진행 정도를 예측하기 위해 상기 나열된 후각수용체 유전자 또는 이의 단백질 발현량 측정수단을 포함하는 통합적인 혼합물(mixture) 또는 장비(device)를 의미하며, 이에“진단용 키트”로 표현될 수도 있다.As used herein, the term “diagnostic composition” refers to an integrated mixture or equipment (mixture) or equipment ( device), and may be expressed as a “diagnostic kit”.
본 발명의 구체적인 구현예에 따르면, 본 발명의 조성물은 OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3 및 OR7E91P로 구성된 군으로부터 선택되는 하나 이상의 유전자 또는 이들이 인코딩하는 단백질의 발현량을 측정하는 제제를 포함한다. 보다 구체적으로, 상기 유전자 또는 단백질의 발현량을 측정하는 제제를 포함할 경우 본 발명의 조성물은 자외선 노출에 의한 피부의 노화 정도를 예측한다. 보다 더 구체적으로, 대상체의 시료에서 상기 유전자 중 OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1 및 OR52W1로 구성된 군으로부터 선택되는 하나 이상의 유전자의 또는 이들이 인코딩하는 단백질이 정상 시료보다 고발현되거나, 또는 OR2D3 또는 OR7E91P 유전자 또는 이들이 인코딩하는 단백질이 정상 시료보다 저발현될 경우, 대상체의 피부가 자외선 자극에 의해 노화되거나 피부 각질층의 장벽기능이 저하된 것으로 판단한다. According to a specific embodiment of the present invention, the composition of the present invention comprises one or more genes selected from the group consisting of OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3 and OR7E91P or a protein encoding them. An agent for measuring the expression level is included. More specifically, when including an agent for measuring the expression level of the gene or protein, the composition of the present invention predicts the degree of skin aging due to UV exposure. More specifically, in the subject's sample, one or more genes selected from the group consisting of OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1 and OR52W1 among the genes, or the protein they encode, are more highly expressed than in the normal sample. Or, when the OR2D3 or OR7E91P gene or the protein they encode is less expressed than the normal sample, it is determined that the skin of the subject is aging by UV stimulation or the barrier function of the stratum corneum of the skin is reduced.
본 발명의 구체적인 구현예에 따르면, 상기 자외선 노출에 의한 피부의 노화는 미세주름, 과색소침착, 피부 탄력의 소실 및 수분 결핍으로 구성된 군으로부터 선택되는 하나 이상의 광노화(Photoaging) 현상을 포함하나, 이에 제한되지 않고 자외선 자극을 직접적 또는 간접적인 원인으로 하는 모든 피부 노화 현상을 포괄적으로 포함한다. According to a specific embodiment of the present invention, the aging of the skin by UV exposure includes one or more photoaging phenomena selected from the group consisting of fine wrinkles, hyperpigmentation, loss of skin elasticity, and lack of moisture. It is not limited and includes all skin aging phenomena that are directly or indirectly caused by UV stimulation.
본 발명의 구체적인 구현예에 따르면, 본 발명의 조성물은 OR1F1, OR2A4, OR2AE1, OR2W3, OR2H2, OR5C1, OR7D2, OR7E91P, OR10A2, OR10H1, OR13D1, OR51B2, OR52I1 및 OR52W1로 구성된 군으로부터 선택되는 하나 이상의 유전자 또는 이들이 인코딩하는 단백질의 발현량을 측정하는 제제를 포함한다. 보다 구체적으로, 상기 유전자 또는 단백질의 발현량을 측정하는 제제를 포함할 경우 본 발명의 조성물은 염증에 의한 피부의 노화 정도를 예측한다. 보다 더 구체적으로, 대상체의 시료에서 상기 유전자 중 하나 이상의 유전자의 또는 이들이 인코딩하는 단백질이 정상 시료보다 고발현될 경우, 대상체의 피부가 염증 자극에 의해 노화되거나 피부 각질층의 장벽기능이 저하된 것으로 판단한다. According to a specific embodiment of the present invention, the composition of the present invention comprises at least one gene selected from the group consisting of OR1F1, OR2A4, OR2AE1, OR2W3, OR2H2, OR5C1, OR7D2, OR7E91P, OR10A2, OR10H1, OR13D1, OR51B2, OR52I1 and OR52W1 or an agent for measuring the expression level of the protein they encode. More specifically, when including an agent for measuring the expression level of the gene or protein, the composition of the present invention predicts the degree of skin aging due to inflammation. More specifically, if one or more of the genes or the protein they encode in the subject's sample are expressed higher than in the normal sample, it is determined that the subject's skin is aged by inflammatory stimulation or the barrier function of the stratum corneum of the skin is lowered do.
본 발명의 구체적인 구현예에 따르면, 상기 염증에 의한 피부의 노화는 아토피 피부염, 피부근염, 피부경화증, 천포창, 환상홍반 및 홍반루푸스로 구성된 군으로부터 선택되는 염증성 또는 자가면역성 피부질환으로 인한 피부 노화를 포함하나, 이에 제한되지 않고 과도한 면역반응 또는 염증에 의한 피부 손상을 직접적 또는 간접적인 원인으로 하는 모든 피부 노화 현상을 포괄적으로 포함한다. According to a specific embodiment of the present invention, the aging of the skin due to inflammation is caused by inflammatory or autoimmune skin diseases selected from the group consisting of atopic dermatitis, dermatomyositis, scleroderma, pemphigus, erythema cyclic erythematosus and lupus erythematosus. Including, but not limited to, all skin aging phenomena that are directly or indirectly caused by skin damage caused by excessive immune response or inflammation are comprehensively included.
본 명세서에서 용어“고발현”은 피부 노화에 대한 양성마커(positive marker)임이 규명된 본 발명의 후각수용체 유전자 또는 이의 인코딩 단백질 발현량이 노화가 진행되지 않거나 정상적인 피부 장벽기능을 가지는 개체에 비하여 유의하게 높은 경우를 의미하며, 구체적으로는 그 발현량이 정상 개체의 130% 이상인 경우를, 보다 구체적으로는 150% 이상인 경우를, 가장 구체적으로는 170% 이상인 경우를 의미하나, 이를 벗어나는 범위를 제외하는 것은 아니다.As used herein, the term “high expression” refers to the olfactory receptor gene of the present invention, which has been found to be a positive marker for skin aging, or its encoding protein expression level is significantly higher than that of an individual with no aging or normal skin barrier function. It means a high case, specifically, a case where the expression level is 130% or more of a normal individual, more specifically a case of 150% or more, and most specifically a case of 170% or more, but excluding the range outside this no.
본 명세서에서 용어“저발현”은 피부 노화에 대한 음성마커(positive marker)임이 규명된 본 발명의 후각수용체 유전자 또는 이의 인코딩 단백질 발현량이 노화가 진행되지 않거나 정상적인 피부 장벽기능을 가지는 개체에 비하여 유의하게 낮은 경우를 의미하며, 구체적으로는 그 발현량이 정상 개체의 약 15% 이상 감소, 보다 구체적으로는 약 30% 이상 감소, 가장 구체적으로는 약 40% 이상 감소한 경우를 의미하나, 이를 벗어나는 범위를 제외하는 것은 아니다.As used herein, the term “low expression” refers to the olfactory receptor gene of the present invention, which has been identified as a positive marker for skin aging, or its encoding protein expression level is significantly higher than that of an individual with no aging or normal skin barrier function. It means a low case, specifically, the expression level is reduced by about 15% or more, more specifically, about 30% or more, and most specifically, about 40% or more of that of a normal individual. it is not doing
본 발명의 구체적인 구현예에 따르면, 본 발명의 유전자의 발현량을 측정하는 제제는 상기 유전자의 핵산 분자에 특이적으로 결합하는 프라이머 또는 프로브이다.According to a specific embodiment of the present invention, the agent for measuring the expression level of a gene of the present invention is a primer or probe that specifically binds to a nucleic acid molecule of the gene.
본 명세서에서, 용어“핵산 분자”는 DNA(gDNA 및 cDNA) 그리고 RNA 분자를 포괄적으로 포함하는 의미를 갖으며, 핵산 분자에서 기본 구성 단위인 뉴클레오타이드는 자연의 뉴클레오타이드뿐만 아니라, 당 또는 염기 부위가 변형된 유사체 (analogue)도 포함한다(Scheit, Nucleotide Analogs, John Wiley, New York(1980); Uhlman 및 Peyman, Chemical Reviews, 90:543-584(1990)).As used herein, the term “nucleic acid molecule” has a meaning comprehensively including DNA (gDNA and cDNA) and RNA molecules. analogues (Scheit, Nucleotide Analogs, John Wiley, New York (1980); Uhlman and Peyman, Chemical Reviews , 90:543-584 (1990)).
본 명세서에서 사용되는 용어“프라이머”는 핵산쇄(주형)에 상보적인 프라이머 연장 산물의 합성이 유도되는 조건, 즉, 뉴클레오타이드와 DNA 중합효소와 같은 중합제의 존재, 적합한 온도와 pH의 조건에서 합성의 개시점으로 작용하는 올리고뉴클레오타이드를 의미한다. 구체적으로는, 프라이머는 디옥시리보뉴클레오타이드 단일쇄이다. 본 발명에서 이용되는 프라이머는 자연(naturally occurring) dNMP(즉, dAMP, dGMP, dCMP 및 dTMP), 변형 뉴클레오타이드 또는 비-자연 뉴클레오타이드를 포함할 수 있으며, 리보뉴클레오타이드도 포함할 수 있다.As used herein, the term “primer” refers to a condition that induces the synthesis of a primer extension product complementary to a nucleic acid strand (template), that is, the presence of a polymerase such as nucleotide and DNA polymerase, and a suitable temperature and pH. It refers to an oligonucleotide that acts as a starting point of Specifically, the primer is a single-stranded deoxyribonucleotide. The primer used in the present invention may include naturally occurring dNMP (ie, dAMP, dGMP, dCMP, and dTMP), modified nucleotides or non-natural nucleotides, and may also include ribonucleotides.
본 발명의 프라이머는 타겟 핵산에 어닐링 되어 주형-의존성 핵산 중합효소에 의해 타겟 핵산에 상보적인 서열을 형성하는 연장 프라이머(extension primer)일 수 있으며, 이는 고정화 프로브가 어닐링 되어 있는 위치까지 연장되어 프로브가 어닐링 되어 있는 부위를 차지한다.The primer of the present invention may be an extension primer that is annealed to a target nucleic acid to form a sequence complementary to the target nucleic acid by a template-dependent nucleic acid polymerase, which is extended to the position where the immobilized probe is annealed so that the probe is It occupies the annealed area.
본 발명에서 이용되는 연장 프라이머는 타겟 핵산 예를 들어 상기 나열된 후각수용체 유전자의 특정 염기서열에 상보적인 혼성화 뉴클레오타이드 서열을 포함한다. 용어“상보적”은 소정의 어닐링 또는 혼성화 조건하에서 프라이머 또는 프로브가 타겟 핵산 서열에 선택적으로 혼성화할 정도로 충분히 상보적인 것을 의미하며, 실질적으로 상보적(substantially complementary)인 경우 및 완전히 상보적(perfectly complementary)인 경우를 모두 포괄하는 의미이며, 구체적으로는 완전히 상보적인 경우를 의미한다. 본 명세서에서 용어“실질적으로 상보적인 서열”은 완전히 일치되는 서열뿐만 아니라, 특정 서열에 어닐링하여 프라이머 역할을 할 수 있는 범위 내에서, 비교 대상의 서열과 부분적으로 불일치되는 서열도 포함되는 의미이다.The extension primer used in the present invention includes a target nucleic acid, for example, a hybridization nucleotide sequence complementary to a specific nucleotide sequence of the olfactory receptor gene listed above. The term “complementary” means that a primer or probe is sufficiently complementary to selectively hybridize to a target nucleic acid sequence under certain annealing or hybridization conditions, and when substantially complementary and perfectly complementary ), and specifically means a completely complementary case. As used herein, the term “substantially complementary sequence” includes not only a completely identical sequence, but also a sequence that is partially mismatched with a sequence to be compared within the range that can function as a primer by annealing to a specific sequence.
프라이머는, 중합제의 존재 하에서 연장 산물의 합성을 프라이밍시킬 수 있을 정도로 충분히 길어야 한다. 프라이머의 적합한 길이는 다수의 요소, 예컨대, 온도, pH 및 프라이머의 소스(source)에 따라 결정되지만 전형적으로 15-30 뉴클레오타이드이다. 짧은 프라이머 분자는 주형과 충분히 안정된 혼성 복합체를 형성하기 위하여 일반적으로 보다 낮은 온도를 요구한다. 이러한 프라이머의 설계는 타겟 뉴클레오티드 서열을 참조하여 당업자가 용이하게 실시할 수 있으며, 예컨대, 프라이머 디자인용 프로그램(예: PRIMER 3 프로그램)을 이용하여 할 수 있다.The primer should be long enough to prime the synthesis of extension products in the presence of a polymerizer. A suitable length of a primer depends on a number of factors, such as temperature, pH and source of the primer, but is typically 15-30 nucleotides. Short primer molecules generally require lower temperatures to form sufficiently stable hybrid complexes with the template. The design of such a primer can be easily performed by those skilled in the art by referring to the target nucleotide sequence, for example, using a primer design program (eg,
본 명세서에서 용어“프로브”는 특정 뉴클레오타이드 서열에 혼성화될 수 있는 디옥시리보뉴클레오타이드 및 리보뉴클레오타이드를 포함하는 자연 또는 변형되는 모노머 또는 결합을 갖는 선형의 올리고머를 의미한다. 구체적으로, 프로브는 혼성화에서의 최대 효율을 위하여 단일가닥이며, 더욱 구체적으로는 디옥시리보뉴클레오타이드이다. 본 발명에 이용되는 프로브로서, 상기 나열된 각 후각수용체 유전자의 특정 염기서열에 완전하게(perfectly) 상보적인 서열이 이용될 수 있으나, 특이적 혼성화를 방해하지 않는 범위 내에서 실질적으로(substantially) 상보적인 서열이 이용될 수도 있다. 일반적으로, 혼성화에 의해 형성되는 듀플렉스(duplex)의 안정성은 말단의 서열의 일치에 의해 결정되는 경향이 있기 때문에, 타겟 서열의 3’-말단 또는 5’-말단에 상보적인 프로브를 사용하는 것이 바람직하다. 혼성화에 적합한 조건은 Joseph Sambrook, et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y.(2001) 및 Haymes, B. D., et al., Nucleic Acid Hybridization, A Practical Approach, IRL Press, Washington, D.C.(1985)에 개시된 사항을 참조하여 결정할 수 있다. As used herein, the term “probe” refers to a natural or modified monomer or a linear oligomer including deoxyribonucleotides and ribonucleotides capable of hybridizing to a specific nucleotide sequence. Specifically, the probe is single-stranded for maximum efficiency in hybridization, more specifically deoxyribonucleotides. As the probe used in the present invention, a sequence that is perfectly complementary to the specific nucleotide sequence of each of the olfactory receptor genes listed above may be used, but is substantially complementary within a range that does not interfere with specific hybridization. Sequences may also be used. In general, since the stability of the duplex formed by hybridization tends to be determined by the match of the sequences at the ends, it is preferable to use a probe complementary to the 3'-end or 5'-end of the target sequence. do. Suitable conditions for hybridization are Joseph Sambrook, et al., Molecular Cloning, A Laboratory Manual , Cold Spring Harbor Laboratory Press, NY (2001) and Haymes, BD, et al., Nucleic Acid Hybridization, A Practical Approach , IRL Press, Washington , can be determined with reference to the details disclosed in DC (1985).
본 발명의 구체적인 구현예에 따르면, 본 발명의 단백질의 발현량을 측정하는 제제는 상기 단백질에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편; 또는 상기 단백질에 특이적으로 결합하는 앱타머일 수 있다.According to a specific embodiment of the present invention, the agent for measuring the expression level of the protein of the present invention may include an antibody or antigen-binding fragment thereof that specifically binds to the protein; Or it may be an aptamer that specifically binds to the protein.
본 발명에 따르면, 본 발명의 후각수용체 단백질을 항원-항체 반응을 이용한 면역분석(immunoassay) 방법에 따라 검출하여 개체의 상피장벽 기능 상실 여부를 분석하는 데 이용될 수 있다. 이러한 면역분석은 종래에 개발된 다양한 면역분석 또는 면역염색 프로토콜에 따라 실시될 수 있다. According to the present invention, the olfactory receptor protein of the present invention can be detected according to an immunoassay method using an antigen-antibody reaction and used to analyze whether an individual has lost the epithelial barrier function. Such an immunoassay may be performed according to various immunoassays or immunostaining protocols previously developed.
예를 들어, 본 발명의 방법이 방사능면역분석 방법에 따라 실시되는 경우, 방사능동위원소(예컨대, C14, I125, P32 및 S35)로 표지된 항체가 이용될 수 있다. For example, when the method of the present invention is performed according to a radioimmunoassay method, antibodies labeled with radioisotopes (eg, C 14 , I 125 , P 32 and S 35 ) may be used.
본 명세서에서 용어 "항체"는 포유류의 면역 체계에 의해 생성된, 항원의 에피토프에 결합하는 하나 이상의 가변 도메인을 포함하여 해당 항원을 특이적으로 인식하는 면역글로불린 단백질을 의미한다. 본 발명에서 각각의 후각수용체 단백질을 특이적으로 인식하는 항체는 폴리클로날 또는 모노클로날 항체이며, 바람직하게는 모노클로날 항체이다. As used herein, the term "antibody" refers to an immunoglobulin protein that specifically recognizes an antigen, including one or more variable domains that bind to an epitope of an antigen, produced by the immune system of a mammal. In the present invention, the antibody specifically recognizing each olfactory receptor protein is a polyclonal or monoclonal antibody, preferably a monoclonal antibody.
본 발명의 항체는 당업계에서 통상적으로 실시되는 방법들, 예를 들어, 융합 방법(Kohler and Milstein, European Journal of Immunology, 6:511-519 (1976)), 재조합 DNA 방법(미국 특허 제4,816,567호) 또는 파아지 항체 라이브러리 방법(Clackson et al, Nature, 352:624-628(1991) 및 Marks et al, J. Mol. Biol., 222:58, 1-597(1991))에 의해 제조될 수 있다. 항체 제조에 대한 일반적인 과정은 Harlow, E. and Lane, D., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Press, New York, 1999; 및 Zola, H., Monoclonal Antibodies: A Manual of Techniques, CRC Press, Inc., Boca Raton, Florida, 1984에 상세하게 기재되어 있다. Antibodies of the present invention can be prepared by methods routinely practiced in the art, for example, fusion methods (Kohler and Milstein, European Journal of Immunology , 6:511-519 (1976)), recombinant DNA methods (U.S. Patent No. 4,816,567). ) or phage antibody library methods (Clackson et al, Nature , 352:624-628 (1991) and Marks et al, J. Mol. Biol. , 222:58, 1-597 (1991)). . General procedures for antibody preparation are described in Harlow, E. and Lane, D., Using Antibodies: A Laboratory Manual , Cold Spring Harbor Press, New York, 1999; and Zola, H., Monoclonal Antibodies: A Manual of Techniques , CRC Press, Inc., Boca Raton, Florida, 1984.
상술한 면역분석 과정에 의한 최종적인 시그널의 강도를 분석함으로써, 상피장벽 기능을 예측할 수 있다. 즉, 개체의 시료에서 양성 마커인 각 후각수용체에 대한 시그널이 정상 시료 보다 강하게 검출되거나 음성 마커인 후각 수용체가 약하게 검출되는 경우, 개체의 피부 장벽기능이 상실되거나 저하되어 피부 노화가 진행된 것으로 판단된다.By analyzing the intensity of the final signal by the immunoassay process described above, the epithelial barrier function can be predicted. That is, when the signal for each olfactory receptor, which is a positive marker, is detected more strongly than in the normal sample, or the olfactory receptor, which is a negative marker, is weakly detected in the sample of the individual, it is determined that the skin barrier function of the individual is lost or deteriorated and skin aging has progressed. .
본 명세서에서 용어“항원 결합 단편(antigen binding fragment)”은 면역글로불린 전체 구조 중 항원이 결합할 수 있는 폴리펩티드의 일부를 의미하며, 예를 들어 F(ab')2, Fab', Fab, Fv 및 scFv를 포함하나, 이에 제한되는 것은 아니다. As used herein, the term “antigen binding fragment” refers to a portion of a polypeptide capable of binding an antigen in the entire structure of an immunoglobulin, for example, F(ab')2, Fab', Fab, Fv and scFvs, but are not limited thereto.
본 명세서에서 용어, "특이적으로 결합(specifically binding)" 은 "특이적으로 인식(specifically recognizing)"과 동일한 의미로서, 항원과 항체(또는 이의 단편)가 면역학적 반응을 통해 특이적으로 상호작용하는 것을 의미한다.As used herein, the term "specifically binding" has the same meaning as "specifically recognizing", and an antigen and an antibody (or a fragment thereof) interact specifically through an immunological reaction. means to do
본 발명은 항체 대신 각 후각수용체 단백질에 특이적으로 결합하는 앱타머를 이용할 수도 있다. 본 명세서에서 용어“앱타머”는 특정 표적물질에 높은 친화력과 특이성으로 결합하는 단일 줄기의(single-stranded) 핵산(RNA 또는 DNA) 분자 또는 펩타이드 분자를 의미한다. 앱타머의 일반적인 내용은 Hoppe-Seyler F, Butz K "Peptide aptamers: powerful new tools for molecular medicine". J Mol Med. 78(8):426-30(2000); Cohen BA, Colas P, Brent R . "An artificial cell-cycle inhibitor isolated from a combinatorial library". Proc Natl Acad Sci USA. 95(24):14272-7(1998)에 상세하게 개시되어 있다.The present invention may use an aptamer that specifically binds to each olfactory receptor protein instead of an antibody. As used herein, the term “aptamer” refers to a single-stranded nucleic acid (RNA or DNA) molecule or peptide molecule that binds to a specific target material with high affinity and specificity. For general information on aptamers, see Hoppe-Seyler F, Butz K "Peptide aptamers: powerful new tools for molecular medicine". J Mol Med. 78(8):426-30(2000); Cohen BA, Colas P, Brent R. "An artificial cell-cycle inhibitor isolated from a combinatorial library". Proc Natl Acad Sci USA. 95(24):14272-7 (1998).
본 발명의 다른 양태에 따르면, 본 발명은 개체로부터 분리된 생물학적 시료 내에서 OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3, OR7E91P, OR2AE1, OR2W3, OR10A2 및 OR51B2로 구성된 군으로부터 선택되는 하나 이상의 유전자 또는 이들이 인코딩하는 단백질의 발현량을 측정하는 단계를 포함하는 피부 노화의 진단에 필요한 정보를 제공하는 방법을 제공한다.According to another aspect of the present invention, the present invention provides a composition comprising OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3, OR7E91P, OR2AE1, OR2W3, OR10A2 and OR51B2 in a biological sample isolated from a subject. It provides a method for providing information necessary for diagnosing skin aging, comprising measuring the expression level of one or more genes selected from the group or a protein encoding them.
본 발명에서 발굴한 신규 바이오마커인 후각수용체 유전자 및 이를 이용하여 진단될 수 있는 피부 노화에 대해서는 이미 상술하였으므로, 과도한 중복을 피하기 위해 이를 생략한다. Since the olfactory receptor gene, a novel biomarker discovered in the present invention, and skin aging that can be diagnosed using the same have already been described above, they are omitted to avoid excessive duplication.
본 발명자들은 상기 나열된 후각수용체 유전자와 피부 노화 간의 상관 관계를 최초로 규명하였다. 이에, 개체 내 상기 후각수용체 유전자 또는 이의 단백질 발현량을 표지자로 하여 개체의 피부 노화 정도를 평가할 수 있다. The present inventors first identified the correlation between the olfactory receptor genes listed above and skin aging. Accordingly, the degree of skin aging of the individual can be evaluated using the olfactory receptor gene or protein expression level thereof in the individual as a marker.
본 명세서에서 용어“개체”는 각 후각수용체 유전자 또는 이의 단백질 발현량을 측정하기 위한 시료를 제공하고, 궁극적으로 피부 노화 및 피부 장벽기능의 분석 대상이 되는 개체를 의미한다. 개체는 제한없이 인간, 마우스, 래트, 기니아 피그, 개, 고양이, 말, 소, 돼지, 원숭이, 침팬지, 비비 또는 붉은털 원숭이를 포함하며, 구체적으로는 인간이다. 본 발명의 조성물은 현재의 피부노화 정도 뿐 아니라 향후 피부노화 과정이 촉진될 유전적 위험성을 예측하기 위한 정보도 제공하므로, 본 발명의“개체”는 피부 노화가 진행되거나 피부 장벽기능이 저하된 환자일 수도 있고 아직 피부 노화가 진행되지 않은 정상개체(healthy subject)일 수도 있다.As used herein, the term “individual” refers to an individual that provides a sample for measuring each olfactory receptor gene or protein expression level thereof, and is ultimately subjected to analysis of skin aging and skin barrier function. Subjects include, but are not limited to, humans, mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, monkeys, chimpanzees, baboons or rhesus monkeys, specifically humans. Since the composition of the present invention provides information for predicting the genetic risk that the skin aging process will be accelerated in the future as well as the current degree of skin aging, the "subject" of the present invention is a patient with advanced skin aging or reduced skin barrier function. It may also be a healthy subject that has not yet undergone skin aging.
본 명세서에서 용어“생물학적 시료”는 인간을 포함한 포유동물로부터 얻어지는, 상술한 후각수용체 유전자를 발현하는 세포를 포함하고 있는 모든 시료로서, 조직, 기관, 세포 또는 세포 배양액을 포함하나, 이에 제한되지 않는다. 구체적으로는, 상기 생물학적 시료는 피부조직 또는 피부조직 유래 세포를 포함하며, 보다 구체적으로는 피부 표피 조직 또는 피부 표피 조직 유래 세포를 포함하고, 가장 구체적으로는 각질형성세포(keratinocyte)를 포함한다.As used herein, the term “biological sample” refers to any sample obtained from a mammal, including a human, containing cells expressing the above-described olfactory receptor gene, and includes, but is not limited to, a tissue, organ, cell or cell culture medium. . Specifically, the biological sample includes skin tissue or skin tissue-derived cells, more specifically includes skin epidermal tissue or skin epidermal tissue-derived cells, and most specifically includes keratinocytes.
본 발명의 또 다른 양태에 따르면, 본 발명은 다음의 단계를 포함하는 피부 장벽기능 증진용 조성물의 스크리닝 방법을 제공한다:According to another aspect of the present invention, the present invention provides a method for screening a composition for enhancing skin barrier function, comprising the following steps:
(a) OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3, OR2AE1, OR2W3, OR10A2 및 OR51B2로 구성된 군으로부터 선택되는 하나 이상의 유전자를 발현하는 세포를 포함하는 생물학적 시료에 후보물질을 접촉시키는 단계; (a) a candidate in a biological sample comprising cells expressing one or more genes selected from the group consisting of OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3, OR2AE1, OR2W3, OR10A2 and OR51B2 contacting the material;
(b) 상기 시료 내 상기 유전자 또는 상기 유전자가 인코딩하는 단백질의 발현량 또는 활성을 측정하는 단계,(b) measuring the expression level or activity of the gene or the protein encoded by the gene in the sample,
상기 OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2AE1, OR2W3, OR10A2 및 OR51B2로 구성된 군으로부터 선택되는 하나 이상의 유전자 또는 이들이 인코딩하는 단백질의 발현량 또는 활성이 감소하거나, 상기 OR2D3 유전자 또는 이의 인코딩 단백질의 발현량 또는 활성이 증가한 경우, 상기 후보물질은 피부 장벽기능 증진용 조성물로 판정한다.The expression level or activity of one or more genes selected from the group consisting of OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1, OR52W1, OR2AE1, OR2W3, OR10A2 and OR51B2, or a protein encoding them is reduced, or the When the expression level or activity of the OR2D3 gene or its encoding protein is increased, the candidate material is determined as a composition for enhancing skin barrier function.
본 발명의 구체적인 구현예에 따르면, 본 발명의 스크리닝 방법에 이용되는 세포는 피부 조직 유래 세포이며, 보다 구체적으로는 피부 표피 조직 유래 세포이고, 가장 구체적으로는 각질형성세포(keratinocyte)이다.According to a specific embodiment of the present invention, the cells used in the screening method of the present invention are skin tissue-derived cells, more specifically skin epidermal tissue-derived cells, and most specifically keratinocytes.
본 발명의 스크리닝 방법을 언급하면서 사용되는 용어“후보물질”은 상기 나열된 후각수용체를 발현하는 세포를 포함하는 시료에 첨가되어 각 후각수용체 유전자 또는 단백질의 활성 또는 발현량에 영향을 미치는지 여부를 검사하기 위하여 스크리닝에서 이용되는 미지의 물질을 의미한다. 상기 후보물질은 화합물, 뉴클레오타이드, 펩타이드 및 천연 추출물을 포함하나, 이에 제한되는 것은 아니다. 시험물질을 처리한 생물학적 시료에서 각 후각수용체의 발현량 또는 활성을 측정하는 단계는 당업계에 공지된 다양한 발현량 및 활성 측정방법에 의해 수행될 수 있다. The term “candidate substance” used while referring to the screening method of the present invention is added to a sample containing the cells expressing the olfactory receptors listed above to test whether the activity or expression level of each olfactory receptor gene or protein is affected. It means an unknown substance used in screening for The candidate materials include, but are not limited to, compounds, nucleotides, peptides and natural extracts. The step of measuring the expression level or activity of each olfactory receptor in the biological sample treated with the test substance may be performed by various methods for measuring the expression level and activity known in the art.
본 명세서에서 용어“활성 또는 발현량의 감소”는 자외선 또는 염증 자극 등으로 인한 피부 장벽기능 손상이 측정 가능한 수준으로 개선될 정도로 피부 노화에 대한 양성마커(positive marker)인 각 후각수용체의 생체 내 고유한 기능 또는 발현량이 감소하는 것을 의미한다. 활성(activity)의 감소는 단순한 기능(function)의 감소 뿐 아니라 안정성(stability)의 감소로 기인한 궁극적인 활성 저해를 포함한다. 구체적으로는 후보물질을 처리하지 않은 대조군에 비하여 활성 또는 발현량이 15% 이상 감소한 상태, 보다 구체적으로는 30% 이상 감소한 상태, 가장 구체적으로는 40% 이상 감소한 상태를 의미할 수 있으나, 이를 벗어나는 범위를 제외하는 것은 아니다.As used herein, the term “reduction in activity or expression level” refers to the intrinsic in vivo characteristics of each olfactory receptor, which is a positive marker for skin aging, to the extent that damage to the skin barrier function due to UV rays or inflammatory stimulation is improved to a measurable level. It means a decrease in one function or expression level. A decrease in activity includes not only a simple decrease in function, but also an eventual inhibition of activity due to a decrease in stability. Specifically, it may mean a state in which the activity or expression level is reduced by 15% or more, more specifically by 30% or more, and most specifically by 40% or more, compared to the control group not treated with the candidate substance, but the range outside this does not exclude
본 명세서에서 용어“활성 또는 발현량의 증가”는 자외선 또는 염증 자극등으로 인한 피부 장벽기능 손상이 측정 가능한 수준으로 개선될 정도로 피부 노화에 대한 음성마커(positive marker)인 후각수용체의 생체 내 고유한 기능 또는 발현량이 증가하는 것을 의미하며, 구체적으로는 후보물질을 처리하지 않은 대조군에 비하여 활성 또는 발현량이 130%인 경우를, 보다 구체적으로는 150% 이상인 경우를, 가장 구체적으로는 170% 이상인 경우를 의미할 수 있으나, 이를 벗어나는 범위를 제외하는 것은 아니다.As used herein, the term “increase in activity or expression level” refers to an olfactory receptor, a negative marker for skin aging, that is unique in vivo to the extent that damage to the skin barrier function due to ultraviolet rays or inflammatory stimulation is improved to a measurable level. It means that the function or expression level is increased, specifically, when the activity or expression level is 130% compared to the control not treated with the candidate substance, more specifically 150% or more, and most specifically, 170% or more may mean, but does not exclude a range beyond this.
본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:
(a) 본 발명의 피부 노화의 진단용 조성물은 피부 각질층의 장벽기능 저하 및 이로 인한 피부 노화 정도를 평가할 뿐 아니라, 이러한 피부 노화의 유전적 위험성을 높은 신뢰도로 예측함으로써 피부 노화에 대한 개인별 맞춤 치료 전략을 조기에 수립하는 데에 유용하게 이용될 수 있다.(a) The composition for diagnosis of skin aging of the present invention not only evaluates the deterioration of the barrier function of the stratum corneum of the skin and the degree of skin aging resulting therefrom, but also predicts the genetic risk of skin aging with high reliability, thereby providing a personalized treatment strategy for skin aging It can be usefully used to establish early.
(c) 본 발명의 피부 장벽기능 증진용 조성물의 스크리닝 방법은 또한 피부 장벽기능이 저하된 개체에서 표피 단백질의 발현을 복원하고 각화세포피(cornified cell envelope, CE) 구조를 회복시킴으로써 수분 공급과 같은 대증적 요법을 넘어서는 근원적인 피부 노화 억제제를 정확하고 신속하게 탐색할 수 있다.(c) the screening method of the composition for enhancing the skin barrier function of the present invention also restores the expression of epidermal protein in an individual with a reduced skin barrier function and restores the cornified cell envelope (CE) structure, such as moisture supply It is possible to accurately and quickly search for a fundamental skin aging inhibitor that goes beyond symptomatic therapy.
도 1은 각질형성세포에서 자외선 처리에 따른 피부 장벽 유전자의 발현 변화를 나타낸 그래프이다. 각 값들은 평균 ± 표준오차(SEM)로 나타내었으며, 그룹 간 유의한 차이가 있는 경우 별표(*p < 0.05)로 표시하였다.
도 2는 각질형성세포에서 자외선 처리에 따른 후각수용체 유전자의 발현 변화를 나타낸 그래프이다. 각 값들은 평균 ± 표준오차(SEM)로 나타내었으며, 그룹 간 유의한 차이가 있는 경우 별표(*p < 0.05)로 표시하였다.
도 3은 각질형성세포에서 염증 물질 처리에 따른 피부 장벽 유전자 발현의 변화를 나타낸 그래프이다. 각 값들은 평균 ± 표준오차(SEM)로 나타내었으며, 그룹 간 유의한 차이가 있는 경우 별표(*p < 0.05)로 표시하였다.
도 4는 각질형성세포에서 염증 물질 처리에 따른 후각수용체 유전자의 발현 변화를 나타낸 그래프이다. 각 값들은 평균 ± 표준오차(SEM)로 나타내었으며, 그룹 간 유의한 차이가 있는 경우 별표(*p < 0.05)로 표시하였다.1 is a graph showing changes in the expression of skin barrier genes according to UV treatment in keratinocytes. Each value was expressed as mean ± standard error (SEM), and if there was a significant difference between groups, it was marked with an asterisk (* p < 0.05).
2 is a graph showing changes in the expression of olfactory receptor genes according to UV treatment in keratinocytes. Each value was expressed as mean ± standard error (SEM), and if there was a significant difference between groups, it was marked with an asterisk (* p < 0.05).
3 is a graph showing changes in skin barrier gene expression according to inflammatory material treatment in keratinocytes. Each value was expressed as mean ± standard error (SEM), and if there was a significant difference between groups, it was marked with an asterisk (* p < 0.05).
4 is a graph showing changes in the expression of olfactory receptor genes according to the treatment of inflammatory substances in keratinocytes. Each value was expressed as mean ± standard error (SEM), and if there was a significant difference between groups, it was marked with an asterisk (* p < 0.05).
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
실시예 1: 자외선 자극에 의한 피부장벽 유전자 및 후각수용체 유전자의 발현 변화Example 1: Changes in the expression of skin barrier genes and olfactory receptor genes by UV stimulation
실험방법 Experimental method
1) 각질형성세포 배양 1) Keratinocyte culture
실험에 사용한 각질형성세포(human keratinocyte cell line, HaCaT)는 ATCC사(Manassas, VA, USA)에서 구입하여 사용하였으며, 10% 우태혈청(fetal bovine serum; HyClone, Logan, UT, USA)과 1% 항생제(페니실린 및 스트렙토마이신; Gibco)를 첨가한 DMEM(Dulbecco’s modified eagle medium; Hyclone) 배지를 사용하여 37℃, 5% CO₂조건 하에서 배양하였다.The human keratinocyte cell line (HaCaT) used in the experiment was purchased from ATCC (Manassas, VA, USA) and used with 10% fetal bovine serum (HyClone, Logan, UT, USA) and 1% Using DMEM (Dulbecco's modified eagle medium; Hyclone) medium supplemented with antibiotics (penicillin and streptomycin; Gibco), it was cultured at 37° C. and 5% CO₂ conditions.
2) 자외선 조사 2) UV irradiation
각질형성세포에 자외선을 조사하기 위해 UV 조사기(Model CL-1000M; UVP, Upland, CA, USA)를 이용하였다. 세포의 배양액을 제거한 후 PBS(phosphate buffered saline; WelGENE, Daegu, Korea)로 세척하고 세포를 살짝 덮을 만큼의 PBS를 넣은 상태에서 자외선(10mJ/cm2)을 조사하였다.A UV irradiator (Model CL-1000M; UVP, Upland, CA, USA) was used to irradiate the keratinocytes with ultraviolet rays. After removing the cell culture medium, it was washed with PBS (phosphate buffered saline; WelGENE, Daegu, Korea), and UV light (10mJ/cm 2 ) was irradiated with enough PBS to lightly cover the cells.
3) RNA 추출 및 실시간 PCR 3) RNA extraction and real-time PCR
각질형성세포에서 자외선 조사에 의해 변화하는 피부 장벽 유전자와 후각수용체 유전자 발현 패턴을 정량적으로 분석하기 위해 실시간 PCR을 이용하였다. 세포에서 RNA를 추출하기 위해 배양액을 제거하고 차가운 PBS로 세척한 다음 TRIzol 시약(Invitrogen, Carlsbad, CA, USA)을 사용하여 총 RNA를 분리한 후 분광광도계(NanoQuant Infinite M200 Pro; Tecan, M
실시간 PCR은 사이버그린 믹스(SYBR green supermix; BioRad, Hercules, CA, USA)에 프라이머와 cDNA를 넣고 CFX Connect™ 실시간 PCR Detection System (BioRad)을 이용하여 95℃에서 10초, 58℃에서 15초, 60℃에서 15초의 과정을 36회 반복하여 수행하였으며 결과는 Bio-Rad CFX Manager 3.0으로 확인하였다. 각 유전자의 발현은 GAPDH의 발현에 대해 표준화하여 비교·분석하였다. 검출하고자 하는 유전자 특이적인 프라이머를 제작하여 사용하였으며, 사용된 프라이머의 염기서열은 표 1에 나타내었다.Real-time PCR was performed by putting primers and cDNA in a SYBR green supermix (BioRad, Hercules, CA, USA) and using CFX Connect™ real-time PCR Detection System (BioRad) for 10 seconds at 95°C, 15 seconds at 58°C, The process for 15 seconds at 60°C was repeated 36 times, and the results were confirmed with Bio-Rad CFX Manager 3.0. The expression of each gene was compared and analyzed by standardizing on the expression of GAPDH. A gene-specific primer to be detected was prepared and used, and the nucleotide sequences of the primers used are shown in Table 1.
4) 통계 분석 4) Statistical analysis
모든 실험결과는 평균 ± 표준오차로 표시하였고, SPSS Statistics (version 24.0, Chicago, IL, USA)를 사용하여 독립표본 t-검정(student's t-test)을 실시하여 p < 0.05 수준에서 유의성을 검증하였다All experimental results were expressed as mean ± standard error, and significance was verified at the level of p < 0.05 by performing an independent sample t - test using SPSS Statistics (version 24.0, Chicago, IL, USA).
실험결과Experiment result
1) 자외선 조사에 의한 피부 장벽 유전자의 발현 변화 1) Changes in the expression of skin barrier genes by UV irradiation
자외선을 조사한 각질형성세포에서 filaggrin과 keratin 10 유전자의 발현이 자외선을 조사하지 않은 각질형성세포에 비해 유의적으로 감소하였다(도 1).The expression of filaggrin and
2) 자외선 조사에 의한 후각수용체 유전자의 발현 변화 2) Changes in the expression of olfactory receptor genes by UV irradiation
자외선을 처리한 각질형성세포에서 후각수용체 유전자 OR1F1, OR2A4, OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1 및 OR52W1의 발현이 자외선을 처리하지 않은 각질형성세포에 비해 유의적으로 증가하였다(도 2a 및 2b). 한편, 후각수용체 유전자 OR2D3 및 OR7E91P의 발현은 유의적으로 감소하였다(도 2b).In keratinocytes treated with UV light, olfactory receptor genes OR1F1, OR2A4, Expression of OR2H2, OR5C1, OR7D2, OR10H1, OR13D1, OR52I1 and OR52W1 was significantly increased compared to that of keratinocytes not treated with UV ( FIGS. 2A and 2B ). On the other hand, the expression of the olfactory receptor genes OR2D3 and OR7E91P was significantly reduced (Fig. 2b).
실시예 2: 염증 자극에 의한 피부 장벽 유전자 및 후각수용체 유전자의 발현 변화Example 2: Changes in the expression of skin barrier genes and olfactory receptor genes by inflammatory stimulation
실험방법 Experimental method
1) 각질형성세포 배양 1) Keratinocyte culture
실험에 사용한 각질형성세포(human keratinocyte cell line, HaCaT)는 실시예 1에서와 동일한 방법으로 배양하였다.The keratinocytes (human keratinocyte cell line, HaCaT) used in the experiment were cultured in the same manner as in Example 1.
2) 염증물질 처리 2) Treatment of inflammatory substances
각질형성세포에서 염증상황을 유발하기 위해 TNF-α(tumor necrosis factor-α) 10 ng/ml와 IFN-γ(interferon-γ) 10 ng/ml를 처리하여 12시간 동안 배양하였다. 음성 대조군은 DMSO(dimethyl sulfoxide; Sigma-Aldrich, St. Louis, MO, USA)를 처리 후 12시간 동안 배양하였다.To induce an inflammatory situation in keratinocytes, TNF-α (tumor necrosis factor-α) 10 ng/ml and IFN-γ (interferon-γ) 10 ng/ml were treated and cultured for 12 hours. The negative control group was incubated for 12 hours after treatment with DMSO (dimethyl sulfoxide; Sigma-Aldrich, St. Louis, MO, USA).
3) RNA 추출 및 실시간 PCR 3) RNA extraction and real-time PCR
각질형성세포에서 염증물질 처리에 의해 변화하는 피부 장벽 유전자와 후각수용체 유전자 발현패턴을 정량적으로 분석하기 위해 실시간 PCR을 이용하였다. 세포에서 RNA를 추출하기 위해 배양액을 제거하고 차가운 PBS로 세척한 다음 TRIzol 시약(Invitrogen, Carlsbad, CA, USA)을 사용하여 총 RNA를 분리한 후 분광광도계(NanoQuant Infinite M200 Pro; Tecan, M
실시간 PCR은 사이버그린 믹스(SYBR green supermix; BioRad, Hercules, CA, USA)에 프라이머와 cDNA를 넣고 CFX Connect™ 실시간 PCR Detection System (BioRad)을 이용하여 95℃에서 10초, 58℃에서 15초, 60℃에서 15초의 과정을 36회 반복하여 수행하였으며 결과는 Bio-Rad CFX Manager 3.0으로 확인하였다. 각 유전자의 발현은 GAPDH의 발현에 대해 표준화하여 비교·분석하였다. 검출하고자 하는 유전자 특이적인 프라이머를 제작하여 사용하였으며, 실시예 2에서 사용된 프라이머의 염기서열은 표 2에 나타내었다.Real-time PCR was performed by putting primers and cDNA in a SYBR green supermix (BioRad, Hercules, CA, USA) and using CFX Connect™ real-time PCR Detection System (BioRad) for 10 seconds at 95°C, 15 seconds at 58°C, The process for 15 seconds at 60°C was repeated 36 times, and the results were confirmed with Bio-Rad CFX Manager 3.0. The expression of each gene was compared and analyzed by standardizing on the expression of GAPDH. A gene-specific primer to be detected was prepared and used, and the nucleotide sequences of the primers used in Example 2 are shown in Table 2.
4) 통계 분석4) Statistical analysis
모든 실험결과는 평균 ± 표준오차로 표시하였고, SPSS Statistics (version 24.0, Chicago, IL, USA)를 사용하여 독립표본 t 검정(student's t test)을 실시하여 p < 0.05 수준에서 유의성을 검증하였다.All experimental results were expressed as mean ± standard error, and significance was verified at the level of p < 0.05 by performing an independent sample t test using SPSS Statistics (version 24.0, Chicago, IL, USA).
실험결과 Experiment result
1) 염증 자극에 의한 피부 장벽 유전자의 발현 변화 1) Changes in the expression of skin barrier genes by inflammatory stimulation
염증물질(TNF-α, IFN-γ)을 처리한 각질형성세포에서 filaggrin과 keratin 10 유전자의 발현이 염증물질을 처리하지 않은 각질형성세포에 비해 유의적으로 감소하였다(도 3).In keratinocytes treated with inflammatory substances (TNF-α, IFN-γ), the expression of filaggrin and
2) 염증 자극에 의한 후각수용체 유전자의 발현 변화 2) Changes in the expression of olfactory receptor genes by inflammatory stimulation
염증물질(TNF-α, IFN-γ)을 처리한 각질형성세포에서 후각수용체 유전자 OR1F1, OR2A4, OR2AE1, OR2W3, OR2H2, OR5C1, OR7D2, OR7E91P, OR10A2, OR10H1, OR13D1, OR51B2, OR52I1 및 OR52W1의 발현이 염증물질을 처리하지 않은 각질형성세포에 비해 유의적으로 증가하였다(도 4).Expression of olfactory receptor genes OR1F1, OR2A4, OR2AE1, OR2W3, OR2H2, OR5C1, OR7D2, OR7E91P, OR10A2, OR10H1, OR13D1, OR51B2, OR52I1 and OR52W1 in inflammatory substances (TNF-α, IFN-γ)-treated keratinocytes Significantly increased compared to keratinocytes not treated with this inflammatory substance (FIG. 4).
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
<110> Industry-Academic cooperation foundation Yonsei University <120> Novel Biomarkers for Diagnosing Skin Aging <130> HPC-9617 <160> 65 <170> KoPatentIn 3.0 <210> 1 <211> 322 <212> PRT <213> Homo sapiens <400> 1 Met Gly Asp Arg Arg Ala Asp Pro Arg Pro Met Ser Gly Thr Asn Gln 1 5 10 15 Ser Ser Val Ser Glu Phe Leu Leu Leu Gly Leu Ser Arg Gln Pro Gln 20 25 30 Gln Gln His Leu Leu Phe Val Phe Phe Leu Ser Met Tyr Leu Ala Thr 35 40 45 Val Leu Gly Asn Leu Leu Ile Ile Leu Ser Val Ser Ile Asp Ser Cys 50 55 60 Leu His Thr Pro Met Tyr Phe Phe Leu Ser Asn Leu Ser Phe Val Asp 65 70 75 80 Ile Cys Phe Ser Phe Thr Thr Val Pro Lys Met Leu Ala Asn His Ile 85 90 95 Leu Glu Thr Gln Thr Ile Ser Phe Cys Gly Cys Leu Thr Gln Met Tyr 100 105 110 Phe Val Phe Met Phe Val Asp Met Asp Asn Phe Leu Leu Ala Val Met 115 120 125 Ala Tyr Asp His Phe Val Ala Val Cys His Pro Leu His Tyr Thr Ala 130 135 140 Lys Met Thr His Gln Leu Cys Ala Leu Leu Val Ala Gly Leu Trp Val 145 150 155 160 Val Ala Asn Leu Asn Val Leu Leu His Thr Leu Leu Met Ala Pro Leu 165 170 175 Ser Phe Cys Ala Asp Asn Ala Ile Thr His Phe Phe Cys Asp Val Thr 180 185 190 Pro Leu Leu Lys Leu Ser Cys Ser Asp Thr His Leu Asn Glu Val Ile 195 200 205 Ile Leu Ser Glu Gly Ala Leu Val Met Ile Thr Pro Phe Leu Cys Ile 210 215 220 Leu Ala Ser Tyr Met His Ile Thr Cys Thr Val Leu Lys Val Pro Ser 225 230 235 240 Thr Lys Gly Arg Trp Lys Ala Phe Ser Thr Cys Gly Ser His Leu Ala 245 250 255 Val Val Leu Leu Phe Tyr Ser Thr Ile Ile Ala Val Tyr Phe Asn Pro 260 265 270 Leu Ser Ser His Ser Ala Glu Lys Asp Thr Met Ala Thr Val Leu Tyr 275 280 285 Thr Val Val Thr Pro Met Leu Asn Pro Phe Ile Tyr Ser Leu Arg Asn 290 295 300 Arg Tyr Leu Lys Gly Ala Leu Lys Lys Val Val Gly Arg Val Val Phe 305 310 315 320 Ser Val <210> 2 <211> 2695 <212> DNA <213> Homo sapiens <400> 2 aaggacagga gactaggaag gcggagggag gctgctattg gcagggcctc agtggagacc 60 tcccggggtc ccgggacgca gacggacggg cctgaatcgc tcgccttggt gaaatgggat 120 ccagcgctgc caactgcggc aactgcggtt aaaggagacg accccgtgca gcaggaggag 180 gttatttaga ataaggaaga atgcgccggg ctcattggtc gctacagggg cataaatttt 240 ttctaggatt ccagagtatg gctgctccag tcccagattc ggctcgactt acagacctca 300 gcgcaggacg tggacgccct gcaaaggaca tttcagcgga cggcagagaa tacagattta 360 tgccagcgcc ctgcggaagg agcctctggc gggtcatctc catttatggg agatcgcaga 420 gcggatccca ggcccatgag cgggacaaac cagtcgagtg tctccgagtt cctcctcctg 480 ggactctcca ggcagcccca gcagcagcat ctcctctttg tgttcttcct cagcatgtac 540 ctggccactg tcctggggaa cctgctcatc atcctgtccg taagcataga ctcctgcctg 600 cacaccccca tgtacttctt cctcagcaac ctgtcttttg tggacatctg cttctccttc 660 accaccgtcc ccaagatgct ggccaatcac atactcgaga ctcagaccat ctccttctgt 720 ggctgtctca cacagatgta tttcgttttc atgttcgtgg acatggacaa tttcctccta 780 gctgtgatgg cctatgacca ctttgtcgcc gtgtgccacc ccttacatta cacagcaaag 840 atgacccatc agctctgtgc cctgctggtt gctggattat gggtggttgc caacctgaat 900 gtccttctgc acaccctgct gatggctcca ctctcattct gtgcagacaa tgccatcact 960 cacttcttct gcgatgtgac tcccctactg aaactctcct gctcagacac acacctcaat 1020 gaggtcataa tccttagtga gggtgccctg gtcatgatca ccccatttct ttgcatcctg 1080 gcttcttata tgcacatcac ctgcactgtc ctgaaggtcc catccacaaa gggaaggtgg 1140 aaagccttct ccacctgtgg ttctcacctg gctgtggttc tcctcttcta cagcaccatc 1200 attgctgtgt attttaaccc tctgtcctcc cactcagctg agaaagacac tatggctact 1260 gtgttgtata cagtagtgac tcccatgcta aaccctttca tctacagcct gaggaacagg 1320 tacttgaaag gggctctgaa aaaagtagtt ggcagggtgg tgttttctgt ctgatgaaat 1380 aatcaagact gaatctcatt cccaaggaaa tttatttttc accaattgag tttaatgcag 1440 tagttgtttc attaaatgat gttcttgcta gtgacacact tagtaattat actaagttaa 1500 actattaatt ataatttttt ttgagacagg gtcatgctct gtcacccagg ctggagtgca 1560 gtgccgtgat cttggctcac tgcaccctcc atctcccagg ctcaagtgat cctcctgcct 1620 cagcctcctg agtagctggg accacaggtg tgtgccacat gcctagctaa attttttttt 1680 ttttttttga gacggagtct ctctatgtcg ccaggctgga tgctgttgcg ggaagtcagg 1740 gaccctgaac agagggacca gctggagctg tgtcagagga acataaattg tgaagatttc 1800 attttaatat ggacatgtat cggttcccaa aattaatact tttataattt cttacgcctg 1860 tctttactgc aatctctgaa cataagctgt gaagatttca cggacattta tcagttcccg 1920 aaattaacac ttataatttc tcatgcctgt ctttacttta atctcttaat cctgttatct 1980 tcgtaagctg acgatgtacg tcacctcagg accactgtga taattctacc taactataca 2040 aattgattgt aaaacatgtg tatttgaaca atatgaaatc agtgcacctt gaaaaagaac 2100 agaataacag tgattttagg gaacaaggga agataatcat aaggtctgac tatctgtgga 2160 gttgggcaga atggagccat atttttcttc ttgcagagag cctataaatg gacgtgcaag 2220 tagggatatc actgaattct tttcctagca aggaatgtta ataattaaga ccttgggaga 2280 ggaatgcact cctcggggga ggtctataaa tggctgctct gggagagtct gtcttatgca 2340 gttgagataa ggactgaaat atgccctggt ctcctgcagt accctcaggc ttattagtgt 2400 ggggaaaaaa ccccaccctg gtgaatttaa ggtcagacag attctctgct cttgaaccct 2460 gttttctgtt gtttaagatg tttatcaaga caatacgtgc acagctgaac atagaccctt 2520 atctggaggt tttgattttg tcctttgcct tgtgatctct attggcttca gaggcatgtg 2580 atctttgttc tcctttttgc cctttgacac ctgtgatctc tgtgacctac tccctgttcg 2640 tacaccccca ccccttttaa agtccttaat aaaaacctcc tggttttgcg gctca 2695 <210> 3 <211> 310 <212> PRT <213> Homo sapiens <400> 3 Met Gly Asp Asn Ile Thr Ser Ile Arg Glu Phe Leu Leu Leu Gly Phe 1 5 10 15 Pro Val Gly Pro Arg Ile Gln Met Leu Leu Phe Gly Leu Phe Ser Leu 20 25 30 Phe Tyr Val Phe Thr Leu Leu Gly Asn Gly Thr Ile Leu Gly Leu Ile 35 40 45 Ser Leu Asp Ser Arg Leu His Ala Pro Met Tyr Phe Phe Leu Ser His 50 55 60 Leu Ala Val Val Asp Ile Ala Tyr Ala Cys Asn Thr Val Pro Arg Met 65 70 75 80 Leu Val Asn Leu Leu His Pro Ala Lys Pro Ile Ser Phe Ala Gly Arg 85 90 95 Met Met Gln Thr Phe Leu Phe Ser Thr Phe Ala Val Thr Glu Cys Leu 100 105 110 Leu Leu Val Val Met Ser Tyr Asp Leu Tyr Val Ala Ile Cys His Pro 115 120 125 Leu Arg Tyr Leu Ala Ile Met Thr Trp Arg Val Cys Ile Thr Leu Ala 130 135 140 Val Thr Ser Trp Thr Thr Gly Val Leu Leu Ser Leu Ile His Leu Val 145 150 155 160 Leu Leu Leu Pro Leu Pro Phe Cys Arg Pro Gln Lys Ile Tyr His Phe 165 170 175 Phe Cys Glu Ile Leu Ala Val Leu Lys Leu Ala Cys Ala Asp Thr His 180 185 190 Ile Asn Glu Asn Met Val Leu Ala Gly Ala Ile Ser Gly Leu Val Gly 195 200 205 Pro Leu Ser Thr Ile Val Val Ser Tyr Met Cys Ile Leu Cys Ala Ile 210 215 220 Leu Gln Ile Gln Ser Arg Glu Val Gln Arg Lys Ala Phe Arg Thr Cys 225 230 235 240 Phe Ser His Leu Cys Val Ile Gly Leu Val Tyr Gly Thr Ala Ile Ile 245 250 255 Met Tyr Val Gly Pro Arg Tyr Gly Asn Pro Lys Glu Gln Lys Lys Tyr 260 265 270 Leu Leu Leu Phe His Ser Leu Phe Asn Pro Met Leu Asn Pro Leu Ile 275 280 285 Cys Ser Leu Arg Asn Ser Glu Val Lys Asn Thr Leu Lys Arg Val Leu 290 295 300 Gly Val Glu Arg Ala Leu 305 310 <210> 4 <211> 1758 <212> DNA <213> Homo sapiens <400> 4 atgggagaca atataacatc catcagagag ttcctcctac tgggatttcc cgttggccca 60 aggattcaga tgctcctctt tgggctcttc tccctgttct acgtcttcac cctgctgggg 120 aacgggacca tactggggct catctcactg gactccagac tgcacgcccc catgtacttc 180 ttcctctcac acctggcggt cgtcgacatc gcctacgcct gcaacacggt gccccggatg 240 ctggtgaacc tcctgcatcc agccaagccc atctcctttg cgggccgcat gatgcagacc 300 tttctgtttt ccacttttgc tgtcacagaa tgtctcctcc tggtggtgat gtcctatgat 360 ctgtacgtgg ccatctgcca ccccctccga tatttggcca tcatgacctg gagagtctgc 420 atcaccctcg cggtgacttc ctggaccact ggagtccttt tatccttgat tcatcttgtg 480 ttacttctac ctttaccctt ctgtaggccc cagaaaattt atcacttttt ttgtgaaatc 540 ttggctgttc tcaaacttgc ctgtgcagat acccacatca atgagaacat ggtcttggcc 600 ggagcaattt ctgggctggt gggacccttg tccacaattg tagtttcata tatgtgcatc 660 ctctgtgcta tccttcagat ccaatcaagg gaagttcaga ggaaagcctt ccgcacctgc 720 ttctcccacc tctgtgtgat tggactcgtt tatggcacag ccattatcat gtatgttgga 780 cccagatatg ggaaccccaa ggagcagaag aaatatctcc tgctgtttca cagcctcttt 840 aatcccatgc tcaatcccct tatctgtagt cttaggaact cagaagtgaa gaatactttg 900 aagagagtgc tgggagtaga aagggcttta tgaaaaggat tatggcattg tgactgacag 960 tgacctagga agttacatca ttgagcggtt cttaacccat ctctgcactg gtgggacctc 1020 tgccctcaat ggacatgaga attatctgag acatttattt aaaatggagc tatctcctgc 1080 cctaccttta aatgactgat ttcagcagat gtgggatgaa attctagaaa ttgatctctt 1140 caagttgtgc tgcagccact ccacaccagg acaatacccc ttacaatatc ctcattagct 1200 tttgatccag tcccatacct cccataatgt tttcctcaaa acactggtcc cttcagagga 1260 ctttaaaaat aagttctata gtcaaataag tttgagactt acttcacatc agatgcctct 1320 gtctagggat cacaattcat attagcatag tgaatgctgt aaatatttct ctaggaaaga 1380 ataattctat accagcttta agccagtgtt ttctaaactt atgtgagcac ataaaatttc 1440 ctttgtaata cttagtaaca gtttcctgga acaggagatc ttgatattaa ttgactcatt 1500 gtgaatactt cctacagccc ccttctaggg cagaatgatt tcttttttcc ttgcaaagtg 1560 agcctctaaa gagatgtagt tctgagcatt atgcctcgat cagtctgtaa aaatccgggt 1620 tctgtttgga tacagaccgt gagggaccct gtctctactg ttcaatggta gatcatctaa 1680 agaaaataaa tgcaatcctg tccttcatca tggatcggca ttcctgctat agaagcttca 1740 ggagatgacc tcattcaa 1758 <210> 5 <211> 323 <212> PRT <213> Homo sapiens <400> 5 Met Trp Gln Lys Asn Gln Thr Ser Leu Ala Asp Phe Ile Leu Glu Gly 1 5 10 15 Leu Phe Asp Asp Ser Leu Thr His Leu Phe Leu Phe Ser Leu Thr Met 20 25 30 Val Val Phe Leu Ile Ala Val Ser Gly Asn Thr Leu Thr Ile Leu Leu 35 40 45 Ile Cys Ile Asp Pro Gln Leu His Thr Pro Met Tyr Phe Leu Leu Ser 50 55 60 Gln Leu Ser Leu Met Asp Leu Met His Val Ser Thr Ile Ile Leu Lys 65 70 75 80 Met Ala Thr Asn Tyr Leu Ser Gly Lys Lys Ser Ile Ser Phe Val Gly 85 90 95 Cys Ala Thr Gln His Phe Leu Tyr Leu Cys Leu Gly Gly Ala Glu Cys 100 105 110 Phe Leu Leu Ala Val Met Ser Tyr Asp Arg Tyr Val Ala Ile Cys His 115 120 125 Pro Leu Arg Tyr Ala Val Leu Met Asn Lys Lys Val Gly Leu Met Met 130 135 140 Ala Val Met Ser Trp Leu Gly Ala Ser Val Asn Ser Leu Ile His Met 145 150 155 160 Ala Ile Leu Met His Phe Pro Phe Cys Gly Pro Arg Lys Val Tyr His 165 170 175 Phe Tyr Cys Glu Phe Pro Ala Val Val Lys Leu Val Cys Gly Asp Ile 180 185 190 Thr Val Tyr Glu Thr Thr Val Tyr Ile Ser Ser Ile Leu Leu Leu Leu 195 200 205 Pro Ile Phe Leu Ile Ser Thr Ser Tyr Val Phe Ile Leu Gln Ser Val 210 215 220 Ile Gln Met Arg Ser Ser Gly Ser Lys Arg Asn Ala Phe Ala Thr Cys 225 230 235 240 Gly Ser His Leu Thr Val Val Ser Leu Trp Phe Gly Ala Cys Ile Phe 245 250 255 Ser Tyr Met Arg Pro Arg Ser Gln Cys Thr Leu Leu Gln Asn Lys Val 260 265 270 Gly Ser Val Phe Tyr Ser Ile Ile Thr Pro Thr Leu Asn Ser Leu Ile 275 280 285 Tyr Thr Leu Arg Asn Lys Asp Val Ala Lys Ala Leu Arg Arg Val Leu 290 295 300 Arg Arg Asp Val Ile Thr Gln Cys Ile Gln Arg Leu Gln Leu Trp Leu 305 310 315 320 Pro Arg Val <210> 6 <211> 972 <212> DNA <213> Homo sapiens <400> 6 atgtggcaga agaatcagac ctctctggca gacttcatcc ttgaggggct cttcgatgac 60 tcccttaccc accttttcct tttctccttg accatggtgg tcttccttat tgcggtgagt 120 ggcaacaccc tcaccattct cctcatctgc attgatcccc agcttcatac accaatgtat 180 ttcctgctca gccagctctc cctcatggat ctgatgcatg tctccacaat catcctgaag 240 atggctacca actacctatc tggcaagaaa tctatctcct ttgtgggctg tgcaacccag 300 cacttcctct atttgtgtct aggtggtgct gaatgttttc tcttagctgt catgtcctat 360 gaccgctatg ttgccatctg tcatccactg cgctatgctg tgctcatgaa caagaaggtg 420 ggactgatga tggctgtcat gtcatggttg ggggcatccg tgaactccct aattcacatg 480 gcgatcttga tgcacttccc tttctgtggg cctcggaaag tctaccactt ctactgtgag 540 ttcccagctg ttgtgaagtt ggtatgtggc gacatcactg tgtatgagac cacagtgtac 600 atcagcagca ttctcctcct cctccccatc ttcctgattt ctacatccta tgtcttcatc 660 cttcaaagtg tcattcagat gcgctcatct gggagcaaga gaaatgcctt tgccacttgt 720 ggctcccacc tcacggtggt ttctctttgg tttggtgcct gcatcttctc ctacatgaga 780 cccaggtccc agtgcactct attgcagaac aaagttggtt ctgtgttcta cagcatcatt 840 acgcccacat tgaattctct gatttatact ctccggaata aagatgtagc taaggctctg 900 agaagagtgc tgaggagaga tgttatcacc cagtgcattc aacgactgca attgtggttg 960 ccccgagtgt ag 972 <210> 7 <211> 330 <212> PRT <213> Homo sapiens <400> 7 Met Cys Ser Phe Phe Leu Cys Gln Thr Gly Lys Gln Ala Lys Ile Ser 1 5 10 15 Met Gly Glu Glu Asn Gln Thr Phe Val Ser Lys Phe Ile Phe Leu Gly 20 25 30 Leu Ser Gln Asp Leu Gln Thr Gln Ile Leu Leu Phe Ile Leu Phe Leu 35 40 45 Ile Ile Tyr Leu Leu Thr Val Leu Gly Asn Gln Leu Ile Ile Ile Leu 50 55 60 Ile Phe Leu Asp Ser Arg Leu His Thr Pro Met Tyr Phe Phe Leu Arg 65 70 75 80 Asn Leu Ser Phe Ala Asp Leu Cys Phe Ser Thr Ser Ile Val Pro Gln 85 90 95 Val Leu Val His Phe Leu Val Lys Arg Lys Thr Ile Ser Phe Tyr Gly 100 105 110 Cys Met Thr Gln Ile Ile Val Phe Leu Leu Val Gly Cys Thr Glu Cys 115 120 125 Ala Leu Leu Ala Val Met Ser Tyr Asp Arg Tyr Val Ala Val Cys Lys 130 135 140 Pro Leu Tyr Tyr Ser Thr Ile Met Thr Gln Arg Val Cys Leu Trp Leu 145 150 155 160 Ser Phe Arg Ser Trp Ala Ser Gly Ala Leu Val Ser Leu Val Asp Thr 165 170 175 Ser Phe Thr Phe His Leu Pro Tyr Trp Gly Gln Asn Ile Ile Asn His 180 185 190 Tyr Phe Cys Glu Pro Pro Ala Leu Leu Lys Leu Ala Ser Ile Asp Thr 195 200 205 Tyr Ser Thr Glu Met Ala Ile Phe Ser Met Gly Val Val Ile Leu Leu 210 215 220 Ala Pro Val Ser Leu Ile Leu Gly Ser Tyr Trp Asn Ile Ile Ser Thr 225 230 235 240 Val Ile Gln Met Gln Ser Gly Glu Gly Arg Leu Lys Ala Phe Ser Thr 245 250 255 Cys Gly Ser His Leu Ile Val Val Val Leu Phe Tyr Gly Ser Gly Ile 260 265 270 Phe Thr Tyr Met Arg Pro Asn Ser Lys Thr Thr Lys Glu Leu Asp Lys 275 280 285 Met Ile Ser Val Phe Tyr Thr Ala Val Thr Pro Met Leu Asn Pro Ile 290 295 300 Ile Tyr Ser Leu Arg Asn Lys Asp Val Lys Gly Ala Leu Arg Lys Leu 305 310 315 320 Val Gly Arg Lys Cys Phe Ser His Arg Gln 325 330 <210> 8 <211> 518 <212> DNA <213> Homo sapiens <400> 8 atgtgttctt ttttcttgtg ccaaacaggt aaacaggcaa aaatatcaat gggagaagaa 60 aaccaaacct ttgtgtccaa gtttatcttc ctgggtcttt cacaggactt gcagacccag 120 atcctgctat ttatcctttt cctcatcatt tatctgctga ccgtgcttgg aaaccagctc 180 atcatcattc tcatcttcct ggattctcgc cttcacactc ccatgtattt ttttcttaga 240 aatctctcct ttgcagatct ctgtttctct actagcattg tccctcaagt gttggttcac 300 ttcttggtaa agaggaaaac catttctttt tatgggtgta tgacacagat aattgtcttt 360 cttctggttg ggtgtacaga gtgtgcgctg ctggcagtga tgtcctatga ccggtatgtg 420 gctgtctgca agcccctgta ctactctacc atcatgacac aacgggtgtg tctctggctg 480 tccttcaggt cctgggccag tggggcacta gtgtcttt 518 <210> 9 <211> 314 <212> PRT <213> Homo sapiens <400> 9 Met Asp Gly Thr Asn Gly Ser Thr Gln Thr His Phe Ile Leu Leu Gly 1 5 10 15 Phe Ser Asp Arg Pro His Leu Glu Arg Ile Leu Phe Val Val Ile Leu 20 25 30 Ile Ala Tyr Leu Leu Thr Leu Val Gly Asn Thr Thr Ile Ile Leu Val 35 40 45 Ser Arg Leu Asp Pro His Leu His Thr Pro Met Tyr Phe Phe Leu Ala 50 55 60 His Leu Ser Phe Leu Asp Leu Ser Phe Thr Thr Ser Ser Ile Pro Gln 65 70 75 80 Leu Leu Tyr Asn Leu Asn Gly Cys Asp Lys Thr Ile Ser Tyr Met Gly 85 90 95 Cys Ala Ile Gln Leu Phe Leu Phe Leu Gly Leu Gly Gly Val Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Ala Tyr Asp Arg Cys Val Ala Ile Cys Lys 115 120 125 Pro Leu His Tyr Met Val Ile Met Asn Pro Arg Leu Cys Arg Gly Leu 130 135 140 Val Ser Val Thr Trp Gly Cys Gly Val Ala Asn Ser Leu Ala Met Ser 145 150 155 160 Pro Val Thr Leu Arg Leu Pro Arg Cys Gly His His Glu Val Asp His 165 170 175 Phe Leu Arg Glu Met Pro Ala Leu Ile Arg Met Ala Cys Val Ser Thr 180 185 190 Val Ala Ile Glu Gly Thr Val Phe Val Leu Ala Val Gly Val Val Leu 195 200 205 Ser Pro Leu Val Phe Ile Leu Leu Ser Tyr Ser Tyr Ile Val Arg Ala 210 215 220 Val Leu Gln Ile Arg Ser Ala Ser Gly Arg Gln Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Thr Val Val Ser Leu Phe Tyr Gly Asn Ile Ile 245 250 255 Tyr Met Tyr Met Gln Pro Gly Ala Ser Ser Ser Gln Asp Gln Gly Met 260 265 270 Phe Leu Met Leu Phe Tyr Asn Ile Val Thr Pro Leu Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Arg Glu Val Lys Gly Ala Leu Gly Arg Leu 290 295 300 Leu Leu Gly Lys Arg Glu Leu Gly Lys Glu 305 310 <210> 10 <211> 945 <212> DNA <213> Homo sapiens <400> 10 atggatggaa ccaatggcag cacccaaacc catttcatcc tactgggatt ctctgaccga 60 ccccatctgg agaggatcct ctttgtggtc atcctgatcg cgtacctcct gaccctcgta 120 ggcaacacca ccatcatcct ggtgtcccgg ctggaccccc acctccacac ccccatgtac 180 ttcttcctcg cccacctttc cttcctggac ctcagtttca ccaccagctc catcccccag 240 ctgctctaca accttaatgg atgtgacaag accatcagct acatgggctg tgccatccag 300 ctcttcctgt tcctgggtct gggtggtgtg gagtgcctgc ttctggctgt catggcctat 360 gaccggtgtg tggctatctg caagcccctg cactacatgg tgatcatgaa ccccaggctc 420 tgccggggct tggtgtcagt gacctggggc tgtggggtgg ccaactcctt ggccatgtct 480 cctgtgaccc tgcgcttacc ccgctgtggg caccacgagg tggaccactt cctgcgtgag 540 atgcccgccc tgatccggat ggcctgcgtc agcactgtgg ccatcgaagg caccgtcttt 600 gtcctggcgg tgggtgttgt gctgtccccc ttggtgttta tcctgctctc ttacagctac 660 attgtgaggg ctgtgttaca aattcggtca gcatcaggaa ggcagaaggc cttcggcacc 720 tgcggctccc atctcactgt ggtctccctt ttctatggaa acatcatcta catgtacatg 780 cagccaggag ccagttcttc ccaggaccag ggcatgttcc tcatgctctt ctacaacatt 840 gtcacccccc tcctcaatcc tctcatctac accctcagaa acagagaggt gaagggggca 900 ctgggaaggt tgcttctggg gaagagagag ctaggaaagg agtaa 945 <210> 11 <211> 312 <212> PRT <213> Homo sapiens <400> 11 Met Val Asn Gln Ser Ser Thr Pro Gly Phe Leu Leu Leu Gly Phe Ser 1 5 10 15 Glu His Pro Gly Leu Glu Arg Thr Leu Phe Val Val Val Leu Thr Ser 20 25 30 Tyr Leu Leu Thr Leu Val Gly Asn Thr Leu Ile Ile Leu Leu Ser Ala 35 40 45 Leu Asp Pro Lys Leu His Ser Pro Met Tyr Phe Phe Leu Ser Asn Leu 50 55 60 Ser Phe Leu Asp Leu Cys Phe Thr Thr Ser Cys Val Pro Gln Met Leu 65 70 75 80 Val Asn Leu Trp Gly Pro Lys Lys Thr Ile Ser Phe Leu Asp Cys Ser 85 90 95 Val Gln Ile Phe Ile Phe Leu Ser Leu Gly Thr Thr Glu Cys Ile Leu 100 105 110 Leu Thr Val Met Ala Phe Asp Arg Tyr Val Ala Val Cys Gln Pro Leu 115 120 125 His Tyr Ala Thr Ile Ile His Pro Arg Leu Cys Trp Gln Leu Ala Ser 130 135 140 Val Ala Trp Val Ile Gly Leu Val Glu Ser Val Val Gln Thr Pro Ser 145 150 155 160 Thr Leu His Leu Pro Phe Cys Pro Asp Arg Gln Val Asp Asp Phe Val 165 170 175 Cys Glu Val Pro Ala Leu Ile Arg Leu Ser Cys Glu Asp Thr Ser Tyr 180 185 190 Asn Glu Ile Gln Val Ala Val Ala Ser Val Phe Ile Leu Val Val Pro 195 200 205 Leu Ser Leu Ile Leu Val Ser Tyr Gly Ala Ile Thr Trp Ala Val Leu 210 215 220 Arg Ile Asn Ser Ala Lys Gly Arg Arg Lys Ala Phe Gly Thr Cys Ser 225 230 235 240 Ser His Leu Thr Val Val Thr Leu Phe Tyr Ser Ser Val Ile Ala Val 245 250 255 Tyr Leu Gln Pro Lys Asn Pro Tyr Ala Gln Glu Arg Gly Lys Phe Phe 260 265 270 Gly Leu Phe Tyr Ala Val Gly Thr Pro Ser Leu Asn Pro Leu Ile Tyr 275 280 285 Thr Leu Arg Asn Lys Glu Val Thr Arg Ala Phe Arg Arg Leu Leu Gly 290 295 300 Lys Glu Met Gly Leu Thr Gln Ser 305 310 <210> 12 <211> 3061 <212> DNA <213> Homo sapiens <400> 12 gataatctga gccagctcca gctcatcaca cacatgtgtg cttagaaaag tgccagatgg 60 tcagcattag caatccctat tgtgaccaga gatgcagttg cccattcaag gatgcccatt 120 cctttttatt tttttgtttc ttcctgatgt acaagtggag gctgggcacc agttaagagc 180 tctgtcatgg ggaattgctg gtaccagaag agatttttat ttgattgaag gaagtcagag 240 gcaccagtgt gagtatccat ctgctgtcca gtacattcat ggattcctca ctctcactag 300 acaatgtttg accaggaaga acagggaatg agaaggagct gctggatggt gatgagcctt 360 ggaaagggag gctgggcgag cagagacaga agagaaacac ctacctgctg tgacctcaca 420 aacacccagg ctgagttttg ataagacagg ttgaatcaca ctggagtgac agcctcatcc 480 ctccaggtac aaacaagaac aggccatggt taaccaaagc tccacaccgg gcttcctcct 540 tctgggcttc tctgaacacc cagggctgga aaggactctc ttcgtggttg tcctcacttc 600 ctacctccta accctagtgg gcaacacact catcatcctg ctgtctgcgc tggaccccaa 660 gctccactct ccaatgtact ttttcctctc caacctctcc ttcttggacc tctgtttcac 720 cacgagttgt gttccccaaa tgctggtcaa cctctggggc ccaaagaaga ccatcagctt 780 cctggactgc tctgtccaga tcttcatctt cctgtccctg gggacaactg agtgcatcct 840 cttgacagtg atggcttttg atcgctacgt ggctgtctgc cagcccctcc actatgccac 900 catcatccac ccccgcctgt gctggcagct ggcatctgtg gcctgggtca ttgggctagt 960 ggagtcagtg gtccagacac catccaccct gcacctgccc ttctgccccg atcggcaggt 1020 ggatgatttt gtctgtgagg tcccagctct aattcgactc tcctgtgaag acacctccta 1080 caatgagatc caggtggctg ttgccagtgt cttcatcttg gttgtgcctc tcagcctcat 1140 ccttgtctct tacggagcca ttacctgggc agtgctgagg attaactctg caaaagggcg 1200 gaggaaagct tttgggacct gctcctccca tctcactgtg gtcaccctct tctacagctc 1260 agtcattgct gtctacctcc agcccaaaaa tccctatgcc caagagaggg gcaagttctt 1320 tggtctcttc tatgcagtgg gcactccttc acttaaccct ctcatataca ccctgaggaa 1380 caaggaggta accagggcat tcaggagatt gctggggaag gaaatggggc tcacacaaag 1440 ctgagggaga gctgcttaat gtgctttaaa agagaggaga ttctatgtgc ttttatcaga 1500 aagtttgagt tccctgcccc tctgccttct tcacacccat tacattgtgg gaatggatga 1560 aagccacatg tctgtgtgtg tgcatgtatg tgtgcaagag acagcgactg aaatgtagta 1620 aagggaggta tctttatgcg aaaaattata ggcatcaagt atattttata tttttttcta 1680 ctttaagtct tcgcctccat agtcatgttc ctacctttat cacttccatt tttaattccc 1740 ctcccttgcc atatccccac tattccttca cctccaattc taattcctac catatcttct 1800 ttgcttctcc ctcatgtttt tcccacttca ctatatgtct gttttgtatt ctcattctat 1860 tttattcctc aaataacagc aaaagagaag gggaagctga agcccagcta agttcggaaa 1920 ctcacccaag aacacacagt gtccacagca tcagaactaa aatccaggcc ccataatttt 1980 cagtcaggca actctcaaat acacactgtt gctttcacac cataatcaaa tatcccagta 2040 tttcaggctt gagccttaca aaggaaactt agcttcttca gtcctatttc ttctcttaca 2100 atgcccacaa atcgcaggta aaggagcagc caaaaagaca caaaaatatc ttcatgttta 2160 ggctggcaca ttgtggacct tggtgtcatc taccggccaa atatggtatt gcatgtgaca 2220 tcccagactt ctgctccagg gtcatccgaa ctgtactttg ctcaaagaca tagatatggt 2280 tatgatacta taagcattta tgtaattgtt atgttaaccc aagtaacact taaagtacag 2340 atgctccttg acttataatg atgttacctc ccaaaaaacc tatcatatac tgaaaatatt 2400 gtaagttgaa tatgcatttc atacacctaa cctaccaaac atcatagctt agcctagcct 2460 accttaaaca tactcagaac acttacatta gcctacagtt cagcaaaatc ctcaatacaa 2520 agtctatttt ataataaagt tttgaatatc tcatgtaatt tactgaatac tgtactaaaa 2580 gtgaaaaaac agaatggtta tattggtact caaagtacgg tttctactga atgtatctct 2640 tttgcattat tataaagtca aaaaatggtc aaagtcagga accccctgca atttacacat 2700 attgacttat ttaaccctta taacaacact atgaagcaga taatattatt atcctttttc 2760 agaggtaaaa actaaaacac agaatttatg ttaccacttg caaatgtgca agacaggatt 2820 tgaacccagg aaaactggct ccagactcct tgctcttaac cttgcctttt ggtaaaaata 2880 atgcctccca ggcccaggtg aaaagcttca acttctcaac aagctttgag gaaatcattt 2940 caatctaaaa ctatatctaa atgatccccc agccgaaggg gtttcacttc cttaaaataa 3000 gagtttttca aatacttcaa agcataagaa acaacagaac aataaaactt ttggaaaaag 3060 t 3061 <210> 13 <211> 320 <212> PRT <213> Homo sapiens <400> 13 Met Asn Ser Glu Asn Leu Thr Arg Ala Ala Val Ala Pro Ala Glu Phe 1 5 10 15 Val Leu Leu Gly Ile Thr Asn Arg Trp Asp Leu Arg Val Ala Leu Phe 20 25 30 Leu Thr Cys Leu Pro Val Tyr Leu Val Ser Leu Leu Gly Asn Met Gly 35 40 45 Met Ala Leu Leu Ile Arg Met Asp Ala Arg Leu His Thr Pro Met Tyr 50 55 60 Phe Phe Leu Ala Asn Leu Ser Leu Leu Asp Ala Cys Tyr Ser Ser Ala 65 70 75 80 Ile Gly Pro Lys Met Leu Val Asp Leu Leu Leu Pro Arg Ala Thr Ile 85 90 95 Pro Tyr Thr Ala Cys Ala Leu Gln Met Phe Val Phe Ala Gly Leu Ala 100 105 110 Asp Thr Glu Cys Cys Leu Leu Ala Ala Met Ala Tyr Asp Arg Tyr Val 115 120 125 Ala Ile Arg Asn Pro Leu Leu Tyr Thr Thr Ala Met Ser Gln Arg Leu 130 135 140 Cys Leu Ala Leu Leu Gly Ala Ser Gly Leu Gly Gly Ala Val Ser Ala 145 150 155 160 Phe Val His Thr Thr Leu Thr Phe Arg Leu Ser Phe Cys Arg Ser Arg 165 170 175 Lys Ile Asn Ser Phe Phe Cys Asp Ile Pro Pro Leu Leu Ala Ile Ser 180 185 190 Cys Ser Asp Thr Ser Leu Asn Glu Leu Leu Leu Phe Ala Ile Cys Gly 195 200 205 Phe Ile Gln Thr Ala Thr Val Leu Ala Ile Thr Val Ser Tyr Gly Phe 210 215 220 Ile Ala Gly Ala Val Ile His Met Arg Ser Val Glu Gly Ser Arg Arg 225 230 235 240 Ala Ala Ser Thr Gly Gly Ser His Leu Thr Ala Val Ala Met Met Tyr 245 250 255 Gly Thr Leu Ile Phe Met Tyr Leu Arg Pro Ser Ser Ser Tyr Ala Leu 260 265 270 Asp Thr Asp Lys Met Ala Ser Val Phe Tyr Thr Leu Val Ile Pro Ser 275 280 285 Leu Asn Pro Leu Ile Tyr Ser Leu Arg Asn Lys Glu Val Lys Glu Ala 290 295 300 Leu Arg Gln Thr Trp Ser Arg Phe His Cys Pro Gly Gln Gly Ser Gln 305 310 315 320 <210> 14 <211> 963 <212> DNA <213> Homo sapiens <400> 14 atgaactcag agaacctcac ccgggccgcg gttgcccctg ctgaattcgt cctcctgggc 60 atcacaaatc gctgggacct gcgtgtggcc ctcttcctga cctgcctgcc tgtctacctg 120 gtgagcctgc tgggaaacat gggcatggcg ctgctgatcc gcatggatgc ccggctccac 180 acacctatgt acttcttcct ggccaacctc tccctgctgg atgcctgcta ttcctccgcc 240 atcggcccca agatgctagt ggacctgctg ctgccccgag ccaccatccc ttacacagcc 300 tgtgccctcc agatgtttgt ctttgcaggt ctggctgata ctgagtgttg cttgctggca 360 gccatggcct atgaccgcta cgtggccatc agaaacccac ttctctatac aacagctatg 420 tcgcagcgtc tatgcctggc cttgctggga gcatcaggcc tgggtggggc agtgagtgcc 480 tttgttcaca caaccctcac cttccgcctg agcttctgcc gctcccggaa gatcaatagc 540 ttcttctgcg atatccctcc actgctggcc atctcgtgca gtgacaccag tctcaatgaa 600 ctccttctct tcgccatctg tggcttcatc cagacagcca cggtgttagc tatcacggtg 660 tcttatggct tcatcgctgg ggctgtgatc cacatgcgct cggtcgaggg cagtcggcga 720 gcagcctcca ccggtggttc ccacctcaca gccgtggcca tgatgtacgg gacactcatt 780 ttcatgtacc tgcgccccag ctccagctat gccctggaca ctgacaagat ggcctctgtg 840 ttctataccc tggtcatccc gtctctcaac ccactcatct acagcctccg caataaggag 900 gtcaaggagg ccctcaggca gacctggagc cgattccact gtccagggca ggggtcccag 960 tga 963 <210> 15 <211> 312 <212> PRT <213> Homo sapiens <400> 15 Met Glu Ala Gly Asn Gln Thr Gly Phe Leu Glu Phe Ile Leu Leu Gly 1 5 10 15 Leu Ser Glu Asp Pro Glu Leu Gln Pro Phe Ile Phe Gly Leu Phe Leu 20 25 30 Ser Met Tyr Leu Val Thr Val Leu Gly Asn Leu Leu Ile Ile Leu Ala 35 40 45 Ile Ser Ser Asp Ser His Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Trp Val Asp Ile Cys Phe Ser Thr Cys Ile Val Pro Lys 65 70 75 80 Met Leu Val Asn Ile Gln Thr Glu Asn Lys Ala Ile Ser Tyr Met Asp 85 90 95 Cys Leu Thr Gln Val Tyr Phe Ser Met Phe Phe Pro Ile Leu Asp Thr 100 105 110 Leu Leu Leu Thr Val Met Ala Tyr Asp Arg Phe Val Ala Val Cys His 115 120 125 Pro Leu His Tyr Met Ile Ile Met Asn Pro His Leu Cys Gly Leu Leu 130 135 140 Val Phe Val Thr Trp Leu Ile Gly Val Met Thr Ser Leu Leu His Ile 145 150 155 160 Ser Leu Met Met His Leu Ile Phe Cys Lys Asp Phe Glu Ile Pro His 165 170 175 Phe Phe Cys Glu Leu Thr Tyr Ile Leu Gln Leu Ala Cys Ser Asp Thr 180 185 190 Phe Leu Asn Ser Thr Leu Ile Tyr Phe Met Thr Gly Val Leu Gly Val 195 200 205 Phe Pro Leu Leu Gly Ile Ile Phe Ser Tyr Ser Arg Ile Ala Ser Ser 210 215 220 Ile Arg Lys Met Ser Ser Ser Gly Gly Lys Gln Lys Ala Leu Ser Thr 225 230 235 240 Cys Gly Ser His Leu Ser Val Val Ser Leu Phe Tyr Gly Thr Gly Ile 245 250 255 Gly Val His Phe Thr Ser Ala Val Thr His Ser Ser Gln Lys Ile Ser 260 265 270 Val Ala Ser Val Met Tyr Thr Val Val Thr Pro Met Leu Asn Pro Phe 275 280 285 Ile Tyr Ser Leu Arg Asn Lys Asp Val Lys Gly Ala Leu Gly Ser Leu 290 295 300 Leu Ser Arg Ala Ala Ser Cys Leu 305 310 <210> 16 <211> 3286 <212> DNA <213> Homo sapiens <400> 16 ccacactcat gcatcttaga gaggagagtt aggatgactt catgacaagt tccatctccc 60 cgcctttccc tgctagattc tgtcttcagc attcaacagt caggggagga agacgtcata 120 ccagcatttt tttttttcaa gcaatctttc catgatgagt acaaagcctt ggggaatatc 180 tggataaagt aaaattttct agaatgtgat ctggacttgc cacaaagaaa cttcagatac 240 atcagctaca tggaagcagg aaaccaaaca ggatttttag agtttatcct tctcggactc 300 tctgaggatc cagaactaca gccgttcata tttgggctgt tcctgtccat gtacctggtg 360 acggtgctgg gaaacctgct catcatcctg gccatcagct ctgactccca cctccacacc 420 cccatgtact tcttcctctc caacctgtcc tgggttgaca tctgtttcag cacttgcatc 480 gtccccaaga tgctggtgaa catccagacc gagaacaaag ccatctccta catggactgc 540 ctcacacagg tctatttctc catgtttttt cctattctgg acacgctact cctgaccgtg 600 atggcctatg accggtttgt ggctgtctgc caccctctgc actatatgat catcatgaac 660 ccccacctct gtggcctcct ggtttttgtc acctggctca ttggtgtcat gacatccctc 720 ctccatattt ctctgatgat gcatctaatc ttctgtaaag attttgaaat tccacatttt 780 ttctgcgaac tgacgtacat cctccagctg gcctgctctg ataccttcct gaacagcacg 840 ttgatatact ttatgacggg tgtgctgggc gtttttcccc tccttgggat cattttctct 900 tattcacgaa ttgcttcatc cataaggaag atgtcctcat ctgggggaaa acaaaaagca 960 ctttccacct gtgggtctca cctctccgtc gtttctttat tttatgggac aggcattggg 1020 gtccacttca cttctgcggt gactcactct tcccagaaaa tctccgtggc ctcggtgatg 1080 tacactgtgg tcacccccat gttgaacccc ttcatctaca gcctgaggaa caaggatgtg 1140 aagggagccc tggggagtct cctcagcagg gcagcctctt gtttgtgatg gatcccttgg 1200 ccccaggact aagaagtttt gtgagcacca atggcaaaaa tgttttattt tgaaattctt 1260 actctttaaa attaaaaaca tttttttata ctttgagagt acaaatgcag atttcttaac 1320 atgcatttgc ataagggtga agtctgagct tttggcgtac caattacctg aatagtgaac 1380 ataaggcact tttttttctt ttttgagacg gagtctcact ctgtctccca ggctggagtg 1440 cagtggagtg atctcggctc actgcaacct ccgcctcccg ggttcaagtg attcttctgt 1500 ctcagcctcc tgagtagctg agattacagg tgtgtgccac ccatgccttt tagtagagac 1560 ggggtttcac catcttggcc aggctggtct cgaactcctg accttgtgat ccacctgcct 1620 tggcctctca aagtgctggg attacaggtg tgagccacca cgcccggcca aggcagtttt 1680 taaactctca ctcccctctc accttttgca gtctccagtg tccattattc tgttataatg 1740 cccatgcgta tacattgttt agctcccaat tataagtgag atcatgcagc atttgacttt 1800 gtttctttac taccttactt aagagaatgg cttccagtcc catcgatgtt gctgcaaaag 1860 acatgatttc atcctttttt atggctgagt agtactccat tgtatatatc ctcgatatct 1920 atatagatat agacatatgt agatacatac catgttttct ttttttaaaa aaatttattt 1980 ttatgtcagt agtttttggg gtacatgtgg tttttcatta cacggatgag ttctttagtg 2040 gtgacttctg agtttttagt gtacccgtca cccaagtggt agtagtctct tattcctcac 2100 ccccctccca acctttctcc cttcaagtca ccaaagttca ttatattgtt catatccctt 2160 tgtgtcctca tagcttagct cccacttata actgagaaca tacgatatgt tcatatggat 2220 cttatgtatg ttggttgaac atacaaacaa gtccaggttt ttcattcctg agttacttca 2280 cctagagtaa tgacctccag ttccatccaa gttgctacaa aagacattat ttggttcctt 2340 tttatggata agtagtattc catgctgtac atataccaca atctttatca ctcattggtt 2400 gatgggcact taggttggtt ccatgccttt gtaattgcta attatgttgc tataaacatg 2460 caggtgtatg tgtctttttc acataatgac tttgtttcct ttgggtagat acccagtagt 2520 ggaactgctg gactgaaagg tagttctact tttagttctt ttttttgttt tttttttaag 2580 acagagtctc actctgttgc ccaggctgga gtgcagtggc gcgatctcat ctcactgcaa 2640 cctccacctc ccaggttcaa gcgattctcc tgcctcaacc tcctgagtag ctgggactac 2700 aggcacctgc caccccaccc agctaattct tctattttta gtagagacag ggtttcacca 2760 tgttggccag gctggtcttg aactcctgac ctcaggtgat acgcccacct cggcctccca 2820 aagtgctggg attacaggtg tgagccactg tgcctggcct tctagttctt taagatacca 2880 ctttaaaaaa agtccagtcc tccattgatg gacacgtagg ttgattccat atctttgcta 2940 atgtgaatag tgccgtgata aacatggggg tgtaagttaa caattaatct ccaagtaatt 3000 tccttgatgg cacttctgtc ctatgtgcta ttcaaaaatt gtgtccttga tcatcgttct 3060 taattctcca ttagtgagtt ctgaacttgg gtttgaagca tttgctatag ctttgttatc 3120 tcaagtggtg gcacagagtt cttaagctat tgattgttca ctgactttat ttctatgtgt 3180 ttgcatgtgg gtttttgttg tttgtgtgtt cgatcatgaa cagatcaaca gtgtttattt 3240 gttttcctac tggatgaagt atgattaaaa tacgtattta aatata 3286 <210> 17 <211> 502 <212> DNA <213> Homo sapiens <400> 17 ggtgtgttac ctgccgacag cataatgtga ggcaaggtcc agccgttccg cccagcatac 60 aagcttatgg agcagccccc tttggagatc tccaggtaga cttcagagag atgccaaagt 120 gtggagatct gattcctaga tttcgactgc ccttacggat cggctcacat aacgggcctg 180 cgtttttggc tgccatggta cagaagacgg caaaggtgtc caagtcacac agagccacgg 240 aatctcacag gagcctgaga actcctcctc ctgggactct cagaggatcc agaactgcag 300 cccatcctcg ctgggctgtc cctgtccatg tatctggtca cggtgctgag gaacctcctc 360 atcagcctgg ctgtcagctc tgactcccac ctccacaccc caatgtgctt cttcctctcc 420 aacctgtgct gggctgacat cggtttcacc tcggccacgg ttcccaagat gattgtggac 480 atgcggtcgc atagcggagt ca 502 <210> 18 <211> 303 <212> PRT <213> Homo sapiens <400> 18 Met Ser Phe Ser Ser Leu Pro Thr Glu Ile Gln Ser Leu Leu Phe Leu 1 5 10 15 Thr Phe Leu Thr Ile Tyr Leu Val Thr Leu Met Gly Asn Cys Leu Ile 20 25 30 Ile Leu Val Thr Leu Ala Asp Pro Met Leu His Ser Pro Met Tyr Phe 35 40 45 Phe Leu Arg Asn Leu Ser Phe Leu Glu Ile Gly Phe Asn Leu Val Ile 50 55 60 Val Pro Lys Met Leu Gly Thr Leu Leu Ala Gln Asp Thr Thr Ile Ser 65 70 75 80 Phe Leu Gly Cys Ala Thr Gln Met Tyr Phe Phe Phe Phe Phe Gly Val 85 90 95 Ala Glu Cys Phe Leu Leu Ala Thr Met Ala Tyr Asp Arg Tyr Val Ala 100 105 110 Ile Cys Ser Pro Leu His Tyr Pro Val Ile Met Asn Gln Arg Thr Arg 115 120 125 Ala Lys Leu Ala Ala Ala Ser Trp Phe Pro Gly Phe Pro Val Ala Thr 130 135 140 Val Gln Thr Thr Trp Leu Phe Ser Phe Pro Phe Cys Gly Thr Asn Lys 145 150 155 160 Val Asn His Phe Phe Cys Asp Ser Pro Pro Val Leu Arg Leu Val Cys 165 170 175 Ala Asp Thr Ala Leu Phe Glu Ile Tyr Ala Ile Val Gly Thr Ile Leu 180 185 190 Val Val Met Ile Pro Cys Leu Leu Ile Leu Cys Ser Tyr Thr His Ile 195 200 205 Ala Ala Ala Ile Leu Lys Ile Pro Ser Ala Lys Gly Lys Asn Lys Ala 210 215 220 Phe Ser Thr Cys Ser Ser His Leu Leu Val Val Ser Leu Phe Tyr Ile 225 230 235 240 Ser Leu Ser Leu Thr Tyr Phe Arg Pro Lys Ser Asn Asn Ser Pro Glu 245 250 255 Gly Lys Lys Leu Leu Ser Leu Ser Tyr Thr Val Met Thr Pro Met Leu 260 265 270 Asn Pro Ile Ile Tyr Ser Leu Arg Asn Asn Glu Val Lys Asn Ala Leu 275 280 285 Ser Arg Thr Val Ser Lys Ala Leu Ala Leu Arg Asn Cys Ile Pro 290 295 300 <210> 19 <211> 5390 <212> DNA <213> Homo sapiens <400> 19 actagcccca agaacaaaag aggcacaggt gggaacaact ctcccaaaac caggactggg 60 agcatggcca aacttcatag tgagcttact tgcctctgac acacaaggca gcagtgagct 120 ggctacagct ccagccatta atagctcagc caggacaggg aataagactt ccctggttct 180 tcttttggct ttgctgaaac agaaatagag ctgttatatt acatgcatga aggacatgca 240 tgaagcatgg atgtcagcca gagttgaaca aggcagatgt tcctgttgga cacagtaaga 300 acgagtctga aaaacaaatt gagaatctga cttccaatca ataatctttc tccatgacca 360 cagttgggga cttctgccca cacttatagc tacaggaaac tggacaagaa taagtgagtt 420 tatcctcatg agcttctctt ccctgcctac tgaaatacag tcattactct ttctgacatt 480 tctaaccatc tacctggtca ccctgatggg aaactgcctc atcattctgg ttaccctagc 540 tgaccccatg ctacacagcc ccatgtactt cttcctcaga aacttatctt tcctggagat 600 tggcttcaac ctagtcattg tgcccaaaat gctggggacc ctgcttgccc aggacacaac 660 catctccttc cttggctgtg ccactcagat gtatttcttc ttcttctttg gagtggctga 720 atgcttcctc ctggctacca tggcatatga ccgctatgtg gccatctgca gtcccttgca 780 ctacccagtc atcatgaacc aaaggactcg tgccaaactg gctgctgcct cctggttccc 840 aggctttcct gtagctactg tgcagaccac atggctcttc agttttccat tctgtggcac 900 caacaaggtg aaccacttct tctgtgacag cccacctgtg ctgaggctgg tctgtgcaga 960 cacagcactc tttgagatct acgccatcgt cggaaccatt ctggtggtca tgatcccctg 1020 cttgctgatc ttgtgttcct atactcacat tgctgctgcc atcctcaaga tcccatcagc 1080 taaagggaag aataaagcct tttctacatg ttcctcacac ctccttgttg tctctctttt 1140 ctatatatca ttaagcctca cctacttccg gcctaaatca aataattcac ctgagggcaa 1200 gaagctgcta tcattgtcct acactgttat gactcccatg ttgaacccca ttatctacag 1260 cctgagaaat aacgaggtga agaatgccct cagcaggacg gtctctaagg ccctagccct 1320 cagaaactgt atcccataga ccttaggaag taaggctaca ttttactgga tgagaaacaa 1380 tcagtcccag atttgagatt cctctctgca tctttccaca tctccaataa gatgaagtcc 1440 tgttgctgaa atggcttttg gaaagctgag tggagagaaa ggagcagaga agtagtttcg 1500 acctagcacc accaactatg aaaactcctc tgcctgccca ttgtagactt acattgtttt 1560 ccttgtttca actggtatga cagcacttct gtggccaact atttccaggt gttatatttc 1620 tttttttttt tttttttgag acggagtctc gctctgtccc ccaggctgga gtgcagtggc 1680 gcatctctgc tcactgcaag ctccgcctcc tgggttcacg ctgttctcct gcctcagcct 1740 cccaagtagc tgggactaca ggtgcccgcc accatgcccg gctaattttt tgtatttttt 1800 tagtagagac agggtttcac cgtgttagcc aggatggtct cgatctcctg acctcgtgat 1860 ccacccgcct cggcctccca aagtgctggg attacaggcg tgagccaccg cgcctggccg 1920 gtgtttatat ttctgtgtga cgtgcattgt gcacaatatg aaactgctag tcattataac 1980 atgggggcac acatagtaac agagggtaaa acccaataaa aatcatcttg tcacttttcc 2040 tcttctgggc agatctgact ctacattcat gacagaaaat ctcatgatct ttcccaacac 2100 ataactctcc tcaccatctt acttcattct catgccctta agcagtgtta gttcttttaa 2160 gcttactggt atgcagtatg catgtatgag agtagatcaa aagttcacat gcatatgcct 2220 ttataacccc aataattatt tccttcacac tagattcttc ccaagaaaaa caacctgagc 2280 ttccctaaga tctctattcc atattcaggt tcttatgttt tgttgaagta atatcgtaaa 2340 tttcagtcat agctttgctt tgatgagaac aaagctccag aataagtctt ctttaaccac 2400 aagatttctc cttcttataa tctggtagta ctctatttgt agatgtgccc taatttattt 2460 agccagtctt ttactactac aaatcatgct gtaaataatg gacttatcca tatatctgtt 2520 tttatatttt tgctagtgta cctgacaaat agaaatctag aaattgagtt tcttgggcaa 2580 aagttaaata catacataat gttgctatat atattgattg tctatctagc tcccctctga 2640 acttattgca ccattttatg ctcccaccag caatttatga ggtgtttgtt tccccacaac 2700 tcaacaataa catttctcat gaaatattta gaatttcgat tatttaatat tttataaaaa 2760 ctcaatgaaa ttttaatttg aatgaaataa attttgaaga ataagaaaga aacagatgat 2820 caaatcagag gaaaggtgtg catttcattg aaacttgagt tatagattag acgattagca 2880 attggtgatg tcttggtgtt ttattttctc ttcttgaaag gttgtttttc acttttattt 2940 tagccaaatc tatcccatct ctcaagaccc cactgtgatt cctcaagaag cagaaatcac 3000 tctttctgta tgcacccatt tcaagtttat taataaatac attaaatttt gtatatacta 3060 catgtagaaa ctgtacatgt acttattttt acatgtttgt cttcctccaa cttttctgta 3120 actcttcaaa aataagaatt gttcaagtgt ttctggtgtt ttgttttgtg tttgagacag 3180 ggtctctctc tctgtcaccc aggctggact gcggtagcag aattatggct cactgtagcc 3240 tcaaacacct gggctcaggc catcttcctg cctcagtctc cctagtggct gggactatag 3300 gcgtacatca ccatgcctgg ccatttaaaa attttttttt agtagagacg aggtcttgct 3360 atgctaccca gtctggtatc gaacttctga gttcaagcaa tccttctgcc tgaacctctc 3420 aaagtgctgg gattataagt gtgagccatt gcatgcaaca caagtgtttc tcttttcttt 3480 tctttctttc tttttttttt tttttttgag acaaaggtct gctctattac tcaggctgct 3540 ggggtgcaat ggcacaatct tggctcactg caacttctgc cttctgggtt caatcaattc 3600 tcatgcctca gcctcttgag tagctgggat tacaggcgtg ccaagccatg cccaactaat 3660 tttttttttg tattttttag tagagatgca gttttaccat gttggagctc ctggcctcaa 3720 gtgatctgcc tgcctcagcc tcccaagggc tgggattaca gacgtgggcc accatgccag 3780 gccaagtatt tcccttttaa tatgacgtag gcattcctga aaagcttatg taatgcaaac 3840 ctttacatta aaaatattat ggggaagtag ggctagggtt agggctagac tcaaaataca 3900 tgcaacttta aagacaaggc attagtagaa acaacatttg gttcccagag agacaatgta 3960 gactgcccag gcaggcagct cattgaggct ggaggttgcc acagtagata tttaaaatat 4020 acaacaacag tagaatgaaa ataccaacaa tgcttggatt agaacaatga tgcttgatgc 4080 tgagacaatt tgtactgggg tagggggtag tccttagtat gggtaaagaa tttgaagtaa 4140 agcaaacaag aataacccaa aacctaaaga aaaagttgta catagtttca gggaaaggat 4200 tccaacagaa gagtgccaca tgcacaaaca caggagtgct gagagactat gatgtgtgta 4260 aggaacacaa agcatttttg tgtcactgaa aaatcagcta cactggggat ttgaaactgg 4320 aaaaataagc agagatcaca ggaaaagacc ttgttaaagg atttacttta tcccaggggc 4380 catacggagt aattgaaaga cattaagcag gtaagtgact taaccagagt tgctggttaa 4440 gacagcaact ggtaagacag ttgctgataa gacagatcac atacaaacca aggatggttt 4500 gaagagaatg aaccagaagc aggttcctac catactctag gccagagaaa ataaatccag 4560 aacctaaagg cagtggtggt agagctggag aaggtgacac tgaattagtg tttaggagta 4620 aaaataatca aatttggggc acaaattaaa ggattatatc ccagttcctg gcttgtactt 4680 tggggtggtg ccatttactg aaatggggta tctacaaaga ggaggtttga ggtggaggaa 4740 gcagacaagc acatttatat ctcttatcat tgtttcagtc cgtgtgaatt gtatgatgct 4800 atattatatt cttttgtgcc tttgtctaaa ttccttatga atggggctca ctgtacctac 4860 tttgtgtctg tgtagatgtt tccctgatta tttaccacat tttcttcatt atctattaaa 4920 ttattcaata acaatttact gggcatctac ctttctaggc attggggtaa aaaaatgaat 4980 aacacaattt ctatttcaag gagcatgtca tctactgtat gagacaaata catacaataa 5040 tgattattct aaaataagaa ctatgaaagt ggtattccag ttctccaatg ttactaatat 5100 attgaaattt tctgcccatc tttagaaatt gtgttgcttt gttcttacta ccaccctgta 5160 ctggatactg gcttgtcctc acctgtgggc tcagatttat tcccattctg aaaaaatgag 5220 tgcaagtgtc acttgtcggc caaatccctg acttggactc agccacccag gattccaaca 5280 cttgctgaaa aaactactca acttatctgt gtctcagatt ccttgactgt aaaatgggta 5340 taatactatc tgtatcttca ggtgttgtga gaatcaaata agataataca 5390 <210> 20 <211> 318 <212> PRT <213> Homo sapiens <400> 20 Met Gln Arg Ala Asn His Ser Thr Val Thr Gln Phe Ile Leu Val Gly 1 5 10 15 Phe Ser Val Phe Pro His Leu Gln Leu Met Leu Phe Leu Leu Phe Leu 20 25 30 Leu Met Tyr Leu Phe Thr Leu Leu Gly Asn Leu Leu Ile Met Ala Thr 35 40 45 Val Trp Ser Glu Arg Ser Leu His Thr Pro Met Tyr Leu Phe Leu Cys 50 55 60 Ala Leu Ser Val Ser Glu Ile Leu Tyr Thr Val Ala Ile Ile Pro Arg 65 70 75 80 Met Leu Ala Asp Leu Leu Ser Thr Gln Arg Ser Ile Ala Phe Leu Ala 85 90 95 Cys Ala Ser Gln Met Phe Phe Ser Phe Ser Phe Gly Phe Thr His Ser 100 105 110 Phe Leu Leu Thr Val Met Gly Tyr Asp Arg Tyr Val Ala Ile Cys His 115 120 125 Pro Leu Arg Tyr Asn Val Leu Met Ser Pro Arg Gly Cys Ala Cys Leu 130 135 140 Val Gly Cys Ser Trp Ala Gly Gly Leu Val Met Gly Met Val Val Thr 145 150 155 160 Ser Ala Ile Phe His Leu Ala Phe Cys Gly His Lys Glu Ile His His 165 170 175 Phe Ala Cys His Val Pro Pro Leu Leu Lys Leu Ala Cys Gly Asp Asp 180 185 190 Val Leu Val Val Ala Lys Gly Val Gly Leu Val Cys Ile Thr Ala Leu 195 200 205 Leu Gly Cys Phe Leu Leu Ile Leu Leu Ser Tyr Ala Phe Ile Val Ala 210 215 220 Ala Ile Leu Lys Ile Pro Ser Ala Glu Gly Arg Asn Lys Ala Phe Ser 225 230 235 240 Thr Cys Ala Ser His Leu Thr Val Val Val Val His Tyr Gly Phe Ala 245 250 255 Ser Val Ile Tyr Leu Lys Pro Lys Ser Pro Gln Ser Leu Glu Gly Asp 260 265 270 Thr Leu Met Gly Ile Thr Tyr Thr Val Leu Thr Pro Phe Leu Ser Pro 275 280 285 Ile Ile Phe Ser Leu Arg Asn Lys Glu Leu Lys Val Ala Met Lys Lys 290 295 300 Thr Phe Phe Ser Lys Leu Tyr Pro Glu Lys Asn Val Met Met 305 310 315 <210> 21 <211> 4376 <212> DNA <213> Homo sapiens <400> 21 tggtgtggct gcttggtgca gcccacacct ggtcagctcc cacctgtgga gaaactccaa 60 actagagcct cctactggga tgaagcagaa gcagatgcct ggagtcccag aatgactgga 120 ctaccctttt agctgcattc tgcatcccat cattccagac ggtgttacat gcagccctca 180 gctacctcct acagacgtga tcggctcctg tcctctcaag gtttctccct ccctcccttc 240 cttcctccct ccattcctcc ctccctcgtt tcttcctatc tcactctcct tctttcctcc 300 ctcactctcc ttccttcctt cctgcctccc tccctccctt tcttccttcc ttcctcactc 360 tccttctttc ctccctcact ctccttcctt cctgcctccc tccctccttt cttccttcct 420 cactctcctc ctttcctccc tcactctcct tccttccttc cttcgttcct tccttcctcc 480 ttccctccct ccctccttcc ttcctcctgc agtccccatc cttccttcct tttatccttc 540 tttccttcct ccctccctcc ctctctttct tcctcccttt tttctttctt ttcctcctcc 600 tcctcctcct ccttttctct ctctctctct ccccccacct tgttcactca ctcgctgtcg 660 attcttgtga tctgaattga tatgaacaag agtgtgtaga cggtcagtca tggggaagca 720 gcatctccta gtggcctttg aaacagccac cagcaactga gactcgctct gtcgccaggg 780 tggagtccag tggcgccatc tcggcttact gcaacctccg cctcccaggt tcaagagatt 840 ctcctgtctc tgcctcccga agagctggga ctacaggcac agcctccatg cagagagcca 900 atcactccac agtgacccaa ttcatcctcg tcggcttctc tgtcttcccc cacctccagc 960 tgatgctctt cctgctgttc ctgctgatgt acctgttcac gctgctgggc aacctgctca 1020 tcatggccac cgtctggagc gagcgcagcc tccacacgcc catgtacctc ttcctgtgcg 1080 ccctctccgt ctccgagatc ctctacaccg tggccatcat cccgcgcatg ctggccgacc 1140 tgctgtccac ccagcgctcc atcgccttcc tggcctgtgc cagtcagatg ttcttctcct 1200 tcagcttcgg cttcacccac tccttcctgc tcaccgtcat gggctacgac cgctacgtgg 1260 ccatctgcca ccccctgcgc tacaacgtgc tcatgagccc gcggggctgc gcctgcctgg 1320 tgggctgctc ctgggctggt ggcttggtca tggggatggt ggtgacctcg gccattttcc 1380 acctcgcctt ctgtggacac aaggagatcc accattttgc ttgccatgtg ccacctctgt 1440 tgaagttggc ctgtggagac gatgtgctgg tggtggccaa aggcgtgggc ttggtgtgta 1500 tcacggccct gctgggctgt tttctcctca tcctcctctc ctatgccttc atcgtggccg 1560 ccatcttgaa gatcccttct gctgaaggtc ggaacaaggc cttctccacc tgtgcctctc 1620 acctcactgt ggtggtcgtg cactatggct ttgcctccgt catttacctg aagcccaaaa 1680 gtccccagtc tctggaagga gacaccttga tgggcatcac ctacacggtc ctcacaccct 1740 tcctcagccc catcatcttc agcctcagga acaaggagct gaaggtcgcc atgaagaaga 1800 ccttcttcag taaactctac ccagaaaaaa atgtaatgat gtaggagaaa ttcactggga 1860 acaactaaat tggattaccg aaggctattg ttaaaaatta cgttccgtgg tgactcatgc 1920 ctgtaatccc agcactttgg gaggccgagg caggcggatc acctgaggtc aggagtttga 1980 gaccagcatg gctaacatgg cgaaacccca tctctactaa aaatacaaaa attagccagg 2040 catgttggca catgcctgta accctagcta cttgggaggc tgaggcataa gaatcgcttg 2100 acccggtagg tggaggttgc agtgagctga gatcacacca ctgcactcca gcctgggcga 2160 cagagtgaga ctgtctcaaa gaagaaagaa agaaagaaaa aaagaaaatt acgttccagc 2220 caagcactgt ggctcacact tataattcca gcaccttggg atgccaaggc aggaggattg 2280 cttgaggcca ggagttcaag actagacttg acaacatagc aagactgcat atctacaaaa 2340 acttagaaaa aaatagcttg gcatggtggt acatgcctgt agtcccagct acctgggaga 2400 ctgaactggg attactgcct aagtccagaa gtttgagctt acagtgaact atgactgtgc 2460 cactgcagtc tagcatggat gacagagtga gaccctatcc cttcccccct aaaagaaaga 2520 caatccatga acatatagta acctctattt gtcatgcttt aaggtttaca agggaccttg 2580 tagacgacat acaattataa acacaaaggt taatcagcat cagggatgta tttggagtgg 2640 aagtgtgtgt gagatactaa cacagagaaa accaggtttg attatttcta tctgctgcaa 2700 gaaactgtgt cagttagcac caaacctcca tctagactcc tcttgccaaa agccagggtc 2760 atctaatacc cccaataatg caaaccagca atgcaaagag agagggaaga tttcatgccc 2820 cactctctat gagtgccgca ccaggtagct acaactcaga ttttgtaagg ctactccaga 2880 ttatagcaga ggagagaaaa gtaccctaaa tttcagcatt gcacagatct atgcaataga 2940 agttagaaat agcaataaac agactctctt taaacatcaa ggaaacctta gaatttcaag 3000 tgtgagtctt gaatagttgt ggagagactg agatgtcttc atggttggat caaggaaaaa 3060 agtcacactg tgagataccg aatgctgtgt tagaagttga cacggctcat gggccagcca 3120 ggagctctct gttgaatctg gacattgagt gtagacccca ggatgagttt atctcatggc 3180 caggcgcagt ggctcatgcc tgtaatccca gcactttggg aggccaaggt gggtggatcc 3240 cctgaggtca ggagttcaag agcagcctgg gcaaatggct gaaaccccat ctctactaaa 3300 aatataaaaa ttagccaggc gtggtggcag gtgcctgtaa tcccagctac tcaggaggct 3360 gagacaggag aatagcttga accatggagg cagaggttgc agtgagctga gatcacacca 3420 ctgcactcca gcctgggtga cagactgaga ctccatctca aaaaaaaaaa aaaaaaaaaa 3480 aaagaaagtt tacctcatgg tctcttccca atgggcaggg atttaagatt gaccctactg 3540 tatagtattt atatatttat tgacaatagg tcttcctgtg tttgagctat gcatcatttt 3600 tttctaaagt gtgaattctc catcattcaa gcagtcaaaa caacccacag tcaaaacatc 3660 ccatattaca aaagccaaaa ttgacaaatg ggatctaatt aaactaaaga gcttctgcac 3720 agcaaaagaa actaccatca gagtgaacag gcaacctaca gaatgggaga aaatttttgc 3780 aatctactca tctgacaaag ggctaatatc cagaatctac aatgaactca aacaaattta 3840 caagaaaaaa acaaacaatc ccatcaaaaa gtgggcaaag gatatgaaca gacacttctc 3900 aaaagaagac atttatgcag ccaaaaaaca tatgaaaaaa tgctcgtcat cactggccat 3960 cagagaaatg caaatggaaa ccacaatgag atatcatctc acaccagtta gaatggcaat 4020 cactaaaaag tcaggaaaca acaggtgctg gagaggatgt ggagaaatag gaacactttt 4080 acactgttgg tgggactgta aactagttcc ccattgtggg agtcagtgtg gcgattcctc 4140 agggatctag aactagaaat atcatttgac ccagccatcc cattactggg tatataccca 4200 aaggattata aatcatgctg ctataaagac acatgcacac atgtttactg cagcactatt 4260 cacagtagca aagacttgga accaacccaa atgtccaaca atgatagact ggattaagaa 4320 aatgtggcac atatacacca tggaatacta tgcagccata aaaaatgatg agttca 4376 <210> 22 <211> 346 <212> PRT <213> Homo sapiens <400> 22 Met Tyr Arg Phe Thr Asp Phe Asp Val Ser Asn Ile Ser Ile Tyr Leu 1 5 10 15 Asn His Val Leu Phe Tyr Thr Thr Gln Gln Ala Gly Asp Leu Glu His 20 25 30 Met Glu Thr Arg Asn Tyr Ser Ala Met Thr Glu Phe Phe Leu Val Gly 35 40 45 Leu Ser Gln Tyr Pro Glu Leu Gln Leu Phe Leu Phe Leu Leu Cys Leu 50 55 60 Ile Met Tyr Met Ile Ile Leu Leu Gly Asn Ser Leu Leu Ile Ile Ile 65 70 75 80 Thr Ile Leu Asp Ser Arg Leu His Thr Pro Met Tyr Phe Phe Leu Gly 85 90 95 Asn Leu Ser Phe Leu Asp Ile Cys Tyr Thr Ser Ser Ser Ile Pro Pro 100 105 110 Met Leu Ile Ile Phe Met Ser Glu Arg Lys Ser Ile Ser Phe Ile Gly 115 120 125 Cys Ala Leu Gln Met Val Val Ser Leu Gly Leu Gly Ser Thr Glu Cys 130 135 140 Val Leu Leu Ala Val Met Ala Tyr Asp His Tyr Val Ala Ile Cys Asn 145 150 155 160 Pro Leu Arg Tyr Ser Ile Ile Met Asn Gly Val Leu Tyr Val Gln Met 165 170 175 Ala Ala Trp Ser Trp Ile Ile Gly Cys Leu Thr Ser Leu Leu Gln Thr 180 185 190 Val Leu Thr Met Met Leu Pro Phe Cys Gly Asn Asn Val Ile Asp His 195 200 205 Ile Thr Cys Glu Ile Leu Ala Leu Leu Lys Leu Val Cys Ser Asp Ile 210 215 220 Thr Ile Asn Val Leu Ile Met Thr Val Thr Asn Ile Val Ser Leu Val 225 230 235 240 Ile Leu Leu Leu Leu Ile Phe Ile Ser Tyr Val Phe Ile Leu Ser Ser 245 250 255 Ile Leu Arg Ile Asn Cys Ala Glu Gly Arg Lys Lys Ala Phe Ser Thr 260 265 270 Cys Ser Ala His Ser Ile Val Val Ile Leu Phe Tyr Gly Ser Ala Leu 275 280 285 Phe Met Tyr Met Lys Pro Lys Ser Lys Asn Thr Asn Thr Ser Asp Glu 290 295 300 Ile Ile Gly Leu Ser Tyr Gly Val Val Ser Pro Met Leu Asn Pro Ile 305 310 315 320 Ile Tyr Ser Leu Arg Asn Lys Glu Val Lys Glu Ala Val Lys Lys Val 325 330 335 Leu Ser Arg His Leu His Leu Leu Lys Met 340 345 <210> 23 <211> 1041 <212> DNA <213> Homo sapiens <400> 23 atgtacagat ttacagattt tgatgtatca aacatttcaa tttacctgaa tcatgtcctt 60 ttctatacta cccagcaggc aggtgaccta gaacacatgg agacaagaaa ttactctgcc 120 atgactgaat tctttctggt ggggctttcc caatatccag agctccagct ttttctgttc 180 ctgctctgcc tcatcatgta catgataatc ctcctgggaa atagcctcct cattatcatc 240 accatcttgg attctcgcct ccatactccc atgtatttct ttcttggaaa cctctcattc 300 ttggacatct gttacacatc ctcatccatt cctccaatgc ttattatatt tatgtctgag 360 agaaaatcca tctccttcat tggctgtgct ctgcagatgg ttgtgtccct tggcttgggc 420 tccactgagt gtgtcctcct ggctgtgatg gcctatgacc actatgtggc catctgcaac 480 ccactgaggt actccatcat catgaacgga gtgctgtatg tgcaaatggc tgcatggtcc 540 tggatcatag gctgtctgac ctccctattg caaacagttc tgacaatgat gttgcctttc 600 tgtgggaata atgtcattga tcatattacc tgtgaaattt tggcccttct aaaacttgtt 660 tgttcagata tcaccatcaa tgtgcttatc atgacagtga caaatattgt ttcactggtg 720 attcttctac tgttaatttt catctcctat gtgtttattc tctcttccat cctgagaatt 780 aattgtgctg agggaagaaa gaaagccttc tctacctgtt cagcgcactc gattgtggtc 840 atcttattct acggttcagc cctttttatg tacatgaaac ccaagtcaaa gaacactaat 900 acatctgatg agattattgg gctgtcttat ggagtggtaa gcccaatgtt aaatcccatc 960 atctatagcc tcaggaataa agaggtcaaa gaggctgtaa agaaagtcct gagcagacat 1020 ctgcatttat tgaaaatgtg a 1041 <210> 24 <211> 312 <212> PRT <213> Homo sapiens <400> 24 Met Trp Pro Asn Ile Thr Ala Ala Pro Phe Leu Leu Thr Gly Phe Pro 1 5 10 15 Gly Leu Glu Ala Ala His His Trp Ile Ser Ile Pro Phe Phe Ala Val 20 25 30 Tyr Val Cys Ile Leu Leu Gly Asn Gly Met Leu Leu Tyr Leu Ile Lys 35 40 45 His Asp His Ser Leu His Glu Pro Met Tyr Tyr Phe Leu Thr Met Leu 50 55 60 Ala Gly Thr Asp Leu Met Val Thr Leu Thr Thr Met Pro Thr Val Met 65 70 75 80 Gly Ile Leu Trp Val Asn His Arg Glu Ile Ser Ser Val Gly Cys Phe 85 90 95 Leu Gln Ala Tyr Phe Ile His Ser Leu Ser Val Val Glu Ser Gly Ser 100 105 110 Leu Leu Ala Met Ala Tyr Asp Cys Phe Ile Ala Ile Arg Asn Pro Leu 115 120 125 Arg Tyr Ala Ser Ile Leu Thr Asn Thr Arg Val Ile Ala Leu Gly Val 130 135 140 Gly Val Phe Leu Arg Gly Phe Val Ser Ile Leu Pro Val Ile Leu Arg 145 150 155 160 Leu Phe Ser Phe Ser Tyr Cys Lys Ser His Val Ile Thr Arg Ala Phe 165 170 175 Cys Leu His Gln Glu Ile Met Arg Leu Ala Cys Ala Asp Ile Thr Phe 180 185 190 Asn Arg Leu Tyr Pro Val Ile Leu Ile Ser Leu Thr Ile Phe Leu Asp 195 200 205 Cys Leu Ile Ile Leu Phe Ser Tyr Ile Leu Ile Leu Asn Thr Val Ile 210 215 220 Gly Ile Ala Ser Gly Glu Glu Arg Ala Lys Ala Leu Asn Thr Cys Ile 225 230 235 240 Ser His Ile Ser Cys Val Leu Ile Phe Tyr Val Thr Val Met Gly Leu 245 250 255 Thr Phe Ile Tyr Arg Phe Gly Lys Asn Val Pro Glu Val Val His Ile 260 265 270 Ile Met Ser Tyr Ile Tyr Phe Leu Phe Pro Pro Leu Met Asn Pro Val 275 280 285 Ile Tyr Ser Ile Lys Thr Lys Gln Ile Gln Tyr Gly Ile Ile Arg Leu 290 295 300 Leu Ser Lys His Arg Phe Ser Ser 305 310 <210> 25 <211> 1055 <212> DNA <213> Homo sapiens <400> 25 ggaggctcct ggtttcaagg tttcaagaaa tctgatcttt accggtggat acactatgtg 60 gcccaatatt actgcagccc cttttttgct gactggcttt ccagggctgg aggcagctca 120 tcactggatc tccatcccct tctttgctgt ttatgtgtgc atccttctgg gcaatggcat 180 gctcctctac ctcatcaagc atgaccacag tcttcatgag cccatgtact acttcctcac 240 catgctggca ggcacagacc tcatggtgac attgaccacg atgcctactg taatgggcat 300 cctatgggtg aatcacaggg agattagcag tgtgggctgc ttcctacagg cttactttat 360 tcactccctt tctgttgtgg aatcaggttc cctcctggca atggcatatg attgtttcat 420 tgccatccgc aatcctttga gatatgcttc cattctcacc aatactagag tcatagcgtt 480 aggagtggga gtgtttctaa ggggttttgt atccatcctg cctgtaattt tgcgtctttt 540 ttcattttca tattgcaaat ctcatgttat cacacgtgct ttctgcctcc accaagaaat 600 catgagactg gcttgtgctg acataacttt caatagactt taccctgtaa ttttgatctc 660 tttaacaatc ttcctagact gtctgatcat cctcttctcc tatattctaa ttcttaatac 720 tgtcataggc attgcttctg gtgaagagag agccaaagcc ctcaatacct gtatctccca 780 cattagttgt gttcttatct tctatgttac agtgatgggt ttgacattca tttacagatt 840 tgggaagaat gtgccagagg ttgtccacat tatcatgagt tacatctact tcctctttcc 900 tcctttaatg aaccctgtca tctacagcat caaaaccaag caaatacaat atggcattat 960 ccgcctttta tctaaacata ggtttagtag ttaaactcgg atctggagaa tcagacacag 1020 acataaaaat gaagccagaa tgaaaaatga aagcc 1055 <210> 26 <211> 324 <212> PRT <213> Homo sapiens <400> 26 Met Leu Gly Pro Ala Tyr Asn His Thr Met Glu Thr Pro Ala Ser Phe 1 5 10 15 Leu Leu Val Gly Ile Pro Gly Leu Gln Ser Ser His Leu Trp Leu Ala 20 25 30 Ile Ser Leu Ser Ala Met Tyr Ile Thr Ala Leu Leu Gly Asn Thr Leu 35 40 45 Ile Val Thr Ala Ile Trp Met Asp Ser Thr Arg His Glu Pro Met Tyr 50 55 60 Cys Phe Leu Cys Val Leu Ala Ala Val Asp Ile Val Met Ala Ser Ser 65 70 75 80 Val Val Pro Lys Met Val Ser Ile Phe Cys Ser Gly Asp Ser Ser Ile 85 90 95 Ser Phe Ser Ala Cys Phe Thr Gln Met Phe Phe Val His Leu Ala Thr 100 105 110 Ala Val Glu Thr Gly Leu Leu Leu Thr Met Ala Phe Asp Arg Tyr Val 115 120 125 Ala Ile Cys Lys Pro Leu His Tyr Lys Arg Ile Leu Thr Pro Gln Val 130 135 140 Met Leu Gly Met Ser Met Ala Val Thr Ile Arg Ala Val Thr Phe Met 145 150 155 160 Thr Pro Leu Ser Trp Met Met Asn His Leu Pro Phe Cys Gly Ser Asn 165 170 175 Val Val Val His Ser Tyr Cys Lys His Ile Ala Leu Ala Arg Leu Ala 180 185 190 Cys Ala Asp Pro Val Pro Ser Ser Leu Tyr Ser Leu Ile Gly Ser Ser 195 200 205 Leu Met Val Gly Ser Asp Val Ala Phe Ile Ala Ala Ser Tyr Ile Leu 210 215 220 Ile Leu Arg Ala Val Phe Asp Leu Ser Ser Lys Thr Ala Gln Leu Lys 225 230 235 240 Ala Leu Ser Thr Cys Gly Ser His Val Gly Val Met Ala Leu Tyr Tyr 245 250 255 Leu Pro Gly Met Ala Ser Ile Tyr Ala Ala Trp Leu Gly Gln Asp Ile 260 265 270 Val Pro Leu His Thr Gln Val Leu Leu Ala Asp Leu Tyr Val Ile Ile 275 280 285 Pro Ala Thr Leu Asn Pro Ile Ile Tyr Gly Met Arg Thr Lys Gln Leu 290 295 300 Leu Glu Gly Ile Trp Ser Tyr Leu Met His Phe Leu Phe Asp His Ser 305 310 315 320 Asn Leu Gly Ser <210> 27 <211> 975 <212> DNA <213> Homo sapiens <400> 27 atgctgggtc cagcttacaa ccacacaatg gaaacccctg cctccttcct ccttgtgggt 60 atcccaggac tgcaatcttc acatctttgg ctggctatct cactgagtgc catgtacatc 120 acagccctgt taggaaacac cctcatcgtg actgcaatct ggatggattc cactcggcat 180 gagcccatgt attgctttct gtgtgttctg gctgctgtgg acattgttat ggcctcctcc 240 gtggtaccca agatggtgag catcttctgc tcgggagaca gctccatcag ctttagtgct 300 tgtttcactc agatgttttt tgtccactta gccacagctg tggagacggg gctgctgctg 360 accatggctt ttgaccgcta tgtagccatc tgcaagcctc tacactacaa gagaattctc 420 acgcctcaag tgatgctggg aatgagtatg gccgtcacca tcagagctgt cacattcatg 480 actccactga gttggatgat gaatcatcta cctttctgtg gctccaatgt ggttgtccac 540 tcctactgta agcacatagc tttggccagg ttagcatgtg ctgaccccgt gcccagcagt 600 ctctacagtc tgattggttc ctctcttatg gtgggctctg atgtggcctt cattgctgcc 660 tcctatatct taattctcag ggcagtattt gatctctcct caaagactgc tcagttgaaa 720 gcattaagca catgtggctc ccatgtgggg gttatggctt tgtactatct acctgggatg 780 gcatccatct atgcggcctg gttggggcag gatatagtgc ccttgcacac ccaagtgctg 840 ctagctgacc tgtacgtgat catcccagcc actttaaatc ccatcatcta tggcatgagg 900 accaaacaat tgctggaggg aatatggagt tatctgatgc acttcctctt tgaccactcc 960 aacctgggtt catga 975 <210> 28 <211> 320 <212> PRT <213> Homo sapiens <400> 28 Met Ala Glu Thr Leu Gln Leu Asn Ser Thr Phe Leu His Pro Asn Phe 1 5 10 15 Phe Ile Leu Thr Gly Phe Pro Gly Leu Gly Ser Ala Gln Thr Trp Leu 20 25 30 Thr Leu Val Phe Gly Pro Ile Tyr Leu Leu Ala Leu Leu Gly Asn Gly 35 40 45 Ala Leu Pro Ala Val Val Trp Ile Asp Ser Thr Leu His Gln Pro Met 50 55 60 Phe Leu Leu Leu Ala Ile Leu Ala Ala Thr Asp Leu Gly Leu Ala Thr 65 70 75 80 Ser Ile Ala Pro Gly Leu Leu Ala Val Leu Trp Leu Gly Pro Arg Ser 85 90 95 Val Pro Tyr Ala Val Cys Leu Val Gln Met Phe Phe Val His Ala Leu 100 105 110 Thr Ala Met Glu Ser Gly Val Leu Leu Ala Met Ala Cys Asp Arg Ala 115 120 125 Ala Ala Ile Gly Arg Pro Leu His Tyr Pro Val Leu Val Thr Lys Ala 130 135 140 Cys Val Gly Tyr Ala Ala Leu Ala Leu Ala Leu Lys Ala Val Ala Ile 145 150 155 160 Val Val Pro Phe Pro Leu Leu Val Ala Lys Phe Glu His Phe Gln Ala 165 170 175 Lys Thr Ile Gly His Thr Tyr Cys Ala His Met Ala Val Val Glu Leu 180 185 190 Val Val Gly Asn Thr Gln Ala Thr Asn Leu Tyr Gly Leu Ala Leu Ser 195 200 205 Leu Ala Ile Ser Gly Met Asp Ile Leu Gly Ile Thr Gly Ser Tyr Gly 210 215 220 Leu Ile Ala His Ala Val Leu Gln Leu Pro Thr Arg Glu Ala His Ala 225 230 235 240 Lys Ala Phe Gly Thr Cys Ser Ser His Ile Cys Val Ile Leu Ala Phe 245 250 255 Tyr Ile Pro Gly Leu Phe Ser Tyr Leu Thr His Arg Phe Gly His His 260 265 270 Thr Val Pro Lys Pro Val His Ile Leu Leu Ser Asn Ile Tyr Leu Leu 275 280 285 Leu Pro Pro Ala Leu Asn Pro Leu Ile Tyr Gly Ala Arg Thr Lys Gln 290 295 300 Ile Arg Asp Arg Leu Leu Glu Thr Phe Thr Phe Arg Lys Ser Pro Leu 305 310 315 320 <210> 29 <211> 963 <212> DNA <213> Homo sapiens <400> 29 atggcagaaa ctctacaact caattccacc ttcctacacc caaacttctt catactgact 60 ggctttccag ggctaggaag tgcccagact tggctgacac tggtctttgg gcccatttat 120 ctgctggccc tgctgggcaa tggagcactg ccggcagtgg tgtggataga ctccacactg 180 caccagccca tgtttctact gttggccatc ctggcagcca cagacctggg cttagccaca 240 tctatagccc cagggttgct ggctgtgctg tggcttgggc cccgatctgt gccatatgct 300 gtgtgcctgg tccagatgtt ctttgtacat gcactgactg ccatggaatc aggtgtgctt 360 ttggccatgg cctgtgatcg tgctgcggca atagggcgtc cactgcacta ccctgtcctg 420 gtcaccaaag cctgtgtggg ttatgcagcc ttggccctgg cactgaaagc tgtggctatt 480 gttgtacctt tcccactgct ggtggcaaag tttgagcact tccaagccaa gaccataggc 540 catacctatt gtgcacacat ggcagtggta gaactggtgg tgggtaacac acaggccacc 600 aacttatatg gtctggcact ttcactggcc atctcaggta tggatattct gggtatcact 660 ggctcctatg gactcattgc ccatgctgtg ctgcagctac ctacccggga ggcccatgcc 720 aaggcctttg gtacatgtag ttctcacatc tgtgtcattc tggccttcta catacctggt 780 ctcttctcct acctcacaca ccgctttggt catcacactg tcccaaagcc tgtgcacatc 840 cttctctcca acatctactt gctgctgcca cctgccctca accccctcat ctatggggcc 900 cgcaccaagc agatcagaga ccgactcctg gaaaccttca cattcagaaa aagcccgttg 960 taa 963 <210> 30 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Filaggrin F primer <400> 30 aggctccttc aggctacatt c 21 <210> 31 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Filaggrin R primer <400> 31 caggagagta gacatctttt ggca 24 <210> 32 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Keratin 10 F primer <400> 32 caactcacat cagggggagc 20 <210> 33 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Keratin 10 R primer <400> 33 cagctcatcc agcaccctac 20 <210> 34 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> OR1F1 F primer <400> 34 atgtatttcg ttttcatgtt cgtg 24 <210> 35 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR1F1 R primer <400> 35 agaagtgagt gatggcattg tct 23 <210> 36 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR2A4 F primer <400> 36 tggatacaga ccgtgaggga 20 <210> 37 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR2A4 R primer <400> 37 atagcaggaa tgccgatcca 20 <210> 38 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR2D3 F primer <400> 38 cggtatgtgg ctgtctgcaa g 21 <210> 39 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR2D3 R primer <400> 39 agacaggggc caggaggatt a 21 <210> 40 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR2H2 F primer <400> 40 ccatctcact gtggtcaccc tcttc 25 <210> 41 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR2H2 R primer <400> 41 gaatgccctg gttacctcct tgttc 25 <210> 42 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR5C1 F primer <400> 42 tatcacggtg tcttatggct tcatc 25 <210> 43 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> OR5C1 R primer <400> 43 ggctgtagat gagtgggttg ag 22 <210> 44 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR7D2 F primer <400> 44 tgctgggaaa cctgctcatc 20 <210> 45 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR7D2 R primer <400> 45 catcacggtc aggagtagcg 20 <210> 46 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR7E91P F primer <400> 46 cagcatcatc gatagcatgt tca 23 <210> 47 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR7E91P R primer <400> 47 gcaaacaact ggcaggtgag 20 <210> 48 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR10H1 F primer <400> 48 atctccctgt cacatctcac c 21 <210> 49 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> OR10H1 R primer <400> 49 gaacaggtac atcagcagga acag 24 <210> 50 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> OR13D1 F primer <400> 50 cactatgtgg ccatctgcaa cc 22 <210> 51 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR13D1 R primer <400> 51 agccatttgc acatacagca ctc 23 <210> 52 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR52I1 F primer <400> 52 caccatcaga gctgtcacat tca 23 <210> 53 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> OR52I1 R primer <400> 53 acaaccacat tggagccaca ga 22 <210> 54 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR52W1 F primer <400> 54 ctgactggct ttccagggct a 21 <210> 55 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR52W1 R primer <400> 55 gccaggatgg ccaacagtag a 21 <210> 56 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> GAPDH F primer <400> 56 atcaagaagg tggtgaagca g 21 <210> 57 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH R primer <400> 57 gtcgctgttg aagtcagagg 20 <210> 58 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR2AE1 F primer <400> 58 tttggtttgg tgcctgcatc ttc 23 <210> 59 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR2AE1 R primer <400> 59 aacatctctc ctcagcactc ttctc 25 <210> 60 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR2W3 F primer <400> 60 ccttggccat gtctcctgtg a 21 <210> 61 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR2W3 R primer <400> 61 tctgccttcc tgatgctgac c 21 <210> 62 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR10A2 F primer <400> 62 ttctcttccc tgcctactga aatac 25 <210> 63 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> OR10A2 R primer <400> 63 tcccatcagg gtgaccaggt ag 22 <210> 64 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR51B2 F primer <400> 64 agagagccaa agccctcaat acc 23 <210> 65 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR51B2 R primer <400> 65 tgtggacaac ctctggcaca ttc 23 <110> Industry-Academic cooperation foundation Yonsei University <120> Novel Biomarkers for Diagnosing Skin Aging <130> HPC-9617 <160> 65 <170> KoPatentIn 3.0 <210> 1 <211> 322 <212> PRT <213> Homo sapiens <400> 1 Met Gly Asp Arg Arg Ala Asp Pro Arg Pro Met Ser Gly Thr Asn Gln 1 5 10 15 Ser Ser Val Ser Glu Phe Leu Leu Leu Gly Leu Ser Arg Gln Pro Gln 20 25 30 Gln Gln His Leu Leu Phe Val Phe Phe Leu Ser Met Tyr Leu Ala Thr 35 40 45 Val Leu Gly Asn Leu Leu Ile Ile Leu Ser Val Ser Ile Asp Ser Cys 50 55 60 Leu His Thr Pro Met Tyr Phe Phe Leu Ser Asn Leu Ser Phe Val Asp 65 70 75 80 Ile Cys Phe Ser Phe Thr Thr Val Pro Lys Met Leu Ala Asn His Ile 85 90 95 Leu Glu Thr Gln Thr Ile Ser Phe Cys Gly Cys Leu Thr Gln Met Tyr 100 105 110 Phe Val Phe Met Phe Val Asp Met Asp Asn Phe Leu Leu Ala Val Met 115 120 125 Ala Tyr Asp His Phe Val Ala Val Cys His Pro Leu His Tyr Thr Ala 130 135 140 Lys Met Thr His Gln Leu Cys Ala Leu Leu Val Ala Gly Leu Trp Val 145 150 155 160 Val Ala Asn Leu Asn Val Leu Leu His Thr Leu Leu Met Ala Pro Leu 165 170 175 Ser Phe Cys Ala Asp Asn Ala Ile Thr His Phe Phe Cys Asp Val Thr 180 185 190 Pro Leu Leu Lys Leu Ser Cys Ser Asp Thr His Leu Asn Glu Val Ile 195 200 205 Ile Leu Ser Glu Gly Ala Leu Val Met Ile Thr Pro Phe Leu Cys Ile 210 215 220 Leu Ala Ser Tyr Met His Ile Thr Cys Thr Val Leu Lys Val Pro Ser 225 230 235 240 Thr Lys Gly Arg Trp Lys Ala Phe Ser Thr Cys Gly Ser His Leu Ala 245 250 255 Val Val Leu Leu Phe Tyr Ser Thr Ile Ile Ala Val Tyr Phe Asn Pro 260 265 270 Leu Ser Ser His Ser Ala Glu Lys Asp Thr Met Ala Thr Val Leu Tyr 275 280 285 Thr Val Val Thr Pro Met Leu Asn Pro Phe Ile Tyr Ser Leu Arg Asn 290 295 300 Arg Tyr Leu Lys Gly Ala Leu Lys Lys Val Val Gly Arg Val Val Phe 305 310 315 320 Ser Val <210> 2 <211> 2695 <212> DNA <213> Homo sapiens <400> 2 aaggacagga gactaggaag gcggagggag gctgctattg gcagggcctc agtggagacc 60 tcccggggtc ccgggacgca gacggacggg cctgaatcgc tcgccttggt gaaatgggat 120 ccagcgctgc caactgcggc aactgcggtt aaaggagacg accccgtgca gcaggaggag 180 gttatttaga ataaggaaga atgcgccggg ctcattggtc gctacagggg cataaatttt 240 ttctaggatt ccagagtatg gctgctccag tcccagattc ggctcgactt acagacctca 300 gcgcaggacg tggacgccct gcaaaggaca tttcagcgga cggcagagaa tacagattta 360 tgccagcgcc ctgcggaagg agcctctggc gggtcatctc catttatggg agatcgcaga 420 gcggatccca ggcccatgag cgggacaaac cagtcgagtg tctccgagtt cctcctcctg 480 ggactctcca ggcagcccca gcagcagcat ctcctctttg tgttcttcct cagcatgtac 540 ctggccactg tcctggggaa cctgctcatc atcctgtccg taagcataga ctcctgcctg 600 cacaccccca tgtacttctt cctcagcaac ctgtcttttg tggacatctg cttctccttc 660 accaccgtcc ccaagatgct ggccaatcac atactcgaga ctcagaccat ctccttctgt 720 ggctgtctca cacagatgta tttcgttttc atgttcgtgg acatggacaa tttcctccta 780 gctgtgatgg cctatgacca ctttgtcgcc gtgtgccacc ccttacatta cacagcaaag 840 atgacccatc agctctgtgc cctgctggtt gctggattat gggtggttgc caacctgaat 900 gtccttctgc acaccctgct gatggctcca ctctcattct gtgcagacaa tgccatcact 960 cacttcttct gcgatgtgac tcccctactg aaactctcct gctcagacac acacctcaat 1020 gaggtcataa tccttagtga gggtgccctg gtcatgatca ccccatttct ttgcatcctg 1080 gcttcttata tgcacatcac ctgcactgtc ctgaaggtcc catccacaaa gggaaggtgg 1140 aaagccttct ccacctgtgg ttctcacctg gctgtggttc tcctcttcta cagcaccatc 1200 attgctgtgt attttaaccc tctgtcctcc cactcagctg agaaagacac tatggctact 1260 gtgttgtata cagtagtgac tcccatgcta aaccctttca tctacagcct gaggaacagg 1320 tacttgaaag gggctctgaa aaaagtagtt ggcagggtgg tgttttctgt ctgatgaaat 1380 aatcaagact gaatctcatt cccaaggaaa tttatttttc accaattgag tttaatgcag 1440 tagttgtttc attaaatgat gttcttgcta gtgacacact tagtaattat actaagttaa 1500 actattaatt ataatttttt ttgagacagg gtcatgctct gtcacccagg ctggagtgca 1560 gtgccgtgat cttggctcac tgcaccctcc atctcccagg ctcaagtgat cctcctgcct 1620 cagcctcctg agtagctggg accacaggtg tgtgccacat gcctagctaa attttttttt 1680 ttttttttga gacggagtct ctctatgtcg ccaggctgga tgctgttgcg ggaagtcagg 1740 gaccctgaac agagggacca gctggagctg tgtcagagga acataaattg tgaagatttc 1800 attttaatat ggacatgtat cggttcccaa aattaatact tttataattt cttacgcctg 1860 tctttactgc aatctctgaa cataagctgt gaagatttca cggacattta tcagttcccg 1920 aaattaacac ttataatttc tcatgcctgt ctttacttta atctcttaat cctgttatct 1980 tcgtaagctg acgatgtacg tcacctcagg accactgtga taattctacc taactataca 2040 aattgattgt aaaacatgtg tatttgaaca atatgaaatc agtgcacctt gaaaaagaac 2100 agaataacag tgattttagg gaacaaggga agataatcat aaggtctgac tatctgtgga 2160 gttgggcaga atggagccat atttttcttc ttgcagagag cctataaatg gacgtgcaag 2220 tagggatatc actgaattct tttcctagca aggaatgtta ataattaaga ccttgggaga 2280 ggaatgcact cctcggggga ggtctataaa tggctgctct gggagagtct gtcttatgca 2340 gttgagataa ggactgaaat atgccctggt ctcctgcagt accctcaggc ttattagtgt 2400 ggggaaaaaa ccccaccctg gtgaatttaa ggtcagacag attctctgct cttgaaccct 2460 gttttctgtt gtttaagatg tttatcaaga caatacgtgc acagctgaac atagaccctt 2520 atctggaggt tttgattttg tcctttgcct tgtgatctct attggcttca gaggcatgtg 2580 atctttgttc tcctttttgc cctttgacac ctgtgatctc tgtgacctac tccctgttcg 2640 tacaccccca ccccttttaa agtccttaat aaaaacctcc tggttttgcg gctca 2695 <210> 3 <211> 310 <212> PRT <213> Homo sapiens <400> 3 Met Gly Asp Asn Ile Thr Ser Ile Arg Glu Phe Leu Leu Leu Gly Phe 1 5 10 15 Pro Val Gly Pro Arg Ile Gln Met Leu Leu Phe Gly Leu Phe Ser Leu 20 25 30 Phe Tyr Val Phe Thr Leu Leu Gly Asn Gly Thr Ile Leu Gly Leu Ile 35 40 45 Ser Leu Asp Ser Arg Leu His Ala Pro Met Tyr Phe Phe Leu Ser His 50 55 60 Leu Ala Val Val Asp Ile Ala Tyr Ala Cys Asn Thr Val Pro Arg Met 65 70 75 80 Leu Val Asn Leu Leu His Pro Ala Lys Pro Ile Ser Phe Ala Gly Arg 85 90 95 Met Met Gln Thr Phe Leu Phe Ser Thr Phe Ala Val Thr Glu Cys Leu 100 105 110 Leu Leu Val Val Met Ser Tyr Asp Leu Tyr Val Ala Ile Cys His Pro 115 120 125 Leu Arg Tyr Leu Ala Ile Met Thr Trp Arg Val Cys Ile Thr Leu Ala 130 135 140 Val Thr Ser Trp Thr Thr Gly Val Leu Leu Ser Leu Ile His Leu Val 145 150 155 160 Leu Leu Leu Pro Leu Pro Phe Cys Arg Pro Gln Lys Ile Tyr His Phe 165 170 175 Phe Cys Glu Ile Leu Ala Val Leu Lys Leu Ala Cys Ala Asp Thr His 180 185 190 Ile Asn Glu Asn Met Val Leu Ala Gly Ala Ile Ser Gly Leu Val Gly 195 200 205 Pro Leu Ser Thr Ile Val Val Ser Tyr Met Cys Ile Leu Cys Ala Ile 210 215 220 Leu Gln Ile Gln Ser Arg Glu Val Gln Arg Lys Ala Phe Arg Thr Cys 225 230 235 240 Phe Ser His Leu Cys Val Ile Gly Leu Val Tyr Gly Thr Ala Ile Ile 245 250 255 Met Tyr Val Gly Pro Arg Tyr Gly Asn Pro Lys Glu Gln Lys Lys Tyr 260 265 270 Leu Leu Leu Phe His Ser Leu Phe Asn Pro Met Leu Asn Pro Leu Ile 275 280 285 Cys Ser Leu Arg Asn Ser Glu Val Lys Asn Thr Leu Lys Arg Val Leu 290 295 300 Gly Val Glu Arg Ala Leu 305 310 <210> 4 <211> 1758 <212> DNA <213> Homo sapiens <400> 4 atgggagaca atataacatc catcagagag ttcctcctac tgggatttcc cgttggccca 60 aggattcaga tgctcctctt tgggctcttc tccctgttct acgtcttcac cctgctgggg 120 aacgggacca tactggggct catctcactg gactccagac tgcacgcccc catgtacttc 180 ttcctctcac acctggcggt cgtcgacatc gcctacgcct gcaacacggt gccccggatg 240 ctggtgaacc tcctgcatcc agccaagccc atctcctttg cgggccgcat gatgcagacc 300 tttctgtttt ccacttttgc tgtcacagaa tgtctcctcc tggtggtgat gtcctatgat 360 ctgtacgtgg ccatctgcca ccccctccga tatttggcca tcatgacctg gagagtctgc 420 atcaccctcg cggtgacttc ctggaccact ggagtccttt tatccttgat tcatcttgtg 480 ttacttctac ctttaccctt ctgtaggccc cagaaaattt atcacttttt ttgtgaaatc 540 ttggctgttc tcaaacttgc ctgtgcagat acccacatca atgagaacat ggtcttggcc 600 ggagcaattt ctgggctggt gggacccttg tccacaattg tagtttcata tatgtgcatc 660 ctctgtgcta tccttcagat ccaatcaagg gaagttcaga ggaaagcctt ccgcacctgc 720 ttctcccacc tctgtgtgat tggactcgtt tatggcacag ccattatcat gtatgttgga 780 cccagatatg ggaaccccaa ggagcagaag aaatatctcc tgctgtttca cagcctcttt 840 aatcccatgc tcaatcccct tatctgtagt cttaggaact cagaagtgaa gaatactttg 900 aagagagtgc tgggagtaga aagggcttta tgaaaaggat tatggcattg tgactgacag 960 tgacctagga agttacatca ttgagcggtt cttaacccat ctctgcactg gtgggacctc 1020 tgccctcaat ggacatgaga attatctgag acatttattt aaaatggagc tatctcctgc 1080 cctaccttta aatgactgat ttcagcagat gtgggatgaa attctagaaa ttgatctctt 1140 caagttgtgc tgcagccact ccacaccagg acaatacccc ttacaatatc ctcattagct 1200 tttgatccag tcccatacct cccataatgt tttcctcaaa acactggtcc cttcagagga 1260 ctttaaaaat aagttctata gtcaaataag tttgagactt acttcacatc agatgcctct 1320 gtctagggat cacaattcat attagcatag tgaatgctgt aaatatttct ctaggaaaga 1380 ataattctat accagcttta agccagtgtt ttctaaactt atgtgagcac ataaaatttc 1440 ctttgtaata cttagtaaca gtttcctgga acaggagatc ttgatattaa ttgactcatt 1500 gtgaatactt cctacagccc ccttctaggg cagaatgatt tcttttttcc ttgcaaagtg 1560 agcctctaaa gagatgtagt tctgagcatt atgcctcgat cagtctgtaa aaatccgggt 1620 tctgtttgga tacagaccgt gagggaccct gtctctactg ttcaatggta gatcatctaa 1680 agaaaataaa tgcaatcctg tccttcatca tggatcggca ttcctgctat agaagcttca 1740 ggagatgacc tcattcaa 1758 <210> 5 <211> 323 <212> PRT <213> Homo sapiens <400> 5 Met Trp Gln Lys Asn Gln Thr Ser Leu Ala Asp Phe Ile Leu Glu Gly 1 5 10 15 Leu Phe Asp Asp Ser Leu Thr His Leu Phe Leu Phe Ser Leu Thr Met 20 25 30 Val Val Phe Leu Ile Ala Val Ser Gly Asn Thr Leu Thr Ile Leu Leu 35 40 45 Ile Cys Ile Asp Pro Gln Leu His Thr Pro Met Tyr Phe Leu Leu Ser 50 55 60 Gln Leu Ser Leu Met Asp Leu Met His Val Ser Thr Ile Ile Leu Lys 65 70 75 80 Met Ala Thr Asn Tyr Leu Ser Gly Lys Lys Ser Ile Ser Phe Val Gly 85 90 95 Cys Ala Thr Gln His Phe Leu Tyr Leu Cys Leu Gly Gly Ala Glu Cys 100 105 110 Phe Leu Leu Ala Val Met Ser Tyr Asp Arg Tyr Val Ala Ile Cys His 115 120 125 Pro Leu Arg Tyr Ala Val Leu Met Asn Lys Lys Val Gly Leu Met Met 130 135 140 Ala Val Met Ser Trp Leu Gly Ala Ser Val Asn Ser Leu Ile His Met 145 150 155 160 Ala Ile Leu Met His Phe Pro Phe Cys Gly Pro Arg Lys Val Tyr His 165 170 175 Phe Tyr Cys Glu Phe Pro Ala Val Val Lys Leu Val Cys Gly Asp Ile 180 185 190 Thr Val Tyr Glu Thr Thr Val Tyr Ile Ser Ser Ile Leu Leu Leu Leu Leu 195 200 205 Pro Ile Phe Leu Ile Ser Thr Ser Tyr Val Phe Ile Leu Gln Ser Val 210 215 220 Ile Gln Met Arg Ser Ser Gly Ser Lys Arg Asn Ala Phe Ala Thr Cys 225 230 235 240 Gly Ser His Leu Thr Val Val Ser Leu Trp Phe Gly Ala Cys Ile Phe 245 250 255 Ser Tyr Met Arg Pro Arg Ser Gln Cys Thr Leu Leu Gln Asn Lys Val 260 265 270 Gly Ser Val Phe Tyr Ser Ile Ile Thr Pro Thr Leu Asn Ser Leu Ile 275 280 285 Tyr Thr Leu Arg Asn Lys Asp Val Ala Lys Ala Leu Arg Arg Val Leu 290 295 300 Arg Arg Asp Val Ile Thr Gln Cys Ile Gln Arg Leu Gln Leu Trp Leu 305 310 315 320 Pro Arg Val <210> 6 <211> 972 <212> DNA <213> Homo sapiens <400> 6 atgtggcaga agaatcagac ctctctggca gacttcatcc ttgaggggct cttcgatgac 60 tcccttaccc accttttcct tttctccttg accatggtgg tcttccttat tgcggtgagt 120 ggcaacaccc tcaccattct cctcatctgc attgatcccc agcttcatac accaatgtat 180 ttcctgctca gccagctctc cctcatggat ctgatgcatg tctccacaat catcctgaag 240 atggctacca actacctatc tggcaagaaa tctatctcct ttgtgggctg tgcaacccag 300 cacttcctct atttgtgtct aggtggtgct gaatgttttc tcttagctgt catgtcctat 360 gaccgctatg ttgccatctg tcatccactg cgctatgctg tgctcatgaa caagaaggtg 420 ggactgatga tggctgtcat gtcatggttg ggggcatccg tgaactccct aattcacatg 480 gcgatcttga tgcacttccc tttctgtggg cctcggaaag tctaccactt ctactgtgag 540 ttcccagctg ttgtgaagtt ggtatgtggc gacatcactg tgtatgagac cacagtgtac 600 atcagcagca ttctcctcct cctccccatc ttcctgattt ctacatccta tgtcttcatc 660 cttcaaagtg tcattcagat gcgctcatct gggagcaaga gaaatgcctt tgccacttgt 720 ggctcccacc tcacggtggt ttctctttgg tttggtgcct gcatcttctc ctacatgaga 780 cccaggtccc agtgcactct attgcagaac aaagttggtt ctgtgttcta cagcatcatt 840 acgcccacat tgaattctct gattatact ctccggaata aagatgtagc taaggctctg 900 agaagagtgc tgaggagaga tgttatcacc cagtgcattc aacgactgca attgtggttg 960 ccccgagtgt ag 972 <210> 7 <211> 330 <212> PRT <213> Homo sapiens <400> 7 Met Cys Ser Phe Phe Leu Cys Gln Thr Gly Lys Gln Ala Lys Ile Ser 1 5 10 15 Met Gly Glu Glu Asn Gln Thr Phe Val Ser Lys Phe Ile Phe Leu Gly 20 25 30 Leu Ser Gln Asp Leu Gln Thr Gln Ile Leu Leu Phe Ile Leu Phe Leu 35 40 45 Ile Ile Tyr Leu Leu Thr Val Leu Gly Asn Gln Leu Ile Ile Ile Leu 50 55 60 Ile Phe Leu Asp Ser Arg Leu His Thr Pro Met Tyr Phe Phe Leu Arg 65 70 75 80 Asn Leu Ser Phe Ala Asp Leu Cys Phe Ser Thr Ser Ile Val Pro Gln 85 90 95 Val Leu Val His Phe Leu Val Lys Arg Lys Thr Ile Ser Phe Tyr Gly 100 105 110 Cys Met Thr Gln Ile Ile Val Phe Leu Leu Val Gly Cys Thr Glu Cys 115 120 125 Ala Leu Leu Ala Val Met Ser Tyr Asp Arg Tyr Val Ala Val Cys Lys 130 135 140 Pro Leu Tyr Tyr Ser Thr Ile Met Thr Gln Arg Val Cys Leu Trp Leu 145 150 155 160 Ser Phe Arg Ser Trp Ala Ser Gly Ala Leu Val Ser Leu Val Asp Thr 165 170 175 Ser Phe Thr Phe His Leu Pro Tyr Trp Gly Gln Asn Ile Ile Asn His 180 185 190 Tyr Phe Cys Glu Pro Pro Ala Leu Leu Lys Leu Ala Ser Ile Asp Thr 195 200 205 Tyr Ser Thr Glu Met Ala Ile Phe Ser Met Gly Val Val Ile Leu Leu 210 215 220 Ala Pro Val Ser Leu Ile Leu Gly Ser Tyr Trp Asn Ile Ile Ser Thr 225 230 235 240 Val Ile Gln Met Gln Ser Gly Glu Gly Arg Leu Lys Ala Phe Ser Thr 245 250 255 Cys Gly Ser His Leu Ile Val Val Val Leu Phe Tyr Gly Ser Gly Ile 260 265 270 Phe Thr Tyr Met Arg Pro Asn Ser Lys Thr Thr Lys Glu Leu Asp Lys 275 280 285 Met Ile Ser Val Phe Tyr Thr Ala Val Thr Pro Met Leu Asn Pro Ile 290 295 300 Ile Tyr Ser Leu Arg Asn Lys Asp Val Lys Gly Ala Leu Arg Lys Leu 305 310 315 320 Val Gly Arg Lys Cys Phe Ser His Arg Gln 325 330 <210> 8 <211> 518 <212> DNA <213> Homo sapiens <400> 8 atgtgttctt ttttcttgtg ccaaacaggt aaacaggcaa aaatatcaat gggagaagaa 60 aaccaaacct ttgtgtccaa gtttatcttc ctgggtcttt cacaggactt gcagacccag 120 atcctgctat ttatcctttt cctcatcatt tatctgctga ccgtgcttgg aaaccagctc 180 atcatcattc tcatcttcct ggattctcgc cttcacactc ccatgtattt ttttcttaga 240 aatctctcct ttgcagatct ctgtttctct actagcattg tccctcaagt gttggttcac 300 ttcttggtaa agaggaaaac catttctttt tatgggtgta tgacacagat aattgtcttt 360 cttctggttg ggtgtacaga gtgtgcgctg ctggcagtga tgtcctatga ccggtatgtg 420 gctgtctgca agcccctgta ctactctacc atcatgacac aacgggtgtg tctctggctg 480 tccttcaggt cctgggccag tggggcacta gtgtcttt 518 <210> 9 <211> 314 <212> PRT <213> Homo sapiens <400> 9 Met Asp Gly Thr Asn Gly Ser Thr Gln Thr His Phe Ile Leu Leu Gly 1 5 10 15 Phe Ser Asp Arg Pro His Leu Glu Arg Ile Leu Phe Val Val Ile Leu 20 25 30 Ile Ala Tyr Leu Leu Thr Leu Val Gly Asn Thr Thr Ile Ile Leu Val 35 40 45 Ser Arg Leu Asp Pro His Leu His Thr Pro Met Tyr Phe Phe Leu Ala 50 55 60 His Leu Ser Phe Leu Asp Leu Ser Phe Thr Thr Ser Ser Ile Pro Gln 65 70 75 80 Leu Leu Tyr Asn Leu Asn Gly Cys Asp Lys Thr Ile Ser Tyr Met Gly 85 90 95 Cys Ala Ile Gln Leu Phe Leu Phe Leu Gly Leu Gly Gly Val Glu Cys 100 105 110 Leu Leu Leu Ala Val Met Ala Tyr Asp Arg Cys Val Ala Ile Cys Lys 115 120 125 Pro Leu His Tyr Met Val Ile Met Asn Pro Arg Leu Cys Arg Gly Leu 130 135 140 Val Ser Val Thr Trp Gly Cys Gly Val Ala Asn Ser Leu Ala Met Ser 145 150 155 160 Pro Val Thr Leu Arg Leu Pro Arg Cys Gly His His Glu Val Asp His 165 170 175 Phe Leu Arg Glu Met Pro Ala Leu Ile Arg Met Ala Cys Val Ser Thr 180 185 190 Val Ala Ile Glu Gly Thr Val Phe Val Leu Ala Val Gly Val Val Leu 195 200 205 Ser Pro Leu Val Phe Ile Leu Leu Ser Tyr Ser Tyr Ile Val Arg Ala 210 215 220 Val Leu Gln Ile Arg Ser Ala Ser Gly Arg Gln Lys Ala Phe Gly Thr 225 230 235 240 Cys Gly Ser His Leu Thr Val Val Ser Leu Phe Tyr Gly Asn Ile Ile 245 250 255 Tyr Met Tyr Met Gln Pro Gly Ala Ser Ser Ser Gln Asp Gln Gly Met 260 265 270 Phe Leu Met Leu Phe Tyr Asn Ile Val Thr Pro Leu Leu Asn Pro Leu 275 280 285 Ile Tyr Thr Leu Arg Asn Arg Glu Val Lys Gly Ala Leu Gly Arg Leu 290 295 300 Leu Leu Gly Lys Arg Glu Leu Gly Lys Glu 305 310 <210> 10 <211> 945 <212> DNA <213> Homo sapiens <400> 10 atggatggaa ccaatggcag cacccaaacc catttcatcc tactgggatt ctctgaccga 60 ccccatctgg agaggatcct ctttgtggtc atcctgatcg cgtacctcct gaccctcgta 120 ggcaacacca ccatcatcct ggtgtcccgg ctggaccccc acctccacac ccccatgtac 180 ttcttcctcg cccacctttc cttcctggac ctcagtttca ccaccagctc catcccccag 240 ctgctctaca accttaatgg atgtgacaag accatcagct acatgggctg tgccatccag 300 ctcttcctgt tcctgggtct gggtggtgtg gagtgcctgc ttctggctgt catggcctat 360 gaccggtgtg tggctatctg caagcccctg cactacatgg tgatcatgaa ccccaggctc 420 tgccggggct tggtgtcagt gacctggggc tgtggggtgg ccaactcctt ggccatgtct 480 cctgtgaccc tgcgcttacc ccgctgtggg caccacgagg tggaccactt cctgcgtgag 540 atgcccgccc tgatccggat ggcctgcgtc agcactgtgg ccatcgaagg caccgtcttt 600 gtcctggcgg tgggtgttgt gctgtccccc ttggtgttta tcctgctctc ttacagctac 660 attgtgaggg ctgtgttaca aattcggtca gcatcaggaa ggcagaaggc cttcggcacc 720 tgcggctccc atctcactgt ggtctccctt ttctatggaa acatcatcta catgtacatg 780 cagccaggag ccagttcttc ccaggaccag ggcatgttcc tcatgctctt ctacaacatt 840 gtcacccccc tcctcaatcc tctcatctac accctcagaa acagagaggt gaagggggca 900 ctgggaaggt tgcttctggg gaagagagag ctaggaaagg agtaa 945 <210> 11 <211> 312 <212> PRT <213> Homo sapiens <400> 11 Met Val Asn Gln Ser Ser Thr Pro Gly Phe Leu Leu Leu Gly Phe Ser 1 5 10 15 Glu His Pro Gly Leu Glu Arg Thr Leu Phe Val Val Val Leu Thr Ser 20 25 30 Tyr Leu Leu Thr Leu Val Gly Asn Thr Leu Ile Ile Leu Leu Ser Ala 35 40 45 Leu Asp Pro Lys Leu His Ser Pro Met Tyr Phe Phe Leu Ser Asn Leu 50 55 60 Ser Phe Leu Asp Leu Cys Phe Thr Thr Ser Cys Val Pro Gln Met Leu 65 70 75 80 Val Asn Leu Trp Gly Pro Lys Lys Thr Ile Ser Phe Leu Asp Cys Ser 85 90 95 Val Gln Ile Phe Ile Phe Leu Ser Leu Gly Thr Thr Glu Cys Ile Leu 100 105 110 Leu Thr Val Met Ala Phe Asp Arg Tyr Val Ala Val Cys Gln Pro Leu 115 120 125 His Tyr Ala Thr Ile Ile His Pro Arg Leu Cys Trp Gln Leu Ala Ser 130 135 140 Val Ala Trp Val Ile Gly Leu Val Glu Ser Val Val Gln Thr Pro Ser 145 150 155 160 Thr Leu His Leu Pro Phe Cys Pro Asp Arg Gln Val Asp Asp Phe Val 165 170 175 Cys Glu Val Pro Ala Leu Ile Arg Leu Ser Cys Glu Asp Thr Ser Tyr 180 185 190 Asn Glu Ile Gln Val Ala Val Ala Ser Val Phe Ile Leu Val Val Pro 195 200 205 Leu Ser Leu Ile Leu Val Ser Tyr Gly Ala Ile Thr Trp Ala Val Leu 210 215 220 Arg Ile Asn Ser Ala Lys Gly Arg Arg Lys Ala Phe Gly Thr Cys Ser 225 230 235 240 Ser His Leu Thr Val Val Thr Leu Phe Tyr Ser Ser Val Ile Ala Val 245 250 255 Tyr Leu Gln Pro Lys Asn Pro Tyr Ala Gln Glu Arg Gly Lys Phe Phe 260 265 270 Gly Leu Phe Tyr Ala Val Gly Thr Pro Ser Leu Asn Pro Leu Ile Tyr 275 280 285 Thr Leu Arg Asn Lys Glu Val Thr Arg Ala Phe Arg Arg Leu Leu Gly 290 295 300 Lys Glu Met Gly Leu Thr Gln Ser 305 310 <210> 12 <211> 3061 <212> DNA <213> Homo sapiens <400> 12 gataatctga gccagctcca gctcatcaca cacatgtgtg cttagaaaag tgccagatgg 60 tcagcattag caatccctat tgtgaccaga gatgcagttg cccattcaag gatgcccatt 120 cctttttatt tttttgtttc ttcctgatgt acaagtggag gctgggcacc agttaagagc 180 tctgtcatgg ggaattgctg gtaccagaag agatttttat ttgattgaag gaagtcagag 240 gcaccagtgt gagtatccat ctgctgtcca gtacattcat ggattcctca ctctcactag 300 acaatgtttg accaggaaga acagggaatg agaaggagct gctggatggt gatgagcctt 360 ggaaagggag gctgggcgag cagagacaga agagaaacac ctacctgctg tgacctcaca 420 aacacccagg ctgagttttg ataagacagg ttgaatcaca ctggagtgac agcctcatcc 480 ctccaggtac aaacaagaac aggccatggt taaccaaagc tccacaccgg gcttcctcct 540 tctgggcttc tctgaacacc cagggctgga aaggactctc ttcgtggttg tcctcacttc 600 ctacctccta accctagtgg gcaacacact catcatcctg ctgtctgcgc tggaccccaa 660 gctccactct ccaatgtact ttttcctctc caacctctcc ttcttggacc tctgtttcac 720 cacgagttgt gttccccaaa tgctggtcaa cctctggggc ccaaagaaga ccatcagctt 780 cctggactgc tctgtccaga tcttcatctt cctgtccctg gggacaactg agtgcatcct 840 cttgacagtg atggcttttg atcgctacgt ggctgtctgc cagcccctcc actatgccac 900 catcatccac ccccgcctgt gctggcagct ggcatctgtg gcctgggtca ttgggctagt 960 ggagtcagtg gtccagacac catccaccct gcacctgccc ttctgccccg atcggcaggt 1020 ggatgatttt gtctgtgagg tcccagctct aattcgactc tcctgtgaag acacctccta 1080 caatgagatc caggtggctg ttgccagtgt cttcatcttg gttgtgcctc tcagcctcat 1140 ccttgtctct tacggagcca ttacctgggc agtgctgagg attaactctg caaaagggcg 1200 gaggaaagct tttgggacct gctcctccca tctcactgtg gtcaccctct tctacagctc 1260 agtcattgct gtctacctcc agcccaaaaa tccctatgcc caagagaggg gcaagttctt 1320 tggtctcttc tatgcagtgg gcactccttc acttaaccct ctcatataca ccctgaggaa 1380 caaggaggta accagggcat tcaggagatt gctggggaag gaaatggggc tcacacaaag 1440 ctgagggaga gctgcttaat gtgctttaaa agagaggaga ttctatgtgc ttttatcaga 1500 aagtttgagt tccctgcccc tctgccttct tcacacccat tacattgtgg gaatggatga 1560 aagccacatg tctgtgtgtg tgcatgtatg tgtgcaagag acagcgactg aaatgtagta 1620 aagggaggta tctttatgcg aaaaattata ggcatcaagt atattttata tttttttcta 1680 ctttaagtct tcgcctccat agtcatgttc ctacctttat cacttccatt tttaattccc 1740 ctcccttgcc atatccccac tattccttca cctccaattc taattcctac catatcttct 1800 ttgcttctcc ctcatgtttt tcccacttca ctatatgtct gttttgtatt ctcattctat 1860 tttattcctc aaataacagc aaaagagaag gggaagctga agcccagcta agttcggaaa 1920 ctcacccaag aacacacagt gtccacagca tcagaactaa aatccaggcc ccataatttt 1980 cagtcaggca actctcaaat acacactgtt gctttcacac cataatcaaa tatcccagta 2040 tttcaggctt gagccttaca aaggaaactt agcttcttca gtcctatttc ttctcttaca 2100 atgcccacaa atcgcaggta aaggagcagc caaaaagaca caaaaatatc ttcatgttta 2160 ggctggcaca ttgtggacct tggtgtcatc taccggccaa atatggtatt gcatgtgaca 2220 tcccagactt ctgctccagg gtcatccgaa ctgtactttg ctcaaagaca tagatatggt 2280 tatgatacta taagcattta tgtaattgtt atgttaaccc aagtaacact taaagtacag 2340 atgctccttg acttataatg atgttacctc ccaaaaaacc tatcatatac tgaaaatatt 2400 gtaagttgaa tatgcatttc atacacctaa cctaccaaac atcatagctt agcctagcct 2460 accttaaaca tactcagaac acttacatta gcctacagtt cagcaaaatc ctcaatacaa 2520 agtctatttt ataataaagt tttgaatatc tcatgtaatt tactgaatac tgtactaaaa 2580 gtgaaaaaac agaatggtta tattggtact caaagtacgg tttctactga atgtatctct 2640 tttgcattat tataaagtca aaaaatggtc aaagtcagga accccctgca atttacacat 2700 attgacttat ttaaccctta taacaacact atgaagcaga taatattatt atcctttttc 2760 agaggtaaaa actaaaacac agaatttatg ttaccacttg caaatgtgca agacaggatt 2820 tgaacccagg aaaactggct ccagactcct tgctcttaac cttgcctttt ggtaaaaata 2880 atgcctccca ggcccaggtg aaaagcttca acttctcaac aagctttgag gaaatcattt 2940 caatctaaaa ctatatctaa atgatccccc agccgaaggg gtttcacttc cttaaaataa 3000 gagtttttca aatacttcaa agcataagaa acaacagaac aataaaactt ttggaaaaag 3060 t 3061 <210> 13 <211> 320 <212> PRT <213> Homo sapiens <400> 13 Met Asn Ser Glu Asn Leu Thr Arg Ala Ala Val Ala Pro Ala Glu Phe 1 5 10 15 Val Leu Leu Gly Ile Thr Asn Arg Trp Asp Leu Arg Val Ala Leu Phe 20 25 30 Leu Thr Cys Leu Pro Val Tyr Leu Val Ser Leu Leu Gly Asn Met Gly 35 40 45 Met Ala Leu Leu Ile Arg Met Asp Ala Arg Leu His Thr Pro Met Tyr 50 55 60 Phe Phe Leu Ala Asn Leu Ser Leu Leu Asp Ala Cys Tyr Ser Ser Ala 65 70 75 80 Ile Gly Pro Lys Met Leu Val Asp Leu Leu Leu Pro Arg Ala Thr Ile 85 90 95 Pro Tyr Thr Ala Cys Ala Leu Gln Met Phe Val Phe Ala Gly Leu Ala 100 105 110 Asp Thr Glu Cys Cys Leu Leu Ala Ala Met Ala Tyr Asp Arg Tyr Val 115 120 125 Ala Ile Arg Asn Pro Leu Leu Tyr Thr Thr Ala Met Ser Gln Arg Leu 130 135 140 Cys Leu Ala Leu Leu Gly Ala Ser Gly Leu Gly Gly Ala Val Ser Ala 145 150 155 160 Phe Val His Thr Thr Leu Thr Phe Arg Leu Ser Phe Cys Arg Ser Arg 165 170 175 Lys Ile Asn Ser Phe Phe Cys Asp Ile Pro Leu Leu Ala Ile Ser 180 185 190 Cys Ser Asp Thr Ser Leu Asn Glu Leu Leu Leu Phe Ala Ile Cys Gly 195 200 205 Phe Ile Gln Thr Ala Thr Val Leu Ala Ile Thr Val Ser Tyr Gly Phe 210 215 220 Ile Ala Gly Ala Val Ile His Met Arg Ser Val Glu Gly Ser Arg Arg 225 230 235 240 Ala Ala Ser Thr Gly Gly Ser His Leu Thr Ala Val Ala Met Met Tyr 245 250 255 Gly Thr Leu Ile Phe Met Tyr Leu Arg Pro Ser Ser Ser Tyr Ala Leu 260 265 270 Asp Thr Asp Lys Met Ala Ser Val Phe Tyr Thr Leu Val Ile Pro Ser 275 280 285 Leu Asn Pro Leu Ile Tyr Ser Leu Arg Asn Lys Glu Val Lys Glu Ala 290 295 300 Leu Arg Gln Thr Trp Ser Arg Phe His Cys Pro Gly Gln Gly Ser Gln 305 310 315 320 <210> 14 <211> 963 <212> DNA <213> Homo sapiens <400> 14 atgaactcag agaacctcac ccgggccgcg gttgcccctg ctgaattcgt cctcctgggc 60 atcacaaatc gctgggacct gcgtgtggcc ctcttcctga cctgcctgcc tgtctacctg 120 gtgagcctgc tgggaaacat gggcatggcg ctgctgatcc gcatggatgc ccggctccac 180 acacctatgt acttcttcct ggccaacctc tccctgctgg atgcctgcta ttcctccgcc 240 atcggcccca agatgctagt ggacctgctg ctgccccgag ccaccatccc ttacacagcc 300 tgtgccctcc agatgtttgt ctttgcaggt ctggctgata ctgagtgttg cttgctggca 360 gccatggcct atgaccgcta cgtggccatc agaaacccac ttctctatac aacagctatg 420 tcgcagcgtc tatgcctggc cttgctggga gcatcaggcc tgggtggggc agtgagtgcc 480 tttgttcaca caaccctcac cttccgcctg agcttctgcc gctcccggaa gatcaatagc 540 ttcttctgcg atatccctcc actgctggcc atctcgtgca gtgacaccag tctcaatgaa 600 ctccttctct tcgccatctg tggcttcatc cagacagcca cggtgttagc tatcacggtg 660 tcttatggct tcatcgctgg ggctgtgatc cacatgcgct cggtcgaggg cagtcggcga 720 gcagcctcca ccggtggttc ccacctcaca gccgtggcca tgatgtacgg gacactcatt 780 ttcatgtacc tgcgccccag ctccagctat gccctggaca ctgacaagat ggcctctgtg 840 ttctataccc tggtcatccc gtctctcaac ccactcatct acagcctccg caataaggag 900 gtcaaggagg ccctcaggca gacctggagc cgattccact gtccagggca ggggtcccag 960 tga 963 <210> 15 <211> 312 <212> PRT <213> Homo sapiens <400> 15 Met Glu Ala Gly Asn Gln Thr Gly Phe Leu Glu Phe Ile Leu Leu Gly 1 5 10 15 Leu Ser Glu Asp Pro Glu Leu Gln Pro Phe Ile Phe Gly Leu Phe Leu 20 25 30 Ser Met Tyr Leu Val Thr Val Leu Gly Asn Leu Leu Ile Ile Leu Ala 35 40 45 Ile Ser Ser Asp Ser His Leu His Thr Pro Met Tyr Phe Phe Leu Ser 50 55 60 Asn Leu Ser Trp Val Asp Ile Cys Phe Ser Thr Cys Ile Val Pro Lys 65 70 75 80 Met Leu Val Asn Ile Gln Thr Glu Asn Lys Ala Ile Ser Tyr Met Asp 85 90 95 Cys Leu Thr Gln Val Tyr Phe Ser Met Phe Phe Pro Ile Leu Asp Thr 100 105 110 Leu Leu Leu Thr Val Met Ala Tyr Asp Arg Phe Val Ala Val Cys His 115 120 125 Pro Leu His Tyr Met Ile Ile Met Asn Pro His Leu Cys Gly Leu Leu 130 135 140 Val Phe Val Thr Trp Leu Ile Gly Val Met Thr Ser Leu Leu His Ile 145 150 155 160 Ser Leu Met Met His Leu Ile Phe Cys Lys Asp Phe Glu Ile Pro His 165 170 175 Phe Phe Cys Glu Leu Thr Tyr Ile Leu Gln Leu Ala Cys Ser Asp Thr 180 185 190 Phe Leu Asn Ser Thr Leu Ile Tyr Phe Met Thr Gly Val Leu Gly Val 195 200 205 Phe Pro Leu Leu Gly Ile Ile Phe Ser Tyr Ser Arg Ile Ala Ser Ser 210 215 220 Ile Arg Lys Met Ser Ser Ser Gly Gly Lys Gln Lys Ala Leu Ser Thr 225 230 235 240 Cys Gly Ser His Leu Ser Val Val Ser Leu Phe Tyr Gly Thr Gly Ile 245 250 255 Gly Val His Phe Thr Ser Ala Val Thr His Ser Ser Gln Lys Ile Ser 260 265 270 Val Ala Ser Val Met Tyr Thr Val Val Thr Pro Met Leu Asn Pro Phe 275 280 285 Ile Tyr Ser Leu Arg Asn Lys Asp Val Lys Gly Ala Leu Gly Ser Leu 290 295 300 Leu Ser Arg Ala Ala Ser Cys Leu 305 310 <210> 16 <211> 3286 <212> DNA <213> Homo sapiens <400> 16 ccacactcat gcatcttaga gaggagagtt aggatgactt catgacaagt tccatctccc 60 cgcctttccc tgctagattc tgtcttcagc attcaacagt caggggagga agacgtcata 120 ccagcatttt tttttttcaa gcaatctttc catgatgagt acaaagcctt ggggaatatc 180 tggataaagt aaaattttct agaatgtgat ctggacttgc cacaaagaaa cttcagatac 240 atcagctaca tggaagcagg aaaccaaaca ggatttttag agtttatcct tctcggactc 300 tctgaggatc cagaactaca gccgttcata tttgggctgt tcctgtccat gtacctggtg 360 acggtgctgg gaaacctgct catcatcctg gccatcagct ctgactccca cctccacacc 420 cccatgtact tcttcctctc caacctgtcc tgggttgaca tctgtttcag cacttgcatc 480 gtccccaaga tgctggtgaa catccagacc gagaacaaag ccatctccta catggactgc 540 ctcacacagg tctatttctc catgtttttt cctattctgg acacgctact cctgaccgtg 600 atggcctatg accggtttgt ggctgtctgc caccctctgc actatatgat catcatgaac 660 ccccacctct gtggcctcct ggtttttgtc acctggctca ttggtgtcat gacatccctc 720 ctccatattt ctctgatgat gcatctaatc ttctgtaaag attttgaaat tccacatttt 780 ttctgcgaac tgacgtacat cctccagctg gcctgctctg ataccttcct gaacagcacg 840 ttgatatact ttatgacggg tgtgctgggc gtttttcccc tccttgggat cattttctct 900 tattcacgaa ttgcttcatc cataaggaag atgtcctcat ctgggggaaa acaaaaagca 960 ctttccacct gtgggtctca cctctccgtc gtttctttat tttatgggac aggcattggg 1020 gtccacttca cttctgcggt gactcactct tcccagaaaa tctccgtggc ctcggtgatg 1080 tacactgtgg tcacccccat gttgaacccc ttcatctaca gcctgaggaa caaggatgtg 1140 aagggagccc tggggagtct cctcagcagg gcagcctctt gtttgtgatg gatcccttgg 1200 ccccaggact aagaagtttt gtgagcacca atggcaaaaa tgttttattt tgaaattctt 1260 actctttaaa attaaaaaca tttttttata ctttgagagt acaaatgcag atttcttaac 1320 atgcatttgc ataagggtga agtctgagct tttggcgtac caattacctg aatagtgaac 1380 ataaggcact tttttttctt ttttgagacg gagtctcact ctgtctccca ggctggagtg 1440 cagtggagtg atctcggctc actgcaacct ccgcctcccg ggttcaagtg attcttctgt 1500 ctcagcctcc tgagtagctg agattacagg tgtgtgccac ccatgccttt tagtagagac 1560 ggggtttcac catcttggcc aggctggtct cgaactcctg accttgtgat ccacctgcct 1620 tggcctctca aagtgctggg attacaggtg tgagccacca cgcccggcca aggcagtttt 1680 taaactctca ctcccctctc accttttgca gtctccagtg tccattattc tgttataatg 1740 cccatgcgta tacattgttt agctcccaat tataagtgag atcatgcagc atttgacttt 1800 gtttctttac taccttactt aagagaatgg cttccagtcc catcgatgtt gctgcaaaag 1860 acatgatttc atcctttttt atggctgagt agtactccat tgtatatatc ctcgatatct 1920 atatagatat agacatatgt agatacatac catgttttct ttttttaaaa aaatttattt 1980 ttatgtcagt agtttttggg gtacatgtgg tttttcatta cacggatgag ttctttagtg 2040 gtgacttctg agtttttagt gtacccgtca cccaagtggt agtagtctct tattcctcac 2100 ccccctccca acctttctcc cttcaagtca ccaaagttca ttatattgtt catatccctt 2160 tgtgtcctca tagcttagct cccacttata actgagaaca tacgatatgt tcatatggat 2220 cttatgtatg ttggttgaac atacaaacaa gtccaggttt ttcattcctg agttacttca 2280 cctagagtaa tgacctccag ttccatccaa gttgctacaa aagacattat ttggttcctt 2340 tttatggata agtagtattc catgctgtac atataccaca atctttatca ctcattggtt 2400 gatgggcact taggttggtt ccatgccttt gtaattgcta attatgttgc tataaacatg 2460 caggtgtatg tgtctttttc acataatgac tttgtttcct ttgggtagat acccagtagt 2520 ggaactgctg gactgaaagg tagttctact tttagttctt ttttttgttt tttttttaag 2580 acagagtctc actctgttgc ccaggctgga gtgcagtggc gcgatctcat ctcactgcaa 2640 cctccacctc ccaggttcaa gcgattctcc tgcctcaacc tcctgagtag ctgggactac 2700 aggcacctgc caccccaccc agctaattct tctattttta gtagagacag ggtttcacca 2760 tgttggccag gctggtcttg aactcctgac ctcaggtgat acgcccacct cggcctccca 2820 aagtgctggg attacaggtg tgagccactg tgcctggcct tctagttctt taagatacca 2880 ctttaaaaaa agtccagtcc tccattgatg gacacgtagg ttgattccat atctttgcta 2940 atgtgaatag tgccgtgata aacatggggg tgtaagttaa caattaatct ccaagtaatt 3000 tccttgatgg cacttctgtc ctatgtgcta ttcaaaaatt gtgtccttga tcatcgttct 3060 taattctcca ttagtgagtt ctgaacttgg gtttgaagca tttgctatag ctttgttatc 3120 tcaagtggtg gcacagagtt cttaagctat tgattgttca ctgactttat ttctatgtgt 3180 ttgcatgtgg gtttttgttg tttgtgtgtt cgatcatgaa cagatcaaca gtgtttattt 3240 gttttcctac tggatgaagt atgattaaaa tacgtattta aatata 3286 <210> 17 <211> 502 <212> DNA <213> Homo sapiens <400> 17 ggtgtgttac ctgccgacag cataatgtga ggcaaggtcc agccgttccg cccagcatac 60 aagcttatgg agcagccccc tttggagatc tccaggtaga cttcagagag atgccaaagt 120 gtggagatct gattcctaga tttcgactgc ccttacggat cggctcacat aacgggcctg 180 cgtttttggc tgccatggta cagaagacgg caaaggtgtc caagtcacac agagccacgg 240 aatctcacag gagcctgaga actcctcctc ctgggactct cagaggatcc agaactgcag 300 cccatcctcg ctgggctgtc cctgtccatg tatctggtca cggtgctgag gaacctcctc 360 atcagcctgg ctgtcagctc tgactcccac ctccacaccc caatgtgctt cttcctctcc 420 aacctgtgct gggctgacat cggtttcacc tcggccacgg ttcccaagat gattgtggac 480 atgcggtcgc atagcggagt ca 502 <210> 18 <211> 303 <212> PRT <213> Homo sapiens <400> 18 Met Ser Phe Ser Ser Leu Pro Thr Glu Ile Gln Ser Leu Leu Phe Leu 1 5 10 15 Thr Phe Leu Thr Ile Tyr Leu Val Thr Leu Met Gly Asn Cys Leu Ile 20 25 30 Ile Leu Val Thr Leu Ala Asp Pro Met Leu His Ser Pro Met Tyr Phe 35 40 45 Phe Leu Arg Asn Leu Ser Phe Leu Glu Ile Gly Phe Asn Leu Val Ile 50 55 60 Val Pro Lys Met Leu Gly Thr Leu Leu Ala Gln Asp Thr Thr Ile Ser 65 70 75 80 Phe Leu Gly Cys Ala Thr Gln Met Tyr Phe Phe Phe Phe Phe Phe Gly Val 85 90 95 Ala Glu Cys Phe Leu Leu Ala Thr Met Ala Tyr Asp Arg Tyr Val Ala 100 105 110 Ile Cys Ser Pro Leu His Tyr Pro Val Ile Met Asn Gln Arg Thr Arg 115 120 125 Ala Lys Leu Ala Ala Ala Ser Trp Phe Pro Gly Phe Pro Val Ala Thr 130 135 140 Val Gln Thr Thr Trp Leu Phe Ser Phe Pro Phe Cys Gly Thr Asn Lys 145 150 155 160 Val Asn His Phe Phe Cys Asp Ser Pro Pro Val Leu Arg Leu Val Cys 165 170 175 Ala Asp Thr Ala Leu Phe Glu Ile Tyr Ala Ile Val Gly Thr Ile Leu 180 185 190 Val Val Met Ile Pro Cys Leu Leu Ile Leu Cys Ser Tyr Thr His Ile 195 200 205 Ala Ala Ala Ile Leu Lys Ile Pro Ser Ala Lys Gly Lys Asn Lys Ala 210 215 220 Phe Ser Thr Cys Ser Ser His Leu Leu Val Val Ser Leu Phe Tyr Ile 225 230 235 240 Ser Leu Ser Leu Thr Tyr Phe Arg Pro Lys Ser Asn Asn Ser Pro Glu 245 250 255 Gly Lys Lys Leu Leu Ser Leu Ser Tyr Thr Val Met Thr Pro Met Leu 260 265 270 Asn Pro Ile Ile Tyr Ser Leu Arg Asn Asn Glu Val Lys Asn Ala Leu 275 280 285 Ser Arg Thr Val Ser Lys Ala Leu Ala Leu Arg Asn Cys Ile Pro 290 295 300 <210> 19 <211> 5390 <212> DNA <213> Homo sapiens <400> 19 actagcccca agaacaaaag aggcacaggt gggaacaact ctcccaaaac caggactggg 60 agcatggcca aacttcatag tgagcttact tgcctctgac acacaaggca gcagtgagct 120 ggctacagct ccagccatta atagctcagc caggacaggg aataagactt ccctggttct 180 tcttttggct ttgctgaaac agaaatagag ctgttatatt acatgcatga aggacatgca 240 tgaagcatgg atgtcagcca gagttgaaca aggcagatgt tcctgttgga cacagtaaga 300 acgagtctga aaaacaaatt gagaatctga cttccaatca ataatctttc tccatgacca 360 cagttgggga cttctgccca cacttatagc tacaggaaac tggacaagaa taagtgagtt 420 tatcctcatg agcttctctt ccctgcctac tgaaatacag tcattactct ttctgacatt 480 tctaaccatc tacctggtca ccctgatggg aaactgcctc atcattctgg tacccctagc 540 tgaccccatg ctacacagcc ccatgtactt cttcctcaga aacttatctt tcctggagat 600 tggcttcaac ctagtcattg tgcccaaaat gctggggacc ctgcttgccc aggacacaac 660 catctccttc cttggctgtg ccactcagat gtatttcttc ttcttctttg gagtggctga 720 atgcttcctc ctggctacca tggcatatga ccgctatgtg gccatctgca gtcccttgca 780 ctacccagtc atcatgaacc aaaggactcg tgccaaactg gctgctgcct cctggttccc 840 aggctttcct gtagctactg tgcagaccac atggctcttc agttttccat tctgtggcac 900 caacaaggtg aaccacttct tctgtgacag cccacctgtg ctgaggctgg tctgtgcaga 960 cacagcactc tttgagatct acgccatcgt cggaaccatt ctggtggtca tgatcccctg 1020 cttgctgatc ttgtgttcct atactcacat tgctgctgcc atcctcaaga tcccatcagc 1080 taaagggaag aataaagcct tttctacatg ttcctcacac ctccttgttg tctctctttt 1140 ctatatatca ttaagcctca cctacttccg gcctaaatca aataattcac ctgagggcaa 1200 gaagctgcta tcattgtcct acactgttat gactcccatg ttgaacccca ttatctacag 1260 cctgagaaat aacgaggtga agaatgccct cagcaggacg gtctctaagg ccctagccct 1320 cagaaactgt atcccataga ccttaggaag taaggctaca ttttactgga tgagaaacaa 1380 tcagtcccag atttgagatt cctctctgca tctttccaca tctccaataa gatgaagtcc 1440 tgttgctgaa atggcttttg gaaagctgag tggagagaaa ggagcagaga agtagtttcg 1500 acctagcacc accaactatg aaaactcctc tgcctgccca ttgtagactt acatgtttt 1560 ccttgtttca actggtatga cagcacttct gtggccaact atttccaggt gttatatttc 1620 tttttttttt tttttttgag acggagtctc gctctgtccc ccaggctgga gtgcagtggc 1680 gcatctctgc tcactgcaag ctccgcctcc tgggttcacg ctgttctcct gcctcagcct 1740 cccaagtagc tgggactaca ggtgcccgcc accatgcccg gctaattttt tgtatttttt 1800 tagtagagac agggtttcac cgtgttagcc aggatggtct cgatctcctg acctcgtgat 1860 ccacccgcct cggcctccca aagtgctggg attacaggcg tgagccaccg cgcctggccg 1920 gtgtttatat ttctgtgtga cgtgcattgt gcacaatatg aaactgctag tcattataac 1980 atgggggcac acatagtaac agagggtaaa acccaataaa aatcatcttg tcacttttcc 2040 tcttctgggc agatctgact ctacattcat gacagaaaat ctcatgatct ttcccaacac 2100 ataactctcc tcaccatctt acttcattct catgccctta agcagtgtta gttcttttaa 2160 gcttactggt atgcagtatg catgtatgag agtagatcaa aagttcacat gcatatgcct 2220 ttataacccc aataattatt tccttcacac tagattcttc ccaagaaaaa caacctgagc 2280 ttccctaaga tctctattcc atattcaggt tcttatgttt tgttgaagta atatcgtaaa 2340 tttcagtcat agctttgctt tgatgagaac aaagctccag aataagtctt ctttaaccac 2400 aagatttctc cttcttataa tctggtagta ctctatttgt agatgtgccc taatttattt 2460 agccagtctt ttactactac aaatcatgct gtaaataatg gacttatcca tatatctgtt 2520 tttatatttt tgctagtgta cctgacaaat agaaatctag aaattgagtt tcttgggcaa 2580 aagttaaata catacataat gttgctatat atattgattg tctatctagc tcccctctga 2640 acttattgca ccattttatg ctcccaccag caatttatga ggtgtttgtt tccccacaac 2700 tcaacaataa catttctcat gaaatattta gaatttcgat tatttaatat tttataaaaa 2760 ctcaatgaaa ttttaatttg aatgaaataa attttgaaga ataagaaaga aacagatgat 2820 caaatcagag gaaaggtgtg catttcattg aaacttgagt tatagattag acgattagca 2880 attggtgatg tcttggtgtt ttattttctc ttcttgaaag gttgtttttc acttttattt 2940 tagccaaatc tatcccatct ctcaagaccc cactgtgatt cctcaagaag cagaaatcac 3000 tctttctgta tgcacccatt tcaagtttat taataaatac attaaatttt gtatatacta 3060 catgtagaaa ctgtacatgt acttattttt acatgtttgt cttcctccaa cttttctgta 3120 actcttcaaa aataagaatt gttcaagtgt ttctggtgtt ttgttttgtg tttgagacag 3180 ggtctctctc tctgtcaccc aggctggact gcggtagcag aattatggct cactgtagcc 3240 tcaaacacct gggctcaggc catcttcctg cctcagtctc cctagtggct gggactatag 3300 gcgtacatca ccatgcctgg ccatttaaaa attttttttt agtagagacg aggtcttgct 3360 atgctaccca gtctggtatc gaacttctga gttcaagcaa tccttctgcc tgaacctctc 3420 aaagtgctgg gattataagt gtgagccatt gcatgcaaca caagtgtttc tcttttcttt 3480 tctttctttt tttttttttt tttttttgag acaaaggtct gctctattac tcaggctgct 3540 ggggtgcaat ggcacaatct tggctcactg caacttctgc cttctgggtt caatcaattc 3600 tcatgcctca gcctcttgag tagctgggat tacaggcgtg ccaagccatg cccaactaat 3660 ttttttttttg tattttttag tagagatgca gttttaccat gttggagctc ctggcctcaa 3720 gtgatctgcc tgcctcagcc tcccaagggc tgggattaca gacgtgggcc accatgccag 3780 gccaagtatt tcccttttaa tatgacgtag gcattcctga aaagcttatg taatgcaaac 3840 ctttacatta aaaatattat ggggaagtag ggctagggtt agggctagac tcaaaataca 3900 tgcaacttta aagacaaggc attagtagaa acaacatttg gttcccagag agacaatgta 3960 gactgcccag gcaggcagct cattgaggct ggaggttgcc acagtagata tttaaaatat 4020 acaacaacag tagaatgaaa ataccaacaa tgcttggatt agaacaatga tgcttgatgc 4080 tgagacaatt tgtactgggg tagggggtag tccttagtat gggtaaagaa tttgaagtaa 4140 agcaaacaag aataacccaa aacctaaaga aaaagttgta catagtttca gggaaaggat 4200 tccaacagaa gagtgccaca tgcacaaaca caggagtgct gagagactat gatgtgtgta 4260 aggaacacaa agcatttttg tgtcactgaa aaatcagcta cactggggat ttgaaactgg 4320 aaaaataagc agagatcaca ggaaaagacc ttgttaaagg atttacttta tcccaggggc 4380 catacggagt aattgaaaga cattaagcag gtaagtgact taaccagagt tgctggttaa 4440 gacagcaact ggtaagacag ttgctgataa gacagatcac atacaaacca aggatggttt 4500 gaagagaatg aaccagaagc aggttcctac catactctag gccagagaaa ataaatccag 4560 aacctaaagg cagtggtggt agagctggag aaggtgacac tgaattagtg tttaggagta 4620 aaaataatca aatttggggc acaaattaaa ggattatatc ccagttcctg gcttgtactt 4680 tggggtggtg ccatttactg aaatggggta tctacaaaga ggaggtttga ggtggaggaa 4740 gcagacaagc acatttatat ctcttatcat tgtttcagtc cgtgtgaatt gtatgatgct 4800 atattatatt cttttgtgcc tttgtctaaa ttccttatga atggggctca ctgtacctac 4860 tttgtgtctg tgtagatgtt tccctgatta tttaccacat tttcttcatt atctattaaa 4920 ttattcaata acaatttact gggcatctac ctttctaggc attggggtaa aaaaatgaat 4980 aacacaattt ctatttcaag gagcatgtca tctactgtat gagacaaata catacaataa 5040 tgattattct aaaataagaa ctatgaaagt ggtattccag ttctccaatg tactaatat 5100 attgaaattt tctgcccatc tttagaaatt gtgttgcttt gttcttacta ccaccctgta 5160 ctggatactg gcttgtcctc acctgtgggc tcagatttat tcccattctg aaaaaatgag 5220 tgcaagtgtc acttgtcggc caaatccctg acttggactc agccacccag gattccaaca 5280 cttgctgaaa aaactactca acttatctgt gtctcagatt ccttgactgt aaaatgggta 5340 taatactatc tgtatcttca ggtgttgtga gaatcaaata agataataca 5390 <210> 20 <211> 318 <212> PRT <213> Homo sapiens <400> 20 Met Gln Arg Ala Asn His Ser Thr Val Thr Gln Phe Ile Leu Val Gly 1 5 10 15 Phe Ser Val Phe Pro His Leu Gln Leu Met Leu Phe Leu Leu Phe Leu 20 25 30 Leu Met Tyr Leu Phe Thr Leu Leu Gly Asn Leu Leu Ile Met Ala Thr 35 40 45 Val Trp Ser Glu Arg Ser Leu His Thr Pro Met Tyr Leu Phe Leu Cys 50 55 60 Ala Leu Ser Val Ser Glu Ile Leu Tyr Thr Val Ala Ile Ile Pro Arg 65 70 75 80 Met Leu Ala Asp Leu Leu Ser Thr Gln Arg Ser Ile Ala Phe Leu Ala 85 90 95 Cys Ala Ser Gln Met Phe Phe Ser Phe Ser Phe Gly Phe Thr His Ser 100 105 110 Phe Leu Leu Thr Val Met Gly Tyr Asp Arg Tyr Val Ala Ile Cys His 115 120 125 Pro Leu Arg Tyr Asn Val Leu Met Ser Pro Arg Gly Cys Ala Cys Leu 130 135 140 Val Gly Cys Ser Trp Ala Gly Gly Leu Val Met Gly Met Val Val Thr 145 150 155 160 Ser Ala Ile Phe His Leu Ala Phe Cys Gly His Lys Glu Ile His His 165 170 175 Phe Ala Cys His Val Pro Leu Leu Lys Leu Ala Cys Gly Asp Asp 180 185 190 Val Leu Val Val Ala Lys Gly Val Gly Leu Val Cys Ile Thr Ala Leu 195 200 205 Leu Gly Cys Phe Leu Leu Ile Leu Leu Ser Tyr Ala Phe Ile Val Ala 210 215 220 Ala Ile Leu Lys Ile Pro Ser Ala Glu Gly Arg Asn Lys Ala Phe Ser 225 230 235 240 Thr Cys Ala Ser His Leu Thr Val Val Val Val His Tyr Gly Phe Ala 245 250 255 Ser Val Ile Tyr Leu Lys Pro Lys Ser Pro Gln Ser Leu Glu Gly Asp 260 265 270 Thr Leu Met Gly Ile Thr Tyr Thr Val Leu Thr Pro Phe Leu Ser Pro 275 280 285 Ile Ile Phe Ser Leu Arg Asn Lys Glu Leu Lys Val Ala Met Lys Lys 290 295 300 Thr Phe Phe Ser Lys Leu Tyr Pro Glu Lys Asn Val Met Met 305 310 315 <210> 21 <211> 4376 <212> DNA <213> Homo sapiens <400> 21 tggtgtggct gcttggtgca gcccacacct ggtcagctcc cacctgtgga gaaactccaa 60 actagagcct cctactggga tgaagcagaa gcagatgcct ggagtcccag aatgactgga 120 ctaccctttt agctgcattc tgcatcccat cattccagac ggtgttacat gcagccctca 180 gctacctcct acagacgtga tcggctcctg tcctctcaag gtttctccct ccctcccttc 240 cttcctccct ccattcctcc ctccctcgtt tcttcctatc tcactctcct tctttcctcc 300 ctcactctcc ttccttcctt cctgcctccc tccctccctt tcttccttcc ttcctcactc 360 tccttctttc ctccctcact ctccttcctt cctgcctccc tccctccttt cttccttcct 420 cactctcctc ctttcctccc tcactctcct tccttccttc cttcgttcct tccttcctcc 480 ttccctccct ccctccttcc ttcctcctgc agtccccatc cttccttcct tttatccttc 540 tttccttcct ccctccctcc ctctctttct tcctcccttt tttctttctt ttcctcctcc 600 tcctcctcct ccttttctct ctctctctct ccccccacct tgttcactca ctcgctgtcg 660 attcttgtga tctgaattga tatgaacaag agtgtgtaga cggtcagtca tggggaagca 720 gcatctccta gtggcctttg aaacagccac cagcaactga gactcgctct gtcgccaggg 780 tggagtccag tggcgccatc tcggcttact gcaacctccg cctcccaggt tcaagagatt 840 ctcctgtctc tgcctcccga agagctggga ctacaggcac agcctccatg cagagagcca 900 atcactccac agtgacccaa ttcatcctcg tcggcttctc tgtcttcccc cacctccagc 960 tgatgctctt cctgctgttc ctgctgatgt acctgttcac gctgctgggc aacctgctca 1020 tcatggccac cgtctggagc gagcgcagcc tccacacgcc catgtacctc ttcctgtgcg 1080 ccctctccgt ctccgagatc ctctacaccg tggccatcat cccgcgcatg ctggccgacc 1140 tgctgtccac ccagcgctcc atcgccttcc tggcctgtgc cagtcagatg ttcttctcct 1200 tcagcttcgg cttcacccac tccttcctgc tcaccgtcat gggctacgac cgctacgtgg 1260 ccatctgcca ccccctgcgc tacaacgtgc tcatgagccc gcggggctgc gcctgcctgg 1320 tgggctgctc ctgggctggt ggcttggtca tggggatggt ggtgacctcg gccattttcc 1380 acctcgcctt ctgtggacac aaggagatcc accattttgc ttgccatgtg ccacctctgt 1440 tgaagttggc ctgtggagac gatgtgctgg tggtggccaa aggcgtgggc ttggtgtgta 1500 tcacggccct gctgggctgt tttctcctca tcctcctctc ctatgccttc atcgtggccg 1560 ccatcttgaa gatcccttct gctgaaggtc ggaacaaggc cttctccacc tgtgcctctc 1620 acctcactgt ggtggtcgtg cactatggct ttgcctccgt catttacctg aagcccaaaa 1680 gtccccagtc tctggaagga gacaccttga tgggcatcac ctacacggtc ctcacaccct 1740 tcctcagccc catcatcttc agcctcagga acaaggagct gaaggtcgcc atgaagaaga 1800 ccttcttcag taaactctac ccagaaaaaa atgtaatgat gtaggagaaa ttcactggga 1860 acaactaaat tggattaccg aaggctattg ttaaaaatta cgttccgtgg tgactcatgc 1920 ctgtaatccc agcactttgg gaggccgagg caggcggatc acctgaggtc aggagtttga 1980 gaccagcatg gctaacatgg cgaaacccca tctctactaa aaatacaaaa attagccagg 2040 catgttggca catgcctgta accctagcta cttgggaggc tgaggcataa gaatcgcttg 2100 acccggtagg tggaggttgc agtgagctga gatcacacca ctgcactcca gcctgggcga 2160 cagagtgaga ctgtctcaaa gaagaaagaa agaaagaaaa aaagaaaatt acgttccagc 2220 caagcactgt ggctcacact tataattcca gcaccttggg atgccaaggc aggaggattg 2280 cttgaggcca ggagttcaag actagacttg acaacatagc aagactgcat atctacaaaa 2340 acttagaaaa aaatagcttg gcatggtggt acatgcctgt agtcccagct acctgggaga 2400 ctgaactggg attactgcct aagtccagaa gtttgagctt acagtgaact atgactgtgc 2460 cactgcagtc tagcatggat gacagagtga gaccctatcc cttcccccct aaaagaaaga 2520 caatccatga acatatagta acctctattt gtcatgcttt aaggtttaca agggaccttg 2580 tagacgacat acaattataa acacaaaggt taatcagcat cagggatgta tttggagtgg 2640 aagtgtgtgt gagatactaa cacagagaaa accaggtttg attatttcta tctgctgcaa 2700 gaaactgtgt cagttagcac caaacctcca tctagactcc tcttgccaaa agccagggtc 2760 atctaatacc cccaataatg caaaccagca atgcaaagag agagggaaga tttcatgccc 2820 cactctctat gagtgccgca ccaggtagct acaactcaga ttttgtaagg ctactccaga 2880 ttatagcaga ggagagaaaa gtaccctaaa tttcagcatt gcacagatct atgcaataga 2940 agttagaaat agcaataaac agactctctt taaacatcaa ggaaacctta gaatttcaag 3000 tgtgagtctt gaatagttgt ggagagactg agatgtcttc atggttggat caaggaaaaa 3060 agtcacactg tgagataccg aatgctgtgt tagaagttga cacggctcat gggccagcca 3120 ggagctctct gttgaatctg gacattgagt gtagacccca ggatgagttt atctcatggc 3180 caggcgcagt ggctcatgcc tgtaatccca gcactttggg aggccaaggt gggtggatcc 3240 cctgaggtca ggagttcaag agcagcctgg gcaaatggct gaaaccccat ctctactaaa 3300 aatataaaaa ttagccaggc gtggtggcag gtgcctgtaa tcccagctac tcaggaggct 3360 gagacaggag aatagcttga accatggagg cagaggttgc agtgagctga gatcacacca 3420 ctgcactcca gcctgggtga cagactgaga ctccatctca aaaaaaaaaa aaaaaaaaaa 3480 aaagaaagtt tacctcatgg tctcttccca atgggcaggg atttaagatt gaccctactg 3540 tatagtattt atatatttat tgacaatagg tcttcctgtg tttgagctat gcatcatttt 3600 tttctaaagt gtgaattctc catcattcaa gcagtcaaaa caacccacag tcaaaacatc 3660 ccatattaca aaagccaaaa ttgacaaatg ggatctaatt aaactaaaga gcttctgcac 3720 agcaaaagaa actaccatca gagtgaacag gcaacctaca gaatgggaga aaatttttgc 3780 aatctactca tctgacaaag ggctaatatc cagaatctac aatgaactca aacaaattta 3840 caagaaaaaa acaaacaatc ccatcaaaaa gtgggcaaag gatatgaaca gacacttctc 3900 aaaagaagac atttatgcag ccaaaaaaca tatgaaaaaa tgctcgtcat cactggccat 3960 cagagaaatg caaatggaaa ccacaatgag atatcatctc acaccagtta gaatggcaat 4020 cactaaaaag tcaggaaaca acaggtgctg gagaggatgt ggagaaatag gaacactttt 4080 acactgttgg tgggactgta aactagttcc ccattgtggg agtcagtgtg gcgattcctc 4140 agggatctag aactagaaat atcatttgac ccagccatcc cattactggg tatataccca 4200 aaggattata aatcatgctg ctataaagac acatgcacac atgtttactg cagcactatt 4260 cacagtagca aagacttgga accaacccaa atgtccaaca atgatagact ggattaagaa 4320 aatgtggcac atatacacca tggaatacta tgcagccata aaaaatgatg agttca 4376 <210> 22 <211> 346 <212> PRT <213> Homo sapiens <400> 22 Met Tyr Arg Phe Thr Asp Phe Asp Val Ser Asn Ile Ser Ile Tyr Leu 1 5 10 15 Asn His Val Leu Phe Tyr Thr Thr Gln Gln Ala Gly Asp Leu Glu His 20 25 30 Met Glu Thr Arg Asn Tyr Ser Ala Met Thr Glu Phe Phe Leu Val Gly 35 40 45 Leu Ser Gln Tyr Pro Glu Leu Gln Leu Phe Leu Phe Leu Leu Cys Leu 50 55 60 Ile Met Tyr Met Ile Ile Leu Leu Gly Asn Ser Leu Leu Ile Ile Ile 65 70 75 80 Thr Ile Leu Asp Ser Arg Leu His Thr Pro Met Tyr Phe Phe Leu Gly 85 90 95 Asn Leu Ser Phe Leu Asp Ile Cys Tyr Thr Ser Ser Ser Ile Pro Pro 100 105 110 Met Leu Ile Ile Phe Met Ser Glu Arg Lys Ser Ile Ser Phe Ile Gly 115 120 125 Cys Ala Leu Gln Met Val Val Ser Leu Gly Leu Gly Ser Thr Glu Cys 130 135 140 Val Leu Leu Ala Val Met Ala Tyr Asp His Tyr Val Ala Ile Cys Asn 145 150 155 160 Pro Leu Arg Tyr Ser Ile Ile Met Asn Gly Val Leu Tyr Val Gln Met 165 170 175 Ala Ala Trp Ser Trp Ile Ile Gly Cys Leu Thr Ser Leu Leu Gln Thr 180 185 190 Val Leu Thr Met Met Leu Pro Phe Cys Gly Asn Asn Val Ile Asp His 195 200 205 Ile Thr Cys Glu Ile Leu Ala Leu Leu Lys Leu Val Cys Ser Asp Ile 210 215 220 Thr Ile Asn Val Leu Ile Met Thr Val Thr Asn Ile Val Ser Leu Val 225 230 235 240 Ile Leu Leu Leu Leu Ile Phe Ile Ser Tyr Val Phe Ile Leu Ser Ser 245 250 255 Ile Leu Arg Ile Asn Cys Ala Glu Gly Arg Lys Lys Ala Phe Ser Thr 260 265 270 Cys Ser Ala His Ser Ile Val Val Ile Leu Phe Tyr Gly Ser Ala Leu 275 280 285 Phe Met Tyr Met Lys Pro Lys Ser Lys Asn Thr Asn Thr Ser Asp Glu 290 295 300 Ile Ile Gly Leu Ser Tyr Gly Val Val Ser Pro Met Leu Asn Pro Ile 305 310 315 320 Ile Tyr Ser Leu Arg Asn Lys Glu Val Lys Glu Ala Val Lys Lys Val 325 330 335 Leu Ser Arg His Leu His Leu Leu Lys Met 340 345 <210> 23 <211> 1041 <212> DNA <213> Homo sapiens <400> 23 atgtacagat ttacagattt tgatgtatca aacatttcaa tttacctgaa tcatgtcctt 60 ttctatacta cccagcaggc aggtgaccta gaacacatgg agacaagaaa ttactctgcc 120 atgactgaat tctttctggt ggggctttcc caatatccag agctccagct ttttctgttc 180 ctgctctgcc tcatcatgta catgataatc ctcctgggaa atagcctcct cattatcatc 240 accatcttgg attctcgcct ccatactccc atgtatttct ttcttggaaa cctctcattc 300 ttggacatct gttacacatc ctcatccatt cctccaatgc ttattatatt tatgtctgag 360 agaaaatcca tctccttcat tggctgtgct ctgcagatgg ttgtgtccct tggcttgggc 420 tccactgagt gtgtcctcct ggctgtgatg gcctatgacc actatgtggc catctgcaac 480 ccactgaggt actccatcat catgaacgga gtgctgtatg tgcaaatggc tgcatggtcc 540 tggatcatag gctgtctgac ctccctattg caaacagttc tgacaatgat gttgcctttc 600 tgtgggaata atgtcattga tcatattacc tgtgaaattt tggcccttct aaaacttgtt 660 tgttcagata tcaccatcaa tgtgcttatc atgacagtga caaatattgt ttcactggtg 720 attcttctac tgttaatttt catctcctat gtgtttattc tctcttccat cctgagaatt 780 aattgtgctg agggaagaaa gaaagccttc tctacctgtt cagcgcactc gattgtggtc 840 atcttattct acggttcagc cctttttatg tacatgaaac ccaagtcaaa gaacactaat 900 acatctgatg agattattgg gctgtcttat ggagtggtaa gcccaatgtt aaatcccatc 960 atctatagcc tcaggaataa agaggtcaaa gaggctgtaa agaaagtcct gagcagacat 1020 ctgcatttat tgaaaatgtg a 1041 <210> 24 <211> 312 <212> PRT <213> Homo sapiens <400> 24 Met Trp Pro Asn Ile Thr Ala Ala Pro Phe Leu Leu Thr Gly Phe Pro 1 5 10 15 Gly Leu Glu Ala Ala His His Trp Ile Ser Ile Pro Phe Phe Ala Val 20 25 30 Tyr Val Cys Ile Leu Leu Gly Asn Gly Met Leu Leu Tyr Leu Ile Lys 35 40 45 His Asp His Ser Leu His Glu Pro Met Tyr Tyr Phe Leu Thr Met Leu 50 55 60 Ala Gly Thr Asp Leu Met Val Thr Leu Thr Thr Met Pro Thr Val Met 65 70 75 80 Gly Ile Leu Trp Val Asn His Arg Glu Ile Ser Ser Val Gly Cys Phe 85 90 95 Leu Gln Ala Tyr Phe Ile His Ser Leu Ser Val Val Glu Ser Gly Ser 100 105 110 Leu Leu Ala Met Ala Tyr Asp Cys Phe Ile Ala Ile Arg Asn Pro Leu 115 120 125 Arg Tyr Ala Ser Ile Leu Thr Asn Thr Arg Val Ile Ala Leu Gly Val 130 135 140 Gly Val Phe Leu Arg Gly Phe Val Ser Ile Leu Pro Val Ile Leu Arg 145 150 155 160 Leu Phe Ser Phe Ser Tyr Cys Lys Ser His Val Ile Thr Arg Ala Phe 165 170 175 Cys Leu His Gln Glu Ile Met Arg Leu Ala Cys Ala Asp Ile Thr Phe 180 185 190 Asn Arg Leu Tyr Pro Val Ile Leu Ile Ser Leu Thr Ile Phe Leu Asp 195 200 205 Cys Leu Ile Ile Leu Phe Ser Tyr Ile Leu Ile Leu Asn Thr Val Ile 210 215 220 Gly Ile Ala Ser Gly Glu Glu Arg Ala Lys Ala Leu Asn Thr Cys Ile 225 230 235 240 Ser His Ile Ser Cys Val Leu Ile Phe Tyr Val Thr Val Met Gly Leu 245 250 255 Thr Phe Ile Tyr Arg Phe Gly Lys Asn Val Pro Glu Val Val His Ile 260 265 270 Ile Met Ser Tyr Ile Tyr Phe Leu Phe Pro Pro Leu Met Asn Pro Val 275 280 285 Ile Tyr Ser Ile Lys Thr Lys Gln Ile Gln Tyr Gly Ile Ile Arg Leu 290 295 300 Leu Ser Lys His Arg Phe Ser Ser 305 310 <210> 25 <211> 1055 <212> DNA <213> Homo sapiens <400> 25 ggaggctcct ggtttcaagg tttcaagaaa tctgatcttt accggtggat acactatgtg 60 gcccaatatt actgcagccc cttttttgct gactggcttt ccagggctgg aggcagctca 120 tcactggatc tccatcccct tctttgctgt ttatgtgtgc atccttctgg gcaatggcat 180 gctcctctac ctcatcaagc atgaccacag tcttcatgag cccatgtact acttcctcac 240 catgctggca ggcacagacc tcatggtgac attgaccacg atgcctactg taatgggcat 300 cctatgggtg aatcacaggg agattagcag tgtgggctgc ttcctacagg cttactttat 360 tcactccctt tctgttgtgg aatcaggttc cctcctggca atggcatatg attgtttcat 420 tgccatccgc aatcctttga gatatgcttc cattctcacc aatactagag tcatagcgtt 480 aggagtggga gtgtttctaa ggggttttgt atccatcctg cctgtaattt tgcgtctttt 540 ttcattttca tattgcaaat ctcatgttat cacacgtgct ttctgcctcc accaagaaat 600 catgagactg gcttgtgctg acataacttt caatagactt taccctgtaa ttttgatctc 660 tttaacaatc ttcctagact gtctgatcat cctcttctcc tatattctaa ttcttaatac 720 tgtcataggc attgcttctg gtgaagagag agccaaagcc ctcaatacct gtatctccca 780 cattagttgt gttcttatct tctatgttac agtgatgggt ttgacattca tttacagatt 840 tgggaagaat gtgccagagg ttgtccacat tatcatgagt tacatctact tcctctttcc 900 tcctttaatg aaccctgtca tctacagcat caaaaccaag caaatacaat atggcattat 960 ccgcctttta tctaaacata ggtttagtag ttaaactcgg atctggagaa tcagacacag 1020 acataaaaat gaagccagaa tgaaaaatga aagcc 1055 <210> 26 <211> 324 <212> PRT <213> Homo sapiens <400> 26 Met Leu Gly Pro Ala Tyr Asn His Thr Met Glu Thr Pro Ala Ser Phe 1 5 10 15 Leu Leu Val Gly Ile Pro Gly Leu Gln Ser Ser His Leu Trp Leu Ala 20 25 30 Ile Ser Leu Ser Ala Met Tyr Ile Thr Ala Leu Leu Gly Asn Thr Leu 35 40 45 Ile Val Thr Ala Ile Trp Met Asp Ser Thr Arg His Glu Pro Met Tyr 50 55 60 Cys Phe Leu Cys Val Leu Ala Ala Val Asp Ile Val Met Ala Ser Ser 65 70 75 80 Val Val Pro Lys Met Val Ser Ile Phe Cys Ser Gly Asp Ser Ser Ile 85 90 95 Ser Phe Ser Ala Cys Phe Thr Gln Met Phe Phe Val His Leu Ala Thr 100 105 110 Ala Val Glu Thr Gly Leu Leu Leu Thr Met Ala Phe Asp Arg Tyr Val 115 120 125 Ala Ile Cys Lys Pro Leu His Tyr Lys Arg Ile Leu Thr Pro Gln Val 130 135 140 Met Leu Gly Met Ser Met Ala Val Thr Ile Arg Ala Val Thr Phe Met 145 150 155 160 Thr Pro Leu Ser Trp Met Met Asn His Leu Pro Phe Cys Gly Ser Asn 165 170 175 Val Val Val His Ser Tyr Cys Lys His Ile Ala Leu Ala Arg Leu Ala 180 185 190 Cys Ala Asp Pro Val Pro Ser Ser Leu Tyr Ser Leu Ile Gly Ser Ser 195 200 205 Leu Met Val Gly Ser Asp Val Ala Phe Ile Ala Ala Ser Tyr Ile Leu 210 215 220 Ile Leu Arg Ala Val Phe Asp Leu Ser Ser Lys Thr Ala Gln Leu Lys 225 230 235 240 Ala Leu Ser Thr Cys Gly Ser His Val Gly Val Met Ala Leu Tyr Tyr 245 250 255 Leu Pro Gly Met Ala Ser Ile Tyr Ala Ala Trp Leu Gly Gln Asp Ile 260 265 270 Val Pro Leu His Thr Gln Val Leu Leu Ala Asp Leu Tyr Val Ile Ile 275 280 285 Pro Ala Thr Leu Asn Pro Ile Ile Tyr Gly Met Arg Thr Lys Gln Leu 290 295 300 Leu Glu Gly Ile Trp Ser Tyr Leu Met His Phe Leu Phe Asp His Ser 305 310 315 320 Asn Leu Gly Ser <210> 27 <211> 975 <212> DNA <213> Homo sapiens <400> 27 atgctgggtc cagcttacaa ccacacaatg gaaacccctg cctccttcct ccttgtgggt 60 atcccaggac tgcaatcttc acatctttgg ctggctatct cactgagtgc catgtacatc 120 acagccctgt taggaaacac cctcatcgtg actgcaatct ggatggattc cactcggcat 180 gagcccatgt attgctttct gtgtgttctg gctgctgtgg acatgttat ggcctcctcc 240 gtggtaccca agatggtgag catcttctgc tcgggagaca gctccatcag ctttagtgct 300 tgtttcactc agatgttttt tgtccactta gccacagctg tggagacggg gctgctgctg 360 accatggctt ttgaccgcta tgtagccatc tgcaagcctc tacactacaa gagaattctc 420 acgcctcaag tgatgctggg aatgagtatg gccgtcacca tcagagctgt cacatcatg 480 actccactga gttggatgat gaatcatcta cctttctgtg gctccaatgt ggttgtccac 540 tcctactgta agcacatagc tttggccagg ttagcatgtg ctgaccccgt gcccagcagt 600 ctctacagtc tgattggttc ctctcttatg gtgggctctg atgtggcctt cattgctgcc 660 tcctatatct taattctcag ggcagtattt gatctctcct caaagactgc tcagttgaaa 720 gcattaagca catgtggctc ccatgtgggg gttatggctt tgtactatct acctgggatg 780 gcatccatct atgcggcctg gttggggcag gatatagtgc ccttgcacac ccaagtgctg 840 ctagctgacc tgtacgtgat catcccagcc actttaaatc ccatcatcta tggcatgagg 900 accaaacaat tgctggaggg aatatggagt tatctgatgc acttcctctt tgaccactcc 960 aacctgggtt catga 975 <210> 28 <211> 320 <212> PRT <213> Homo sapiens <400> 28 Met Ala Glu Thr Leu Gln Leu Asn Ser Thr Phe Leu His Pro Asn Phe 1 5 10 15 Phe Ile Leu Thr Gly Phe Pro Gly Leu Gly Ser Ala Gln Thr Trp Leu 20 25 30 Thr Leu Val Phe Gly Pro Ile Tyr Leu Leu Ala Leu Leu Gly Asn Gly 35 40 45 Ala Leu Pro Ala Val Val Trp Ile Asp Ser Thr Leu His Gln Pro Met 50 55 60 Phe Leu Leu Leu Ala Ile Leu Ala Ala Thr Asp Leu Gly Leu Ala Thr 65 70 75 80 Ser Ile Ala Pro Gly Leu Leu Ala Val Leu Trp Leu Gly Pro Arg Ser 85 90 95 Val Pro Tyr Ala Val Cys Leu Val Gln Met Phe Phe Val His Ala Leu 100 105 110 Thr Ala Met Glu Ser Gly Val Leu Leu Ala Met Ala Cys Asp Arg Ala 115 120 125 Ala Ala Ile Gly Arg Pro Leu His Tyr Pro Val Leu Val Thr Lys Ala 130 135 140 Cys Val Gly Tyr Ala Ala Leu Ala Leu Ala Leu Lys Ala Val Ala Ile 145 150 155 160 Val Val Pro Phe Pro Leu Leu Val Ala Lys Phe Glu His Phe Gln Ala 165 170 175 Lys Thr Ile Gly His Thr Tyr Cys Ala His Met Ala Val Val Glu Leu 180 185 190 Val Val Gly Asn Thr Gln Ala Thr Asn Leu Tyr Gly Leu Ala Leu Ser 195 200 205 Leu Ala Ile Ser Gly Met Asp Ile Leu Gly Ile Thr Gly Ser Tyr Gly 210 215 220 Leu Ile Ala His Ala Val Leu Gln Leu Pro Thr Arg Glu Ala His Ala 225 230 235 240 Lys Ala Phe Gly Thr Cys Ser Ser His Ile Cys Val Ile Leu Ala Phe 245 250 255 Tyr Ile Pro Gly Leu Phe Ser Tyr Leu Thr His Arg Phe Gly His His 260 265 270 Thr Val Pro Lys Pro Val His Ile Leu Leu Ser Asn Ile Tyr Leu Leu 275 280 285 Leu Pro Pro Ala Leu Asn Pro Leu Ile Tyr Gly Ala Arg Thr Lys Gln 290 295 300 Ile Arg Asp Arg Leu Leu Glu Thr Phe Thr Phe Arg Lys Ser Pro Leu 305 310 315 320 <210> 29 <211> 963 <212> DNA <213> Homo sapiens <400> 29 atggcagaaa ctctacaact caattccacc ttcctacacc caaacttctt catactgact 60 ggctttccag ggctaggaag tgcccagact tggctgacac tggtctttgg gcccatttat 120 ctgctggccc tgctgggcaa tggagcactg ccggcagtgg tgtggataga ctccacactg 180 caccagccca tgtttctact gttggccatc ctggcagcca cagacctggg cttagccaca 240 tctatagccc cagggttgct ggctgtgctg tggcttgggc cccgatctgt gccatatgct 300 gtgtgcctgg tccagatgtt ctttgtacat gcactgactg ccatggaatc aggtgtgctt 360 ttggccatgg cctgtgatcg tgctgcggca atagggcgtc cactgcacta ccctgtcctg 420 gtcaccaaag cctgtgtggg ttatgcagcc ttggccctgg cactgaaagc tgtggctatt 480 gttgtacctt tcccactgct ggtggcaaag tttgagcact tccaagccaa gaccataggc 540 catacctatt gtgcacacat ggcagtggta gaactggtgg tgggtaacac acaggccacc 600 aacttatatg gtctggcact ttcactggcc atctcaggta tggatattct gggtatcact 660 ggctcctatg gactcattgc ccatgctgtg ctgcagctac ctacccggga ggcccatgcc 720 aaggcctttg gtacatgtag ttctcacatc tgtgtcattc tggccttcta catacctggt 780 ctcttctcct acctcacaca ccgctttggt catcacactg tcccaaagcc tgtgcacatc 840 cttctctcca acatctactt gctgctgcca cctgccctca accccctcat ctatggggcc 900 cgcaccaagc agatcagaga ccgactcctg gaaaccttca cattcagaaa aagcccgttg 960 taa 963 <210> 30 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Filaggrin F primer <400> 30 aggctccttc aggctacatt c 21 <210> 31 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Filaggrin R primer <400> 31 caggagagta gacatctttt ggca 24 <210> 32 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Keratin 10 F primer <400> 32 caactcacat cagggggagc 20 <210> 33 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Keratin 10 R primer <400> 33 cagctcatcc agcaccctac 20 <210> 34 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> OR1F1 F primer <400> 34 atgtatttcg ttttcatgtt cgtg 24 <210> 35 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR1F1 R primer <400> 35 agaagtgagt gatggcattg tct 23 <210> 36 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR2A4 F primer <400> 36 tggatacaga ccgtgaggga 20 <210> 37 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR2A4 R primer <400> 37 atagcaggaa tgccgatcca 20 <210> 38 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR2D3 F primer <400> 38 cggtatgtgg ctgtctgcaa g 21 <210> 39 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR2D3 R primer <400> 39 agacaggggc caggaggatt a 21 <210> 40 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR2H2 F primer <400> 40 ccatctcact gtggtcaccc tcttc 25 <210> 41 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR2H2 R primer <400> 41 gaatgccctg gttacctcct tgttc 25 <210> 42 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR5C1 F primer <400> 42 tattacggtg tcttatggct tcatc 25 <210> 43 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> OR5C1 R primer <400> 43 ggctgtagat gagtgggttg ag 22 <210> 44 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR7D2 F primer <400> 44 tgctgggaaa cctgctcatc 20 <210> 45 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR7D2 R primer <400> 45 catcacggtc aggagtagcg 20 <210> 46 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR7E91P F primer <400> 46 cagcatcatc gatagcatgt tca 23 <210> 47 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> OR7E91P R primer <400> 47 gcaaacaact ggcaggtgag 20 <210> 48 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR10H1 F primer <400> 48 atctccctgt cacatctcac c 21 <210> 49 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> OR10H1 R primer <400> 49 gaacaggtac atcagcagga acag 24 <210> 50 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> OR13D1 F primer <400> 50 cactatgtgg ccatctgcaa cc 22 <210> 51 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR13D1 R primer <400> 51 agccatttgc acatacagca ctc 23 <210> 52 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR52I1 F primer <400> 52 caccatcaga gctgtcacat tca 23 <210> 53 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> OR52I1 R primer <400> 53 acaaccacat tggagccaca ga 22 <210> 54 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR52W1 F primer <400> 54 ctgactggct ttccagggct a 21 <210> 55 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR52W1 R primer <400> 55 gccaggatgg ccaacagtag a 21 <210> 56 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> GAPDH F primer <400> 56 atcaagaagg tggtgaagca g 21 <210> 57 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH R primer <400> 57 gtcgctgttg aagtcagagg 20 <210> 58 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR2AE1 F primer <400> 58 tttggtttgg tgcctgcatc ttc 23 <210> 59 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR2AE1 R primer <400> 59 aacatctctc ctcagcactc ttctc 25 <210> 60 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR2W3 F primer <400> 60 ccttggccat gtctcctgtg a 21 <210> 61 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> OR2W3 R primer <400> 61 tctgccttcc tgatgctgac c 21 <210> 62 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> OR10A2 F primer <400> 62 ttctcttccc tgcctactga aatac 25 <210> 63 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> OR10A2 R primer <400> 63 tcccatcagg gtgaccaggt ag 22 <210> 64 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR51B2 F primer <400> 64 agagagccaa agccctcaat acc 23 <210> 65 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> OR51B2 R primer <400> 65 tgtggacaac ctctggcaca ttc 23
Claims (14)
A composition for diagnosing skin aging due to UV exposure, comprising an agent for measuring the expression level of the OR7D2 gene or its encoding protein as an active ingredient.
According to claim 1, wherein the composition comprises an agent for measuring the expression level of one or more genes selected from the group consisting of OR1F1, OR2A4, OR2H2, OR5C1, OR10H1, OR13D1, OR52I1, OR52W1, OR2D3 and OR7E91P, or a protein encoding them. Composition, characterized in that it further comprises.
The composition according to claim 1, wherein the aging of the skin due to UV exposure is at least one photoaging phenomenon selected from the group consisting of fine wrinkles, hyperpigmentation, loss of skin elasticity, and lack of moisture.
(ⅱ) OR1F1, OR2A4, OR2AE1, OR2W3, OR2H2, OR5C1, OR7E91P, OR10A2, OR10H1, OR13D1, OR51B2, OR52I1 및 OR52W1로 구성된 군으로부터 선택되는 하나 이상의 유전자 또는 이들이 인코딩하는 단백질의 발현량을 측정하는 제제를 유효성분으로 포함하는 염증에 의한 피부 노화의 진단용 조성물.
(i) an agent for measuring the expression level of the OR7D2 gene or its encoding protein; and
(ii) an agent for measuring the expression level of one or more genes selected from the group consisting of OR1F1, OR2A4, OR2AE1, OR2W3, OR2H2, OR5C1, OR7E91P, OR10A2, OR10H1, OR13D1, OR51B2, OR52I1 and OR52W1, or a protein encoding them A composition for diagnosis of skin aging due to inflammation comprising as an active ingredient.
The method of claim 5, wherein the aging of the skin due to inflammation is skin aging due to inflammatory or autoimmune skin diseases selected from the group consisting of atopic dermatitis, dermatomyositis, scleroderma, pemphigus, erythema annulus and lupus erythematosus. composition to do.
The composition according to claim 1 or 5, wherein the agent for measuring the expression level of the gene is a primer or probe that specifically binds to the nucleic acid molecule of the gene.
According to claim 1 or 5, wherein the agent for measuring the expression level of the protein is an antibody or antigen-binding fragment thereof that specifically binds to the protein; Or the composition characterized in that it is an aptamer that specifically binds to the protein.
A method for providing information necessary for diagnosing skin aging due to UV exposure, comprising measuring the expression level of the OR7D2 gene or its encoding protein in a biological sample isolated from an individual.
(i) OR7D2 유전자 또는 이의 인코딩 단백질의 발현량; 및
(ii) OR1F1, OR2A4, OR2AE1, OR2W3, OR2H2, OR5C1, OR7E91P, OR10A2, OR10H1, OR13D1, OR51B2, OR52I1 및 OR52W1로 구성된 군으로부터 선택되는 하나 이상의 유전자 또는 이들이 인코딩하는 단백질의 발현량을 측정하는 단계를 포함하는 염증에 의한 피부 노화의 진단에 필요한 정보를 제공하는 방법.
in a biological sample isolated from a subject
(i) the expression level of the OR7D2 gene or its encoding protein; and
(ii) measuring the expression level of one or more genes selected from the group consisting of OR1F1, OR2A4, OR2AE1, OR2W3, OR2H2, OR5C1, OR7E91P, OR10A2, OR10H1, OR13D1, OR51B2, OR52I1 and OR52W1, or the protein they encode; A method of providing information necessary for the diagnosis of skin aging caused by inflammation, including.
The method of claim 10 or 11, wherein the biological sample comprises skin tissue or cells derived from skin tissue.
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| KR1020200132585A KR102331854B1 (en) | 2020-10-14 | 2020-10-14 | Novel Biomarkers for Diagnosing Skin Aging |
| PCT/KR2021/013489 WO2022080718A1 (en) | 2020-10-14 | 2021-10-01 | Novel biomarker for diagnosis of skin aging |
| KR1020210150457A KR20220049484A (en) | 2020-10-14 | 2021-11-04 | Novel Biomarkers for Diagnosing Skin Aging |
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- 2020-10-14 KR KR1020200132585A patent/KR102331854B1/en active IP Right Grant
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