KR101240136B1 - Biomarker for diagnosing aspirin intolerant asthma - Google Patents
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Abstract
The present invention provides a biomarker composition for diagnosing aspirin-sensitive asthma, a diagnostic kit, and a method for detecting protein for providing information necessary for diagnosing aspirin-sensitive asthma. The present invention can predict the risk of aspirin-sensitive asthma, and can be usefully used in the field of prevention and treatment of aspirin-sensitive asthma.
Description
The present invention relates to aspirin hypersensitivity asthma diagnostic biomarker and a method for detecting the biomarker.
Aspirin-intolerant asthma (AIA) is the development of bronchial contraction in asthma patients after ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). This syndrome is characterized by chronic hyperplastic eosinophilic sinusitis accompanied by aspirin swallowing, ie aspirin hypersensitivity, bronchial asthma, and nasal polyposis. Like other asthmatic patients, airways in patients with AIA show signs of persistent inflammation with pronounced eosinophils, rupture of the epithelium, cytokine overproduction, and upregulation of inflammatory molecules. Overexpression or underexpression of important mediators, including leukotrienes, lipoxins, thromboxins and prostaglandins in arachidonic acid metabolism, may explain the sensitivity to aspirin (acetylsalicylic acid: ASA). In arachidonic acid metabolism, ASA directly affects inflammation.
In the past, protein expression in nasal polyps of AIA patients has not been studied. Diagnosis of nasal polyps has been shown to characterize aspirin hypersensitivity in AIA patients. Nasal polyps in AIA patients are characterized by the infiltration of inflammatory cells into the bronchial mucosa. Inflammatory cells appear to infiltrate and establish a strong network of intracellular interactions and promote nasal polyp proliferation. For a better understanding of the molecular aspect of aspirin hypersensitivity in asthmatic patients, we have adopted a proteomics approach.
An object of the present invention is to provide a biomarker composition for diagnosing aspirin-sensitive asthma, a diagnostic kit, and a method for detecting a protein for providing information necessary for diagnosing aspirin-sensitive asthma.
In order to achieve the above object, the present invention comprises a chaperonin (Chaperonin) having an amino acid sequence of SEQ ID NO: 1; Fatty acid binding protein 1 (FABP1) having the amino acid sequence of SEQ ID NO: 2; Beta actin having the amino acid sequence of SEQ ID NO: 3; Transketolase having the amino acid sequence of SEQ ID NO: 4; Carbamyl phosphate synthetase I having the amino acid sequence of SEQ ID NO: 5; Transketolase variants having the amino acid sequence of SEQ ID NO: 6; Heat shock 70kDa protein 9 precursor having the amino acid sequence of SEQ ID NO: 7; UDP-
The present invention also provides an aspirin-sensitive asthma diagnostic composition comprising an antibody that specifically binds to the protein or immunogenic fragment thereof as an active ingredient.
The present invention also provides an aspirin-sensitive asthma diagnostic kit comprising an antibody that specifically binds to the protein or immunogenic fragment thereof.
The present invention also relates to a) chaperronin having the amino acid sequence of SEQ ID NO: 1 from nasal polyps tissue; Fatty acid binding protein 1 (FABP1) having the amino acid sequence of SEQ ID NO: 2; Beta actin having the amino acid sequence of SEQ ID NO: 3; Transketolase having the amino acid sequence of SEQ ID NO: 4; Carbamyl phosphate synthetase I having the amino acid sequence of SEQ ID NO: 5; Transketolase variants having the amino acid sequence of SEQ ID NO: 6; Heat shock 70kDa protein 9 precursor having the amino acid sequence of SEQ ID NO: 7; UDP-
Aspirin-sensitive asthma diagnostic biomarker containing the protein of the present invention as an active ingredient is closely related to aspirin hypersensitivity in asthma patients, and by measuring this, it is possible to predict the risk of aspirin-sensitive asthma, prevention of aspirin-sensitive asthma and It can be usefully used in the therapeutic field.
FIG. 1 shows two-dimensional electrophoresis (2-DE) separation of 1 mg of nasal polyp protein from ATA subjects (n = 8) and AIA subjects (n = 5). Protein spots identified by LC-MS (arrows) are indicated by their spot numbers. The image of
In FIG. 2, the y-axis of each graph represents the relative intensity of the spot (%). P-value represents the difference between ATA and AIA.
Figure 3 compares FABP1 expression in ATA patients and AIA group.
4 shows immunohistochemical analysis of nasal polyps from ATA patients (n = 3) and AIA patients (n = 3).
Hereinafter, the present invention will be described in detail.
The present invention provides chaperronin (Chaperonin) having an amino acid sequence of SEQ ID NO: 1; Fatty acid binding protein 1 (FABP1) having the amino acid sequence of SEQ ID NO: 2; Beta actin having the amino acid sequence of SEQ ID NO: 3; Transketolase having the amino acid sequence of SEQ ID NO: 4; Carbamyl phosphate synthetase I having the amino acid sequence of SEQ ID NO: 5; Transketolase variants having the amino acid sequence of SEQ ID NO: 6; Heat shock 70kDa protein 9 precursor having the amino acid sequence of SEQ ID NO: 7; UDP-
The composition of the present invention may essentially include FABP1 (Fatty acid binding protein 1) having an amino acid sequence of SEQ ID NO: 2.
The present invention is the first invention to show in a map that different proteins are expressed in nasal polyps tissue from AIA patients and ATA patients using proteomics.
As a result of LC-MS analysis of the present invention, it was found that several different types of proteins were changed in contrast to changes in complement and apolipoprotein in plasma. FABP1 was 6 times higher in the AIA group than in the ATA grum (P = 0.007) in the 2-DE analysis and 8 times higher in the Western blot analysis. The present inventors confirmed that the hat FABP1 protein was expressed more in the nasal polyps of the AIA group than the ATA group. In particular, FABP1 protein was strongly expressed in vascular epithelial cells, smooth muscle cells, myofibrogenic mesenchymal cells and macrophages. Fatty acid transport in cells is a complex and dynamic process that affects many functions of the cell. Fatty acids act as signals of energy sources and metabolic regulation, acting through enzymatic transcriptional networks to regulate gene expression, growth, survival pathways, and inflammation and response. Fatty acids, especially linoleic acid and arachidonic acid, are metabolized into large families of bio-active lipid mediators, eicosanoids, to function as pro- and anti-inflammatory mediators. FABP1 is a small, abundantly expressed intracellular protein that reversibly binds saturated and unsaturated long chain fatty acids, eicosanoids and other lipids. The presence of FABP1 decreases the intracellular concentration of unbound fatty acids. It is a lipid chaperone in the cytoplasm that functions to protect against the potential cytotoxic effects of free fatty acids and their degradation products. Another function of FABP1 is to play a role in arachidonic acid metabolism inside cells. FABP1 also converts fatty acids into eicosanoid intermediates and is therefore associated with stabilization of leukotrienes.
Immunohistochemical studies of the present invention demonstrated significant amounts of FABP1 in the nasal polyps of AIA patients. Increased FABP1 levels may highlight new functions as modulator candidates for inflammatory responses by FABP1 and arachidonic acid metabolism. Since FABP1 is a 15.7 kDa protein produced mainly in the liver, it determines the level of hepatic production blood FABP1, so we measured FABP1 in plasma.
Chaperonin was 10-fold higher in the AIA group than in the ATA group. This protein belongs to a family of proteins that help fold proteins called molecular chaperones. Molecular chaperones, including chaperonin, including Hsp70 and TCP-1 Ring Complex (TRiC) / TCP-1 (CCT) are mediators of misfolding diseases. Proteins do not fold or misfold when they encounter certain stresses, such as changes in the intracellular environment, such as aging, temperature fluctuations, exposure to genetic mutations or amino acid analogs. Increases in these misfolded or unfolded proteins are normally regulated by regulatory mechanisms, including chaperones activated through intracellular stress pathways or heat shock responses. In this pathway, expression of genes that are mediated by heat shock transcription factors, including HSF-1, encoding chaperones, such as heat shock proteins, occurs almost immediately.
Heat shock 70kDa protein 9 precursor (Heat shock 70kDa protein 9 precursor) and heat-responsive protein 12 (Heat-responsive protein 12) was 2 times lower in AIA than ATA. Molecular chaperones, members of the Hsp70 family, function simultaneously with and post-transcriptional folds and regulate the quality of misfolded proteins. Elevated cytoplasmic Hsp70 levels appear to play a protective role in protecting against cell damage induced by stress stimuli including heat shock, tumor necrosis factor, oxidative stress, cell proliferation inhibitor, radioactivity. After treating ASA with non-toxic content, it was confirmed that Hsp70 membrane expression was specifically upregulated with Hsp70 bound to the membrane.
As described above, the change of chaperonin in the present invention has been shown to change the intracellular response of nasal species to aspirin in AIA compared to ATA. In the present invention, the possibility of changing by age at the protein level of Hsp70 was excluded.
In addition, the present invention is an intracellular enzyme carbamyl phosphate synthetase I, aldehyde dehydrogenase 4A1 precursor, betaine-homocysteine methyltransferase isoform CRA b (Betaine) -homocysteine methyltransferase, isoform CRA b), transketolase, UDP-
Among these, carbamyl phosphate synthetase I (CPSⅠ), aldehyde dehydrogenase 4A1 precursor, betaine-homocysteine methyltransferase isoform CRA b (Betaine-homocysteine methyltransRAferase, isoform b), Glyceraldehyde-3-phosphate dehydrogenase was increased in AIA. Carbamyl phosphatase is an enzyme that catalyzes the production of carbamoyl phosphate, a precursor of arginine and NO. The CPSI gene affects NO production following the L-citrulline / L-arginine cycle. The amount of CPSI protein in the present invention was 150% higher in AIA than ATA. Pathological findings of AIA with more dilated blood vessels compared to ATA provide indirect evidence of the possible role of CPS I in nasal polyps of subjects with AIA.
Aldehyde dehydrogenase 4A1 precursor is associated with mitochondrial matrix NAD-dependent dehydrogenase, which catalyzes the second stage of the proline degradation pathway that converts pyrroline-5-carboxylate to glutamate. . Betaine-
The present invention also provides an aspirin-sensitive asthma diagnostic composition comprising an antibody that specifically binds to the protein or immunogenic fragment thereof as an active ingredient.
The diagnostic composition may be provided in the form of a diagnostic kit, biochip or microarray.
The said immunogenic fragment means a part of the protein which allows production of a reactive antibody in an external host.
The antibody of the present invention can be prepared by injecting a biomarker protein or fragment thereof as an immunogen into an external host according to a conventional method for producing a polyclonal antibody. External hosts include, but are not limited to, mammals such as mice, rats, sheep, rabbits, goats. Immunogens are injected by intramuscular, intraperitoneal or subcutaneous injection and are usually administered with an adjuvant to increase antigenicity. Antibodies are purified by collecting blood periodically from external hosts to collect blood showing improved titers and specificity for the antigen.
The antibody of the present invention may be a polyclonal antibody, but is preferably a monoclonal antibody. Monoclonal antibodies can be prepared by methods known to those skilled in the art.
The present invention also provides an aspirin hypersensitivity asthma diagnostic kit, monitoring kit or screening kit comprising an antibody that specifically binds to the protein or immunogenic fragment thereof.
The antibody can be bound to a solid substrate. The solid substrate is not particularly limited, but may be selected from the group consisting of synthetic resins, nitrocellulose, glass substrates, metal substrates, glass fibers, microspheres, and microbeads. The synthetic resin may be selected from the group consisting of polyester, polyvinyl chloride, polystyrene, polypropylene, PVDF and nylon.
The diagnostic kit, monitoring kit or screening kit may further include an antibody for detection that binds to the protein. The detection antibody is not limited, but may be, for example, a conjugate labeled with a chromophore, a fluorescent substance, a radioisotope, or a colloid-detector, and preferably binds specifically to the biomarker protein. May be a primary antibody.
The diagnostic kit, monitoring kit or screening kit may further include a detection antibody that binds to the protein and a ligand that can specifically bind to the detection antibody. The ligand is a secondary antibody, and may be a conjugate labeled with a detector such as a chromophore, a fluorescent substance, a radioisotope, or a colloid. The detection antibody is preferably a biotinylated or digoxigenin-treated primary antibody for the ligand, but is not limited thereto. As the ligand, streptavidin, avidin, etc. may be used, but is not limited thereto.
The detection antibody can be measured by methods such as fluorescence, luminescence, chemiluminescence, absorbance, reflection or transmission. In addition, a method for detecting the amount of the antibody or ligand for detection may use an ultra-high speed screening (HTS) system, including a surface plasmon resonance (SPR) method or a surface plasmon resonance imaging (SPRI) method, but is not limited thereto. It doesn't work.
The present invention also provides a biochip for monitoring or screening aspirin-sensitive asthma, in which biological molecules specifically binding to the protein or immunogenic fragment thereof are integrated on a solid substrate.
The biological molecule is not limited, but may be, for example, a small molecule compound, a ligand, an aptamer, a peptide, a polypeptide, a specific binding protein, a polymer material or an antibody. Either can be used and it is preferable to use an antibody or an aptamer.
The solid substrate is not limited, but may be, for example, plastic, glass, metal or silicon, preferably may be chemically treated or linker molecules bound to attach the antibody to its surface, but is not limited thereto. It doesn't work.
The present invention also relates to a) chaperronin having the amino acid sequence of SEQ ID NO: 1 from nasal polyps tissue; Fatty acid binding protein 1 (FABP1) having the amino acid sequence of SEQ ID NO: 2; Beta actin having the amino acid sequence of SEQ ID NO: 3; Transketolase having the amino acid sequence of SEQ ID NO: 4; Carbamyl phosphate synthetase I having the amino acid sequence of SEQ ID NO: 5; Transketolase variants having the amino acid sequence of SEQ ID NO: 6; Heat shock 70kDa protein 9 precursor having the amino acid sequence of SEQ ID NO: 7; UDP-glucose phosphorylase 2 isoform a having the amino acid sequence of SEQ ID NO: 8; Aldehyde dehydrogenase 4A1 precursor having the amino acid sequence of SEQ ID NO: 9; Betaine-homocysteine methyltransferase (isoform CRA b) having the amino acid sequence of SEQ ID NO: 10; Ig γ light chain having the amino acid sequence of SEQ ID NO: 11; Glyceraldehyde-3-phosphate dehydrogenase having the amino acid sequence of SEQ ID NO: 12; Heat-responsive protein 12 having the amino acid sequence of SEQ ID NO: 13; KIAA1361 protein having the amino acid sequence of SEQ ID NO: 14; And zinc finger protein 609 having the amino acid sequence of SEQ ID NO: 15; Measuring the expression level of one or more proteins selected from the group consisting of; And b) identifying the aspirin hypersensitivity asthma risk by analyzing the expression level of the protein measured in step a). It provides a protein detection method for providing information necessary for diagnosing aspirin-sensitive asthma comprising a.
In step a), the nasal species tissue refers to a biological sample. The biological sample refers to blood and other liquid samples of biological origin. Preferably blood, plasma or serum. The nasal species tissue can be obtained from an animal, preferably a mammal, most preferably a human. The sample may be pretreated before use for detection. For example, it can include filtration, distillation, extraction, concentration, inactivation of disturbing components, addition of reagents, and the like.
Measuring the expression level of the protein in step a) can be measured using an antibody that specifically binds to two-dimensional electrophoresis, biochips or proteins or immunogenic fragments thereof. Two-dimensional electrophoresis can also be used to directly detect the presence of a protein.
For the measurement, enzyme immunoassay (ELISA), western blot, immunoprecipitation method, magnetic particle method or latex particle method can be used.
Chaperronin having an amino acid sequence of SEQ ID NO: 1 in step b); Fatty acid binding protein 1 (FABP1) having the amino acid sequence of SEQ ID NO: 2; Carbamyl phosphate synthetase I having the amino acid sequence of SEQ ID NO: 5; Aldehyde dehydrogenase 4A1 precursor having the amino acid sequence of SEQ ID NO: 9; Betaine-homocysteine methyltransferase (isoform CRA b) having the amino acid sequence of SEQ ID NO: 10; Ig γ light chain having the amino acid sequence of SEQ ID NO: 11; And glyceraldehyde-3-phosphate dehydrogenase having the amino acid sequence of SEQ ID NO: 12; If the expression level of one or more proteins selected from the group consisting of aspirin-resistant asthma patients higher than the expression level can be confirmed that the risk of aspirin hypersensitivity asthma.
Beta actin having the amino acid sequence of SEQ ID NO: 3 in step b); Transketolase having the amino acid sequence of SEQ ID NO: 4 Transketolase variant having the amino acid sequence of SEQ ID NO: 6; Heat shock 70kDa protein 9 precursor having the amino acid sequence of SEQ ID NO: 7; UDP-
Hereinafter, the present invention will be described in detail by way of examples.
However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.
Example 1 Selection of Subjects
Thirteen nasal polyps tissues (five AIA and eight ATA) were donated from a biobank at the Genome Research Center for Allergic and Respiratory Diseases in Bucheon, Suncheon, Korea. All subjects were Korean and met the criteria for asthma set in the World Asthma Organization (GINA) guidelines. All patients had a history of shortness of breath and gasping for the last 12 months and increased by more than 12% by inhaling 200 ml more of ESR or short-active bronchial dilator for at least 15%; PC20 methacholine less than 10 mg / ml; Or had an increase in FEV1 of 20% or more when inhaled for two weeks with steroids and long-acting bronchodilators. Skin tests were performed on 24 general inhalation allergens (such as dust, cat hair, dog hair, cockroaches, grass, trees, hives wormwood pollen) (Bencard Co. Ltd., Brentford, UK). Total IgE was measured by the CAP system (Pharmacia Diagnostics, Uppsala, Sweden). Atopy was defined as one or more positive responses (> 3 mm diameter) from skin tests. Asthmatic patients did not experience seizures and respiratory infections of the disease within six weeks of oral aspirin challenge (OAC). Oral provocation testing was performed using a slightly modified method of the conventional method with increasing aspirin content (10-450 mg Astrix; Melbourne, Australia, Maine Pharma Ltd.).
The FEV1 change lasted for 5 hours after the last dose of aspirin. Aspirin-induced bronchospasms were calculated as [FEV1 before administration]-[FEV1 after administration] / [FEV1 before administration]. Nasal polyps and chronic rhinosinusitis may be seen as an endoscopy that occurs in the nasal meatus, and the association between the ethmoid sinus and the maxillary sinus, which can be seen only by CT scanning of the sinuses, is determined by symptoms measured from a medical history. Diagnosis was made based on this. The clinical characteristics of the subjects are summarized in Table 1. All polyps were frozen at −80 ° C. until use. Consents to participate in this study were given in writing to all subjects and the protocol used in this study was approved by the hospital's ethics committee.
Example 2 2D electrophoresis and image analysis
Immobilin DryStrps (24 cm, pH 3-10, pH 3-7; Amersham Biosciences, Uppsala, Sweden) was used for isoelectric point electrophoresis (IEF). DryStrps were first rehydrated in 450 ml of rehydration buffer containing 8 M urea, 2% CHAPS, 13 mM DTT, 1.2% IPG buffer, and trace bromophenol blue and then mixed with each sample. IEF was performed at 146 kVh in total using 40 mg of plasma protein using the IPGphore system (Amersham Biosciences). After IEF separation, the gel strips were equilibrated twice by shaking gently for 10 minutes in an equilibration buffer containing 50 mM Tris-HCl buffer, pH 8.8, 6 M urea, 20% glycerol, 0.1% SDS, and 1% DTT. In the second equilibration buffer, DTT was replaced with 2.5% idoacetamide to remove excess DTT. After equilibration, proteins were separated on 5-18.5% SDS polyacrylamide gels using the Ettan Dalt II system (Amersham Pharmacia Biotech, Inc., Sweden). After two-dimensional electrophoresis, the gel was stained with Coomassie brilliant blue G-250. Digitized images of gels stained with Coomassie brilliant blue G-250 were analyzed using a two-dimensional electrophoresis (2-DE) gel analysis program Imagemaster 2D (version 4.0; Amersham Pharmacia Biotech, Inc.). Coomassie stained spots of 13-DE gels of 13 subjects were quantified based on standardized volume. For example, each spot volume was divided by the total sum of all spot volumes. A ranking procedure based on relative intensity was found to be approximately twice or more of the spots seen in 2DE and predicted high or low expression in nasal species.
result
Nasal species samples were subjected to 1-DE in a 3-10 pH range on IPG gel strips and 2-DE on a homogeneous 7.5-20% SDS-PAGE (FIG. 1). After Coomassie blue staining and analysis, 984 spots (range 853-994) significant figures were detected in patients with A mg and 907 spots (range 790-984) significant figures in patients with AIA. All identified spots were located in the range of pi 4-8 with a molecular weight range of 10-150 kDa. The location of the identified protein spots is shown in the master image (FIG. 1A). The relative intensity (%) of the spots was expressed as the difference range between the median and quartiles of each group (FIG. 1B). Fifteen proteins showed significant differences in relative intensities between the two groups following the Mann-Whitney U-test ( P <0.05). The relative intensity of AIA patients was significantly higher at 7 spots and lower at 8 spots compared to ATA patients. These spots were separated from the gel and incubated with trypsin to degrade protein and identified as LC-MS / MS and MALDI-TOF / TOF. The results of this analysis are summarized in Table 2.
The relative intensity of spot number 1 (chaperon group 2: chaperonin group 2) was 10 times higher in the AIA group than in the ATA group (P = 0.003). Fatty acid binding protein 1 (FABP1), Carbamyl phosphate synthetase I, aldehyde dehydrogenase 4A1 precursor, betaine-homocysteine methyltransferase isoform CRA b (Betaine- homocysteine methyltransferase, isoform CRA b), Ig γ light chain and glyceraldehyde-3-phosphate dehydrogenase were increased in AIA subjects compared to ATA subjects. . On the other hand, the relative intensities of the other eight spots were significantly lower in AIA subjects compared to TA subjects (FIG. 1, Table 2). They are Beta actin, Transketolase, Transketolase variant, Heat shock 70kDa protein 9 precursor, UDP-
Example 3 Protein Identification and Database Search by Nano-LC-MS
Differently expressed protein spots in 2-DE were cut into smaller pieces and digested with trypsin (Promega). All LC-MS experiments were performed using the Agilent Nanoflow Proteomics Solution, in which the Agilent 1100 Series nano-LC for MS / MS was loaded with a nanospray ion source perpendicular to the Agilent 1100 Series LC / MSC Trap XCT ion trap mass spectrometer. Connected through. The nano-LC system was run in sample concentration / desalting mode using a ZORBAX 300SB-C18 concentration column (0.3 × 50 mm, 5 μm). Chromatography was performed using ZORBAX 300 SB-C18 (75 um × 150 mm) nanocolumns. The solvent gradient was started for 5 minutes in 3% solvent B (acetonitrile containing 0.1% formic acid) and 97% solvent A (0.1% formic acid containing). Solvent gradient proceeded as follows. B from 3% to 10% for 5-10 minutes, B from 10% to 45% for 10-50 minutes, B from 45% to 90% for 50-55 minutes, 90% for 55-60 minutes B was washed from 90% to 3% for 60-61 minutes, with no change in composition, and 3% of B for 10 minutes.
LC / MSD Trap XCT was run in a unique peptide scan auto-MS / MS mode. Ionization mode was performed using Agilent's right-angle positive nanoelectronic spray source. The dry gas flowed at 5 L / min and the dry gas temperature was 300 ° C. The V cap was generally 1800-1900 V with passages at 30V and capillary escape offset at 75V. Trap drives were set at 85V with an average of one or two. The maximum accumulation time was 150ms, the smart target was 125,000 and the MS scan range was 300-2200. Automated MS / MS features
Example 4 Immunohistochemical Staining of Nasal Polyps for Western Blot and FABP1 Protein Expression
Proteins were fragmented by 15% SDS-PAGE and delivered to nitrocellulose membranes (Amersham Pharmacia Biotech, Inc.). The protein-blotting membrane was incubated in blocking solution with 1: 500 diluted mouse anti-human FABP1 monoclonal antibody and then polyclonal anti-conjugated with 1: 5000 diluted horseradish peroxidase. -Incubated with blocking solution containing mouse IgG antibody. Enhanced chemiluminescence (ECL) was performed (Boehringer Mannheim, Germany). For immunohistochemical analysis of FABP1 protein, the nasal polyps tissue on the slides were treated with 0.3% H 2 O 2 for 20 minutes, followed by goat anti-human FABP1 monoclonal antibody (1: 100 dilution; Meridian Life Science Inc.). , Saco, ME, USA) and incubated at 4 ℃. Slides were incubated with ABC kit (Vector Laboratories, Burlingame, Calif., USA) and color developed with 3,3'-diaminobenzidine tetrachloride (Zymed Laboratory Inc., South San Francisco, Calif., USA). Immunohistochemical analysis of CD31, smooth muscle actin and vimentin was found in endothelial CD31 (1/20, DAKO, Glostrup, Denmark, clone JC70A), smooth muscle actin (1/50, DAKO, Glostrup, Denmark, clone 1A4) and Performed by night at 4 ° C. with non-mentin (1/50, DAKO, Glostrup, Denmark, clone V9). For signal detection, sections were incubated with the DAKO Real Vision Detection System (DAKO, Glostrup, Denmark, K5007) according to the protocol.
result
In the Western Blot analysis, the 15.7 kDa band of FABP1 protein was clearly demonstrated in both groups. The density normalized to beta actin was significantly higher in the nasal species from the AIA group than in the ATA group (0.84 ± 0.09, P = 0.009, Figure 2). Immunohistochemical staining clearly showed increased expression of FABP 1 in the nasal species of the AIA group rather than the TA group. Vascular epithelial cells, smooth muscle cells, myofibrogenic mesenchymal cells and macrophages were strongly expressed in FABP1 protein in nasaloma tissue.
Example 5 Statistical Analysis
Statistical analysis used SPSS version 8.0 (SPSS Inc., Chicago, IL) software package. In the analysis of spot intensity and FABP1 concentration in a two-dimensional gel, the Mann-Whitmey test (two-sample rank sum test) analyzed the difference between the two groups of AIA and ATA. All data were expressed as mean ± SE and the validity was defined as P <0.05.
<110> Soonchunhyang University Industry Academy Cooperation Foundation <120> BIOMARKER FOR DIAGNOSING ASPIRIN INTOLERANT ASTHMA <130> 10P237IND <160> 15 <170> Kopatentin 1.71 <210> 1 <211> 573 <212> PRT <213> Homo sapiens <400> 1 Met Leu Arg Leu Pro Thr Val Phe Arg Gln Met Arg Pro Val Ser Arg 1 5 10 15 Val Leu Ala Pro His Leu Thr Arg Ala Tyr Ala Lys Asp Val Lys Phe 20 25 30 Gly Ala Asp Ala Arg Ala Leu Met Leu Gln Gly Val Asp Leu Leu Ala 35 40 45 Asp Ala Val Ala Val Thr Met Gly Pro Lys Gly Arg Thr Val Ile Ile 50 55 60 Glu Gln Ser Trp Gly Ser Pro Lys Val Thr Lys Asp Gly Val Thr Val 65 70 75 80 Ala Lys Ser Ile Asp Leu Lys Asp Lys Tyr Lys Asn Ile Gly Ala Lys 85 90 95 Leu Val Gln Asp Val Ala Asn Asn Thr Asn Glu Glu Ala Gly Asp Gly 100 105 110 Thr Thr Thr Ala Thr Val Leu Ala Arg Ser Ile Ala Lys Glu Gly Phe 115 120 125 Glu Lys Ile Ser Lys Gly Ala Asn Pro Val Glu Ile Arg Arg Gly Val 130 135 140 Met Leu Ala Val Asp Ala Val Ile Ala Glu Leu Lys Lys Gln Ser Lys 145 150 155 160 Pro Val Thr Thr Pro Glu Glu Ile Ala Gln Val Ala Thr Ile Ser Ala 165 170 175 Asn Gly Asp Lys Glu Ile Gly Asn Ile Ile Ser Asp Ala Met Lys Lys 180 185 190 Val Gly Arg Lys Gly Val Ile Thr Val Lys Asp Gly Lys Thr Leu Asn 195 200 205 Asp Glu Leu Glu Ile Ile Glu Gly Met Lys Phe Asp Arg Gly Tyr Ile 210 215 220 Ser Pro Tyr Phe Ile Asn Thr Ser Lys Gly Gln Lys Cys Glu Phe Gln 225 230 235 240 Asp Ala Tyr Val Leu Leu Ser Glu Lys Lys Ile Ser Ser Ile Gln Ser 245 250 255 Ile Val Pro Ala Leu Glu Ile Ala Asn Ala His Arg Lys Pro Leu Val 260 265 270 Ile Ile Ala Glu Asp Val Asp Gly Glu Ala Leu Ser Thr Leu Val Leu 275 280 285 Asn Arg Leu Lys Val Gly Leu Gln Val Val Ala Val Lys Ala Pro Gly 290 295 300 Phe Gly Asp Asn Arg Lys Asn Gln Leu Lys Asp Met Ala Ile Ala Thr 305 310 315 320 Gly Gly Ala Val Phe Gly Glu Glu Gly Leu Thr Leu Asn Leu Glu Asp 325 330 335 Val Gln Pro His Asp Leu Gly Lys Val Gly Glu Val Ile Val Thr Lys 340 345 350 Asp Asp Ala Met Leu Leu Lys Gly Lys Gly Asp Lys Ala Gln Ile Glu 355 360 365 Lys Arg Ile Gln Glu Ile Ile Glu Gln Leu Asp Val Thr Thr Ser Glu 370 375 380 Tyr Glu Lys Glu Lys Leu Asn Glu Arg Leu Ala Lys Leu Ser Asp Gly 385 390 395 400 Val Ala Val Leu Lys Val Gly Gly Thr Ser Asp Val Glu Val Asn Glu 405 410 415 Lys Lys Asp Arg Val Thr Asp Ala Leu Asn Ala Thr Arg Ala Ala Val 420 425 430 Glu Glu Gly Ile Val Leu Gly Gly Gly Cys Ala Leu Leu Arg Cys Ile 435 440 445 Pro Ala Leu Asp Ser Leu Thr Pro Ala Asn Glu Asp Gln Lys Ile Gly 450 455 460 Ile Glu Ile Ile Lys Arg Thr Leu Lys Ile Pro Ala Met Thr Ile Ala 465 470 475 480 Lys Asn Ala Gly Val Glu Gly Ser Leu Ile Val Glu Lys Ile Met Gln 485 490 495 Ser Ser Ser Glu Val Gly Tyr Asp Ala Met Ala Gly Asp Phe Val Asn 500 505 510 Met Val Glu Lys Gly Ile Ile Asp Pro Thr Lys Val Val Arg Thr Ala 515 520 525 Leu Leu Asp Ala Ala Gly Val Ala Ser Leu Leu Thr Thr Ala Glu Val 530 535 540 Val Val Thr Glu Ile Pro Lys Glu Glu Lys Asp Pro Gly Met Gly Ala 545 550 555 560 Met Gly Gly Met Gly Gly Gly Met Gly Gly Gly Met Phe 565 570 <210> 2 <211> 134 <212> PRT <213> Homo sapiens <400> 2 Met Ser Phe Ser Gly Lys Tyr Gln Leu Gln Ser Gln Glu Asn Phe Glu 1 5 10 15 Ala Phe Met Lys Ala Ile Gly Leu Pro Glu Glu Leu Ile Gln Lys Gly 20 25 30 Lys Asp Ile Lys Gly Val Ser Glu Ile Val Gln Asn Gly Lys His Phe 35 40 45 Lys Phe Thr Ile Thr Ala Gly Ser Lys Val Ile Gln Asn Glu Phe Thr 50 55 60 Val Gly Glu Glu Cys Glu Leu Glu Thr Met Thr Gly Glu Lys Val Lys 65 70 75 80 Thr Val Val Gln Leu Glu Gly Asp Asn Lys Leu Val Thr Thr Phe Lys 85 90 95 Asn Ile Lys Ser Val Thr Glu Leu Asn Gly Asp Ile Ile Thr Asn Thr 100 105 110 Met Thr Leu Gly Asp Ile Val Phe Lys Arg Ile Ser Lys Lys Lys Lys 115 120 125 Lys Lys Lys Lys Lys Lys Lys 130 <210> 3 <211> 375 <212> PRT <213> Homo sapiens <400> 3 Met Asp Asp Asp Ile Ala Ala Leu Val Val Asp Asn Gly Ser Gly Met 1 5 10 15 Cys Lys Ala Gly Phe Ala Gly Asp Asp Ala Pro Arg Ala Val Phe Pro 20 25 30 Ser Ile Val Gly Arg Pro Arg His Gln Gly Val Met Val Gly Met Gly 35 40 45 Gln Lys Asp Ser Tyr Val Gly Asp Glu Ala Gln Ser Lys Arg Gly Ile 50 55 60 Leu Thr Leu Lys Tyr Pro Ile Glu His Gly Ile Val Thr Asn Trp Asp 65 70 75 80 Asp Met Glu Lys Ile Trp His His Thr Phe Tyr Asn Glu Leu Arg Val 85 90 95 Ala Pro Glu Glu His Pro Val Leu Leu Thr Glu Ala Pro Leu Asn Pro 100 105 110 Lys Ala Asn Arg Glu Lys Met Thr Gln Ile Met Phe Glu Thr Phe Asn 115 120 125 Thr Pro Ala Met Tyr Val Ala Ile Gln Ala Val Leu Ser Leu Tyr Ala 130 135 140 Ser Gly Arg Thr Thr Gly Ile Val Met Asp Ser Gly Asp Gly Val Thr 145 150 155 160 His Thr Val Pro Ile Tyr Glu Gly Tyr Ala Leu Pro His Ala Ile Leu 165 170 175 Arg Leu Asp Leu Ala Gly Arg Asp Leu Thr Asp Tyr Leu Met Lys Ile 180 185 190 Leu Thr Glu Arg Gly Tyr Ser Phe Thr Thr Thr Ala Glu Arg Glu Ile 195 200 205 Val Arg Asp Ile Lys Glu Lys Leu Cys Tyr Val Ala Leu Asp Phe Glu 210 215 220 Gln Glu Met Ala Thr Ala Ala Ser Ser Ser Ser Leu Glu Lys Ser Tyr 225 230 235 240 Glu Leu Pro Asp Gly Gln Val Ile Thr Ile Gly Asn Glu Arg Phe Arg 245 250 255 Cys Pro Glu Ala Leu Phe Gln Pro Ser Phe Leu Gly Met Glu Ser Cys 260 265 270 Gly Ile His Glu Thr Thr Phe Asn Ser Ile Met Lys Cys Asp Val Asp 275 280 285 Ile Arg Lys Asp Leu Tyr Ala Asn Thr Val Leu Ser Gly Gly Thr Thr 290 295 300 Met Tyr Pro Gly Ile Ala Asp Arg Met Gln Lys Glu Ile Thr Ala Leu 305 310 315 320 Ala Pro Ser Thr Met Lys Ile Lys Ile Ile Ala Pro Pro Glu Arg Lys 325 330 335 Tyr Ser Val Trp Ile Gly Gly Ser Ile Leu Ala Ser Leu Ser Thr Phe 340 345 350 Gln Gln Met Trp Ile Ser Lys Gln Glu Tyr Asp Glu Ser Gly Pro Ser 355 360 365 Ile Val His Arg Lys Cys Phe 370 375 <210> 4 <211> 623 <212> PRT <213> Homo sapiens <400> 4 Met Glu Ser Tyr His Lys Pro Asp Gln Gln Lys Leu Gln Ala Leu Lys 1 5 10 15 Asp Thr Ala Asn Arg Leu Arg Ile Ser Ser Ile Gln Ala Ser Ser Ala 20 25 30 Ala Gly Ser Gly His Pro Thr Ser Cys Cys Ser Ala Ala Val Ile Met 35 40 45 Ala Val Leu Phe Phe His Thr Met Arg Tyr Lys Ser Gln Asp Pro Arg 50 55 60 Asn Pro His Asn Asp Arg Phe Val Leu Ser Lys Gly His Ala Ala Pro 65 70 75 80 Ile Leu Tyr Ala Val Trp Ala Glu Ala Gly Phe Leu Ala Glu Ala Glu 85 90 95 Leu Leu Asn Leu Arg Lys Ile Ser Ser Asp Leu Asp Gly His Pro Val 100 105 110 Pro Lys Gln Ala Phe Thr Asp Val Ala Thr Gly Ser Leu Gly Gln Gly 115 120 125 Leu Gly Ala Ala Cys Gly Met Ala Tyr Thr Gly Lys Tyr Phe Asp Lys 130 135 140 Ala Ser Tyr Arg Val Tyr Cys Leu Leu Gly Asp Gly Glu Leu Ser Glu 145 150 155 160 Gly Ser Val Trp Glu Ala Met Ala Phe Ala Ser Ile Tyr Lys Leu Asp 165 170 175 Asn Leu Val Ala Ile Leu Asp Ile Asn Arg Leu Gly Gln Ser Asp Pro 180 185 190 Ala Pro Leu Gln His Gln Met Asp Ile Tyr Gln Lys Arg Cys Glu Ala 195 200 205 Phe Gly Trp His Ala Ile Ile Val Asp Gly His Ser Val Glu Glu Leu 210 215 220 Cys Lys Ala Phe Gly Gln Ala Lys His Gln Pro Thr Ala Ile Ila 225 230 235 240 Lys Thr Phe Lys Gly Arg Gly Ile Thr Gly Val Glu Asp Lys Glu Ser 245 250 255 Trp His Gly Lys Pro Leu Pro Lys Asn Met Ala Glu Gln Ile Ile Gln 260 265 270 Glu Ile Tyr Ser Gln Ile Gln Ser Lys Lys Lys Ile Leu Ala Thr Pro 275 280 285 Pro Gln Glu Asp Ala Pro Ser Val Asp Ile Ala Asn Ile Arg Met Pro 290 295 300 Ser Leu Pro Ser Tyr Lys Val Gly Asp Lys Ile Ala Thr Arg Lys Ala 305 310 315 320 Tyr Gly Gln Ala Leu Ala Lys Leu Gly His Ala Ser Asp Arg Ile Ile 325 330 335 Ala Leu Asp Gly Asp Thr Lys Asn Ser Thr Phe Ser Glu Ile Phe Lys 340 345 350 Lys Glu His Pro Asp Arg Phe Ile Glu Cys Tyr Ile Ala Glu Gln Asn 355 360 365 Met Val Ser Ile Ala Val Gly Cys Ala Thr Arg Asn Arg Thr Val Pro 370 375 380 Phe Cys Ser Thr Phe Ala Ala Phe Phe Thr Arg Ala Phe Asp Gln Ile 385 390 395 400 Arg Met Ala Ala Ile Ser Glu Ser Asn Ile Asn Leu Cys Gly Ser His 405 410 415 Cys Gly Val Ser Ile Gly Glu Asp Gly Ala Ser Gln Met Ala Leu Glu 420 425 430 Asp Leu Ala Met Phe Arg Ser Val Pro Thr Ser Thr Val Phe Tyr Pro 435 440 445 Ser Asp Gly Val Ala Thr Glu Lys Ala Val Glu Leu Ala Ala Asn Thr 450 455 460 Lys Gly Ile Cys Phe Ile Arg Thr Ser Arg Pro Glu Asn Ala Ile Ile 465 470 475 480 Tyr Asn Asn Asn Glu Asp Phe Gln Val Gly Gln Ala Lys Val Val Leu 485 490 495 Lys Ser Lys Asp Asp Gln Val Thr Val Ile Gly Ala Gly Val Thr Leu 500 505 510 His Glu Ala Leu Ala Ala Ala Glu Leu Leu Lys Lys Glu Lys Ile Asn 515 520 525 Ile Arg Val Leu Asp Pro Phe Thr Ile Lys Pro Leu Asp Arg Lys Leu 530 535 540 Ile Leu Asp Ser Ala Arg Ala Thr Lys Gly Arg Ile Leu Thr Val Glu 545 550 555 560 Asp His Tyr Tyr Glu Gly Gly Ile Gly Glu Ala Val Ser Ser Ala Val 565 570 575 Val Gly Glu Pro Gly Ile Thr Val Thr His Leu Ala Val Asn Arg Val 580 585 590 Pro Arg Ser Gly Lys Pro Ala Glu Leu Leu Lys Met Phe Gly Ile Asp 595 600 605 Arg Asp Ala Ile Ala Gln Ala Val Arg Gly Leu Ile Thr Lys Ala 610 615 620 <210> 5 <211> 1500 <212> PRT <213> Homo sapiens <400> 5 Met Thr Arg Ile Leu Thr Ala Phe Lys Val Val Arg Thr Leu Lys Thr 1 5 10 15 Gly Phe Gly Phe Thr Asn Val Thr Ala His Gln Lys Trp Lys Phe Ser 20 25 30 Arg Pro Gly Ile Arg Leu Leu Ser Val Lys Ala Gln Thr Ala His Ile 35 40 45 Val Leu Glu Asp Gly Thr Lys Met Lys Gly Tyr Ser Phe Gly His Pro 50 55 60 Ser Ser Val Ala Gly Glu Val Val Phe Asn Thr Gly Leu Gly Gly Tyr 65 70 75 80 Pro Glu Ala Ile Thr Asp Pro Ala Tyr Lys Gly Gln Ile Leu Thr Met 85 90 95 Ala Asn Pro Ile Ile Gly Asn Gly Gly Ala Pro Asp Thr Thr Ser Leu 100 105 110 Asp Glu Leu Gly Leu Ser Lys Tyr Leu Glu Ser Asn Gly Ile Lys Val 115 120 125 Ser Gly Leu Leu Val Leu Asp Tyr Ser Lys Asp Tyr Asn His Trp Leu 130 135 140 Ala Thr Lys Ser Leu Gly Gln Trp Leu Gln Glu Glu Lys Val Pro Ala 145 150 155 160 Ile Tyr Gly Val Asp Thr Arg Met Leu Thr Lys Ile Ile Arg Asp Lys 165 170 175 Gly Thr Met Leu Gly Lys Ile Glu Phe Glu Gly Gln Pro Val Asp Phe 180 185 190 Val Asp Pro Asn Lys Gln Asn Leu Ile Ala Glu Val Ser Thr Lys Asp 195 200 205 Val Lys Val Tyr Gly Lys Gly Asn Pro Thr Lys Val Val Ala Val Asp 210 215 220 Cys Gly Ile Lys Asn Asn Val Ile Arg Leu Leu Val Lys Arg Gly Ala 225 230 235 240 Glu Val His Leu Val Pro Trp Asn His Asp Phe Thr Lys Met Glu Tyr 245 250 255 Asp Gly Ile Leu Ile Ala Gly Gly Pro Gly Asn Pro Ala Leu Ala Glu 260 265 270 Pro Leu Ile Gln Asn Val Gln Lys Ile Leu Glu Ser Asp Arg Lys Glu 275 280 285 Pro Leu Phe Gly Ile Ser Thr Gly Asn Leu Ile Thr Gly Leu Ala Ala 290 295 300 Gly Ala Lys Thr Tyr Lys Met Ser Met Ala Asn Arg Gly Gln Asn Gln 305 310 315 320 Pro Val Leu Asn Ile Thr Asn Lys Gln Ala Phe Ile Thr Ala Gln Asn 325 330 335 His Cys Tyr Ala Leu Asp Asn Thr Leu Pro Ala Gly Trp Lys Pro Leu 340 345 350 Phe Val Asn Val Asn Asp Gln Thr Asn Glu Gly Ile Met His Glu Ser 355 360 365 Lys Pro Phe Phe Ala Val Gln Phe His Pro Glu Val Thr Pro Gly Pro 370 375 380 Ile Asp Thr Glu Tyr Leu Phe Asp Ser Phe Phe Ser Leu Ile Lys Lys 385 390 395 400 Gly Lys Ala Thr Thr Ile Thr Ser Val Leu Pro Lys Pro Ala Leu Val 405 410 415 Ala Ser Arg Val Glu Val Ser Lys Val Leu Ile Leu Gly Ser Gly Gly 420 425 430 Leu Ser Ile Gly Gln Ala Gly Glu Phe Asp Tyr Ser Gly Ser Gln Ala 435 440 445 Val Lys Ala Met Lys Glu Glu Asn Val Lys Thr Val Leu Met Asn Pro 450 455 460 Asn Ile Ala Ser Val Gln Thr Asn Glu Val Gly Leu Lys Gln Ala Asp 465 470 475 480 Thr Val Tyr Phe Leu Pro Ile Thr Pro Gln Phe Val Thr Glu Val Ile 485 490 495 Lys Ala Glu Gln Pro Asp Gly Leu Ile Leu Gly Met Gly Gly Gln Thr 500 505 510 Ala Leu Asn Cys Gly Val Glu Leu Phe Lys Arg Gly Val Leu Lys Glu 515 520 525 Tyr Gly Val Lys Val Leu Gly Thr Ser Val Glu Ser Ile Met Ala Thr 530 535 540 Glu Asp Arg Gln Leu Phe Ser Asp Lys Leu Asn Glu Ile Asn Glu Lys 545 550 555 560 Ile Ala Pro Ser Phe Ala Val Glu Ser Ile Glu Asp Ala Leu Lys Ala 565 570 575 Ala Asp Thr Ile Gly Tyr Pro Val Met Ile Arg Ser Ala Tyr Ala Leu 580 585 590 Gly Gly Leu Gly Ser Gly Ile Cys Pro Asn Arg Glu Thr Leu Met Asp 595 600 605 Leu Ser Thr Lys Ala Phe Ala Met Thr Asn Gln Ile Leu Val Glu Lys 610 615 620 Ser Val Thr Gly Trp Lys Glu Ile Glu Tyr Glu Val Val Arg Asp Ala 625 630 635 640 Asp Asp Asn Cys Val Thr Val Cys Asn Met Glu Asn Val Asp Ala Met 645 650 655 Gly Val His Thr Gly Asp Ser Val Val Ala Pro Ala Gln Thr Leu 660 665 670 Ser Asn Ala Glu Phe Gln Met Leu Arg Arg Thr Ser Ile Asn Val Val 675 680 685 Arg His Leu Gly Ile Val Gly Glu Cys Asn Ile Gln Phe Ala Leu His 690 695 700 Pro Thr Ser Met Glu Tyr Cys Ile Glu Val Asn Ala Lys Met Ser 705 710 715 720 Pro Asn Ser Ala Leu Ala Ser Lys Thr Thr Gly Tyr Pro Leu Ala Phe 725 730 735 Ile Ala Ala Lys Ile Ala Leu Gly Ile Pro Leu Pro Gly Ile Lys Asn 740 745 750 Val Val Ser Gly Lys Thr Ser Ala Cys Phe Glu Pro Ser Leu Asp Tyr 755 760 765 Met Val Thr Lys Ile Pro Arg Trp Asp Leu Asp Arg Phe His Gly Thr 770 775 780 Ser Ser Arg Ile Gly Ser Ser Met Lys Ser Val Gly Glu Val Met Ala 785 790 795 800 Ile Gly Arg Thr Phe Glu Glu Ser Phe Gln Lys Ala Leu Arg Met Cys 805 810 815 His Pro Ser Ile Glu Gly Phe Thr Pro Arg Leu Pro Met Asn Lys Glu 820 825 830 Trp Pro Ser Asn Leu Asp Leu Arg Lys Glu Leu Ser Glu Pro Ser Ser 835 840 845 Thr Arg Ile Tyr Ala Ile Ala Lys Ala Ile Asp Asp Asn Met Ser Leu 850 855 860 Asp Glu Ile Glu Lys Leu Thr Tyr Ile Asp Lys Trp Phe Leu Tyr Lys 865 870 875 880 Met Arg Asp Ile Leu Asn Met Glu Lys Thr Leu Lys Gly Leu Asn Ser 885 890 895 Glu Ser Met Thr Glu Glu Thr Leu Lys Arg Ala Lys Glu Ile Gly Phe 900 905 910 Ser Asp Lys Gln Ile Ser Lys Cys Leu Gly Leu Thr Glu Ala Gln Thr 915 920 925 Arg Glu Leu Arg Leu Lys Lys Asn Ile His Pro Trp Val Lys Gln Ile 930 935 940 Asp Thr Leu Ala Ala Glu Tyr Pro Ser Val Thr Asn Tyr Leu Tyr Val 945 950 955 960 Thr Tyr Asn Gly Gln Glu His Asp Val Asn Phe Asp Asp His Gly Met 965 970 975 Met Val Leu Gly Cys Gly Pro Tyr His Ile Gly Ser Ser Val Glu Phe 980 985 990 Asp Trp Cys Ala Val Ser Ser Ile Arg Thr Leu Arg Gln Leu Gly Lys 995 1000 1005 Lys Thr Val Val Val Asn Cys Asn Pro Glu Thr Val Ser Thr Asp Phe 1010 1015 1020 Asp Glu Cys Asp Lys Leu Tyr Phe Glu Glu Leu Ser Leu Glu Arg Ile 1025 1030 1035 1040 Leu Asp Ile Tyr His Gln Glu Ala Cys Gly Gly Cys Ile Ile Ser Val 1045 1050 1055 Gly Gly Gln Ile Pro Asn Asn Leu Ala Val Pro Leu Tyr Lys Asn Gly 1060 1065 1070 Val Lys Ile Met Gly Thr Ser Pro Leu Gln Ile Asp Arg Ala Glu Asp 1075 1080 1085 Arg Ser Ile Phe Ser Ala Val Leu Asp Glu Leu Lys Val Ala Gln Ala 1090 1095 1100 Pro Trp Lys Ala Val Asn Thr Leu Asn Glu Ala Leu Glu Phe Ala Lys 1105 1110 1115 1120 Ser Val Asp Tyr Pro Cys Leu Leu Arg Pro Ser Tyr Val Leu Ser Gly 1125 1130 1135 Ser Ala Met Asn Val Val Phe Ser Glu Asp Glu Met Lys Lys Phe Leu 1140 1145 1150 Glu Glu Ala Thr Arg Val Ser Gln Ala Thr Pro Val Val Leu Thr Lys 1155 1160 1165 Phe Val Glu Gly Ala Arg Glu Val Glu Met Asp Ala Val Gly Lys Asp 1170 1175 1180 Gly Arg Val Ile Ser His Ala Ile Ser Glu His Val Glu Asp Ala Gly 1185 1190 1195 1200 Val His Ser Glu Asn Ala Thr Leu Met Leu Pro Thr Gln Thr Ile Ser 1205 1210 1215 Gln Gly Ala Ile Glu Lys Val Lys Asp Ala Thr Arg Lys Ile Ala Lys 1220 1225 1230 Ala Phe Ala Ile Ser Gly Pro Phe Asn Val Gln Phe Leu Val Lys Gly 1235 1240 1245 Asn Asp Val Leu Val Asn Glu Cys Asn Leu Arg Ala Ser Arg Ser Phe 1250 1255 1260 Pro Ser Val Ser Lys Thr Leu Gly Val Asp Phe Ile Asp Val Ala Thr 1265 1270 1275 1280 Lys Val Leu Ile Gly Glu Asn Val Asp Glu Lys His Leu Pro Thr Leu 1285 1290 1295 Asp His Pro Ile Ile Pro Val Asp Tyr Val Ala Ile Lys Ala Pro Met 1300 1305 1310 Phe Ser Trp Pro Arg Leu Arg Asp Ala Asp Pro Ile Leu Arg Cys Glu 1315 1320 1325 Met Ala Ser Thr Gly Glu Val Ala Cys Phe Gly Glu Gly Ile His Thr 1330 1335 1340 Ala Phe Leu Lys Ala Met Leu Ser Thr Gly Phe Lys Ile Pro Gln Lys 1345 1350 1355 1360 Gly Ile Leu Ile Gly Ile Gln Gln Ser Phe Arg Pro Arg Phe Leu Gly 1365 1370 1375 Val Ala Glu Gln Leu His Asn Glu Gly Phe Lys Leu Phe Ala Thr Glu 1380 1385 1390 Ala Thr Ser Asp Trp Leu Asn Ala Asn Asn Val Pro Ala Asn Pro Val 1395 1400 1405 Ala Trp Pro Ser Gln Glu Gly Gln Asn Pro Ser Leu Ser Ser Ile Arg 1410 1415 1420 Lys Leu Ile Arg Asp Gly Ser Ile Asp Leu Val Ile Asn Leu Pro Asn 1425 1430 1435 1440 Asn Asn Thr Lys Phe Val His Asp Asn Tyr Val Ile Arg Arg Thr Ala 1445 1450 1455 Val Asp Ser Gly Ile Pro Leu Leu Thr Asn Phe Gln Val Thr Lys Leu 1460 1465 1470 Phe Ala Glu Ala Val Gln Lys Ser Arg Lys Val Asp Ser Lys Ser Leu 1475 1480 1485 Phe His Tyr Arg Gln Tyr Ser Ala Gly Lys Ala Ala 1490 1495 1500 <210> 6 <211> 623 <212> PRT <213> Homo sapiens <400> 6 Met Glu Ser Tyr His Lys Pro Asp Gln Gln Lys Leu Gln Ala Leu Lys 1 5 10 15 Asp Thr Ala Asn Arg Leu Arg Ile Ser Ser Ile Gln Ala Thr Thr Ala 20 25 30 Ala Gly Ser Gly His Pro Thr Ser Cys Cys Ser Ala Ala Glu Ile Met 35 40 45 Ala Val Leu Phe Phe His Thr Met Arg Tyr Lys Ser Gln Asp Pro Arg 50 55 60 Asn Pro His Asn Asp Arg Phe Val Leu Ser Lys Gly His Ala Ala Pro 65 70 75 80 Ile Leu Tyr Ala Val Trp Ala Glu Ala Gly Phe Leu Ala Glu Ala Glu 85 90 95 Leu Leu Asn Leu Arg Lys Ile Ser Ser Asp Leu Asp Gly His Pro Val 100 105 110 Pro Lys Gln Ala Phe Thr Asp Val Ala Thr Gly Ser Leu Gly Gln Gly 115 120 125 Leu Gly Ala Ala Cys Gly Met Ala Tyr Thr Gly Lys Tyr Phe Asp Lys 130 135 140 Ala Ser Tyr Arg Val Tyr Cys Leu Leu Gly Asp Gly Glu Leu Ser Glu 145 150 155 160 Gly Ser Val Trp Glu Ala Met Ala Phe Ala Ser Ile Tyr Lys Leu Asp 165 170 175 Asn Leu Val Ala Ile Leu Asp Ile Asn Arg Leu Gly Gln Ser Asp Pro 180 185 190 Ala Pro Leu Gln His Gln Met Asp Ile Tyr Gln Lys Arg Cys Glu Ala 195 200 205 Phe Gly Trp His Ala Ile Ile Val Asp Gly His Ser Val Glu Glu Leu 210 215 220 Cys Lys Ala Phe Gly Gln Ala Lys His Gln Pro Thr Ala Ile Ila 225 230 235 240 Lys Thr Phe Lys Gly Arg Gly Ile Thr Gly Val Glu Asp Lys Glu Ser 245 250 255 Trp His Gly Lys Pro Leu Pro Lys Asn Met Ala Glu Gln Ile Ile Gln 260 265 270 Glu Ile Tyr Ser Gln Ile Gln Ser Lys Lys Lys Ile Leu Ala Thr Pro 275 280 285 Pro Gln Glu Asp Ala Pro Ser Val Asp Ile Ala Asn Ile Arg Met Pro 290 295 300 Ser Leu Pro Ser Tyr Lys Val Gly Asp Lys Ile Ala Thr Arg Lys Ala 305 310 315 320 Tyr Gly Gln Ala Leu Ala Lys Leu Gly His Ala Ser Asp Arg Ile Ile 325 330 335 Ala Leu Asp Gly Asp Thr Lys Asn Ser Thr Phe Ser Glu Ile Phe Lys 340 345 350 Lys Glu His Pro Asp Arg Phe Ile Glu Cys Tyr Ile Ala Glu Arg Asn 355 360 365 Met Val Ser Ile Ala Val Gly Cys Ala Thr Arg Asn Arg Thr Val Pro 370 375 380 Phe Cys Ser Thr Phe Ala Ala Phe Phe Thr Arg Ala Phe Asp Gln Ile 385 390 395 400 Arg Met Ala Ala Ile Ser Glu Ser Asn Ile Asn Leu Cys Gly Ser His 405 410 415 Cys Gly Val Ser Ile Gly Glu Asp Gly Pro Ser Gln Met Ala Leu Glu 420 425 430 Asp Leu Ala Met Phe Arg Ser Val Pro Thr Ser Thr Val Phe Tyr Pro 435 440 445 Ser Asp Gly Val Ala Thr Glu Lys Ala Val Glu Leu Ala Ala Asn Thr 450 455 460 Lys Gly Ile Cys Phe Ile Arg Thr Ser Arg Pro Glu Asn Ala Ile Ile 465 470 475 480 Tyr Asn Asn Asn Glu Asp Phe Gln Val Gly Gln Ala Lys Val Val Leu 485 490 495 Lys Ser Lys Asp Asp Gln Val Thr Val Ile Gly Ala Gly Val Thr Leu 500 505 510 His Glu Ala Leu Ala Ala Ala Glu Leu Leu Lys Lys Glu Lys Ile Asn 515 520 525 Ile Arg Val Leu Asp Pro Phe Thr Ile Lys Pro Leu Asp Arg Lys Leu 530 535 540 Ile Leu Asp Ser Ala Arg Ala Thr Lys Gly Arg Ile Leu Thr Val Glu 545 550 555 560 Asp His Tyr Tyr Glu Gly Gly Ile Gly Glu Ala Val Ser Ser Ala Val 565 570 575 Val Gly Glu Pro Gly Ile Thr Val Thr His Leu Ala Val Asn Arg Val 580 585 590 Pro Arg Ser Gly Lys Pro Ala Glu Leu Leu Lys Met Phe Gly Ile Asp 595 600 605 Arg Asp Ala Ile Ala Gln Ala Val Arg Gly Leu Ile Thr Lys Ala 610 615 620 <210> 7 <211> 679 <212> PRT <213> Homo sapiens <400> 7 Met Ile Ser Ala Ser Arg Ala Ala Ala Ala Arg Leu Val Gly Ala Ala 1 5 10 15 Ala Ser Arg Gly Pro Thr Ala Ala Arg His Gln Asp Ser Trp Asn Gly 20 25 30 Leu Ser His Glu Ala Phe Arg Leu Val Ser Arg Arg Asp Tyr Ala Ser 35 40 45 Glu Ala Ile Lys Gly Ala Val Val Gly Ile Asp Leu Gly Thr Thr Asn 50 55 60 Ser Cys Val Ala Val Met Glu Gly Lys Gln Ala Lys Val Leu Glu Asn 65 70 75 80 Ala Glu Gly Ala Arg Thr Thr Pro Ser Val Val Ala Phe Thr Ala Asp 85 90 95 Gly Glu Arg Leu Val Gly Met Pro Ala Lys Arg Gln Ala Val Thr Asn 100 105 110 Pro Asn Asn Thr Phe Tyr Ala Thr Lys Arg Leu Ile Gly Arg Arg Tyr 115 120 125 Asp Asp Pro Glu Val Gln Lys Asp Ile Lys Asn Val Pro Phe Lys Ile 130 135 140 Val Arg Ala Ser Asn Gly Asp Ala Trp Val Glu Ala His Gly Lys Leu 145 150 155 160 Tyr Ser Pro Ser Gln Ile Gly Ala Phe Val Leu Met Lys Met Lys Glu 165 170 175 Thr Ala Glu Asn Tyr Leu Gly His Thr Ala Lys Asn Ala Val Ile Thr 180 185 190 Val Pro Ala Tyr Phe Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp Ala 195 200 205 Gly Gln Ile Ser Gly Leu Asn Val Leu Arg Val Ile Asn Glu Pro Thr 210 215 220 Ala Ala Ala Leu Ala Tyr Gly Leu Asp Lys Ser Glu Asp Lys Val Ile 225 230 235 240 Ala Val Tyr Asp Leu Gly Gly Gly Thr Phe Asp Ile Ser Ile Leu Glu 245 250 255 Ile Gln Lys Gly Val Phe Glu Val Lys Ser Thr Asn Gly Asp Thr Phe 260 265 270 Leu Gly Gly Glu Asp Phe Asp Gln Ala Leu Leu Arg His Ile Val Lys 275 280 285 Glu Phe Lys Arg Glu Thr Gly Val Asp Leu Thr Lys Asp Asn Met Ala 290 295 300 Leu Gln Arg Val Arg Glu Ala Ala Glu Lys Ala Lys Cys Glu Leu Ser 305 310 315 320 Ser Ser Val Gln Thr Asp Ile Asn Leu Pro Tyr Leu Thr Met Asp Ser 325 330 335 Ser Gly Pro Lys His Leu Asn Met Lys Leu Thr Arg Ala Gln Phe Glu 340 345 350 Gly Ile Val Thr Asp Leu Ile Arg Arg Thr Ile Ala Pro Cys Gln Lys 355 360 365 Ala Met Gln Asp Ala Glu Val Ser Lys Ser Asp Ile Gly Glu Val Ile 370 375 380 Leu Val Gly Gly Met Thr Arg Met Pro Lys Val Gln Gln Thr Val Gln 385 390 395 400 Asp Leu Phe Gly Arg Ala Pro Ser Lys Ala Val Asn Pro Asp Glu Ala 405 410 415 Val Ala Ile Gly Ala Ala Ile Gln Gly Gly Val Leu Ala Gly Asp Val 420 425 430 Thr Asp Val Leu Leu Leu Asp Val Thr Pro Leu Ser Leu Gly Ile Glu 435 440 445 Thr Leu Gly Gly Val Phe Thr Lys Leu Ile Asn Arg Asn Thr Thr Ile 450 455 460 Pro Thr Lys Lys Ser Gln Val Phe Ser Thr Ala Ala Asp Gly Gln Thr 465 470 475 480 Gln Val Glu Ile Lys Val Cys Gln Gly Glu Arg Glu Met Ala Gly Asp 485 490 495 Asn Lys Leu Leu Gly Gln Phe Thr Leu Ile Gly Ile Pro Pro Ala Pro 500 505 510 Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile Asp Ala Asn Gly 515 520 525 Ile Val His Val Ser Ala Lys Asp Lys Gly Thr Gly Arg Glu Gln Gln 530 535 540 Ile Val Ile Gln Ser Ser Gly Gly Leu Ser Lys Asp Asp Ile Glu Asn 545 550 555 560 Met Val Lys Asn Ala Glu Lys Tyr Ala Glu Glu Asp Arg Arg Lys Lys 565 570 575 Glu Arg Val Glu Ala Val Asn Met Ala Glu Gly Ile Ile His Asp Thr 580 585 590 Glu Thr Lys Met Glu Glu Phe Lys Asp Gln Leu Pro Ala Asp Glu Cys 595 600 605 Asn Lys Leu Lys Glu Glu Ile Ser Lys Met Arg Glu Leu Leu Ala Arg 610 615 620 Lys Asp Ser Glu Thr Gly Glu Asn Ile Arg Gln Ala Ala Ser Ser Leu 625 630 635 640 Gln Gln Ala Ser Leu Lys Leu Phe Glu Met Ala Tyr Lys Lys Met Ala 645 650 655 Ser Glu Arg Glu Gly Ser Gly Ser Ser Gly Thr Gly Glu Gln Lys Glu 660 665 670 Asp Gln Lys Glu Glu Lys Gln 675 <210> 8 <211> 508 <212> PRT <213> Homo sapiens <400> 8 Met Ser Arg Phe Val Gln Asp Leu Ser Lys Ala Met Ser Gln Asp Gly 1 5 10 15 Ala Ser Gln Phe Gln Glu Val Ile Arg Gln Glu Leu Glu Leu Ser Val 20 25 30 Lys Lys Glu Leu Glu Lys Ile Leu Thr Thr Ala Ser Ser His Glu Phe 35 40 45 Glu His Thr Lys Lys Asp Leu Asp Gly Phe Arg Lys Leu Phe His Arg 50 55 60 Phe Leu Gln Glu Lys Gly Pro Ser Val Asp Trp Gly Lys Ile Gln Arg 65 70 75 80 Pro Pro Glu Asp Ser Ile Gln Pro Tyr Glu Lys Ile Lys Ala Arg Gly 85 90 95 Leu Pro Asp Asn Ile Ser Ser Val Leu Asn Lys Leu Val Val Val Lys 100 105 110 Leu Asn Gly Gly Leu Gly Thr Ser Met Gly Cys Lys Gly Pro Lys Ser 115 120 125 Leu Ile Gly Val Arg Asn Glu Asn Thr Phe Leu Asp Leu Thr Val Gln 130 135 140 Gln Ile Glu His Leu Asn Lys Thr Tyr Asn Thr Asp Val Pro Leu Val 145 150 155 160 Leu Met Asn Ser Phe Asn Thr Asp Glu Asp Thr Lys Lys Ile Leu Gln 165 170 175 Lys Tyr Asn His Cys Arg Val Lys Ile Tyr Thr Phe Asn Gln Ser Arg 180 185 190 Tyr Pro Arg Ile Asn Lys Glu Ser Leu Leu Pro Val Ala Lys Asp Val 195 200 205 Ser Tyr Ser Gly Glu Asn Thr Glu Ala Trp Tyr Pro Pro Gly His Gly 210 215 220 Asp Ile Tyr Ala Ser Phe Tyr Asn Ser Gly Leu Leu Asp Thr Phe Ile 225 230 235 240 Gly Glu Gly Lys Glu Tyr Ile Phe Val Ser Asn Ile Asp Asn Leu Gly 245 250 255 Ala Thr Val Asp Leu Tyr Ile Leu Asn His Leu Met Asn Pro Pro Asn 260 265 270 Gly Lys Arg Cys Glu Phe Val Met Glu Val Thr Asn Lys Thr Arg Ala 275 280 285 Asp Val Lys Gly Gly Thr Leu Thr Gln Tyr Glu Gly Lys Leu Arg Leu 290 295 300 Val Glu Ile Ala Gln Val Pro Lys Ala His Val Asp Glu Phe Lys Ser 305 310 315 320 Val Ser Lys Phe Lys Ile Phe Asn Thr Asn Asn Leu Trp Ile Ser Leu 325 330 335 Ala Ala Val Lys Arg Leu Gln Glu Gln Asn Ala Ile Asp Met Glu Ile 340 345 350 Ile Val Asn Ala Lys Thr Leu Asp Gly Gly Leu Asn Val Ile Gln Leu 355 360 365 Glu Thr Ala Val Gly Ala Ala Ile Lys Ser Phe Glu Asn Ser Leu Gly 370 375 380 Ile Asn Val Pro Arg Ser Arg Phe Leu Pro Val Lys Thr Thr Ser Asp 385 390 395 400 Leu Leu Leu Val Met Ser Asn Leu Tyr Ser Leu Asn Ala Gly Ser Leu 405 410 415 Thr Met Ser Glu Lys Arg Glu Phe Pro Thr Val Pro Leu Val Lys Leu 420 425 430 Gly Ser Ser Phe Thr Lys Val Gln Asp Tyr Leu Arg Arg Phe Glu Ser 435 440 445 Ile Pro Asp Met Leu Glu Leu Asp His Leu Thr Val Ser Gly Asp Val 450 455 460 Thr Phe Gly Lys Asn Val Ser Leu Lys Gly Thr Val Ile Ile Ile Ala 465 470 475 480 Asn His Gly Asp Arg Ile Asp Ile Pro Pro Gly Ala Val Leu Glu Asn 485 490 495 Lys Ile Val Ser Gly Asn Leu Arg Ile Leu Asp His 500 505 <210> 9 <211> 563 <212> PRT <213> Homo sapiens <400> 9 Met Leu Leu Pro Ala Pro Ala Leu Arg Arg Ala Leu Leu Ser Arg Pro 1 5 10 15 Trp Thr Gly Ala Gly Leu Arg Trp Lys His Thr Ser Ser Leu Lys Val 20 25 30 Ala Asn Glu Pro Val Leu Ala Phe Thr Gln Gly Ser Pro Glu Arg Asp 35 40 45 Ala Leu Gln Lys Ala Leu Lys Asp Leu Lys Gly Arg Met Glu Ala Ile 50 55 60 Pro Cys Val Val Gly Asp Glu Glu Val Trp Thr Ser Asp Val Gln Tyr 65 70 75 80 Gln Val Ser Pro Phe Asn His Gly His Lys Val Ala Lys Phe Cys Tyr 85 90 95 Ala Asp Lys Ser Leu Leu Asn Lys Ala Ile Glu Ala Ala Leu Ala Ala 100 105 110 Arg Lys Glu Trp Asp Leu Lys Pro Ile Ala Asp Arg Ala Gln Ile Phe 115 120 125 Leu Lys Ala Ala Asp Met Leu Ser Gly Pro Arg Arg Ala Glu Ile Leu 130 135 140 Ala Lys Thr Met Val Gly Gln Gly Lys Thr Val Ile Gln Ala Glu Ile 145 150 155 160 Asp Ala Ala Ala Glu Leu Ile Asp Phe Phe Arg Phe Asn Ala Lys Tyr 165 170 175 Ala Val Glu Leu Glu Gly Gln Gln Pro Ile Ser Val Pro Pro Ser Thr 180 185 190 Asn Ser Thr Val Tyr Arg Gly Leu Glu Gly Phe Val Ala Ala Ile Ser 195 200 205 Pro Phe Asn Phe Thr Ala Ile Gly Gly Asn Leu Ala Gly Ala Pro Ala 210 215 220 Leu Met Gly Asn Val Val Leu Trp Lys Pro Ser Asp Thr Ala Met Leu 225 230 235 240 Ala Ser Tyr Ala Val Tyr Arg Ile Leu Arg Glu Ala Gly Leu Pro Pro 245 250 255 Asn Ile Ile Gln Phe Val Pro Ala Asp Gly Pro Leu Phe Gly Asp Thr 260 265 270 Val Thr Ser Ser Glu His Leu Cys Gly Ile Asn Phe Thr Gly Ser Val 275 280 285 Pro Thr Phe Lys His Leu Trp Lys Gln Val Ala Gln Asn Leu Asp Arg 290 295 300 Phe His Thr Phe Pro Arg Leu Ala Gly Glu Cys Gly Gly Lys Asn Phe 305 310 315 320 His Phe Val His Arg Ser Ala Asp Val Glu Ser Val Val Ser Gly Thr 325 330 335 Leu Arg Ser Ala Phe Glu Tyr Gly Gly Gln Lys Cys Ser Ala Cys Ser 340 345 350 Arg Leu Tyr Val Pro His Ser Leu Trp Pro Gln Ile Lys Gly Arg Leu 355 360 365 Leu Glu Glu His Ser Arg Ile Lys Val Gly Asp Pro Ala Glu Asp Phe 370 375 380 Gly Thr Phe Phe Ser Ala Val Ile Asp Ala Lys Ser Phe Ala Arg Ile 385 390 395 400 Lys Lys Trp Leu Glu His Ala Arg Ser Ser Pro Ser Leu Thr Ile Leu 405 410 415 Ala Gly Gly Lys Cys Asp Asp Ser Val Gly Tyr Phe Val Glu Pro Cys 420 425 430 Ile Val Glu Ser Lys Asp Pro Gln Glu Pro Ile Met Lys Glu Glu Ile 435 440 445 Phe Gly Pro Val Leu Ser Val Tyr Val Tyr Pro Asp Asp Lys Tyr Lys 450 455 460 Glu Thr Leu Gln Leu Val Asp Ser Thr Thr Ser Tyr Gly Leu Thr Gly 465 470 475 480 Ala Val Phe Ser Gln Asp Lys Asp Val Val Gln Glu Ala Thr Lys Val 485 490 495 Leu Arg Asn Ala Ala Gly Asn Phe Tyr Ile Asn Asp Lys Ser Thr Gly 500 505 510 Ser Ile Val Gly Gln Gln Pro Phe Gly Gly Ala Arg Ala Ser Gly Thr 515 520 525 Asn Asp Lys Pro Gly Gly Pro His Tyr Ile Leu Arg Trp Thr Ser Pro 530 535 540 Gln Val Ile Lys Glu Thr His Lys Pro Leu Gly Asp Trp Ser Tyr Ala 545 550 555 560 Tyr Met Gln <210> 10 <211> 284 <212> PRT <213> Homo sapiens <400> 10 Met Pro Pro Val Gly Gly Lys Lys Ala Lys Lys Gly Ile Leu Glu Arg 1 5 10 15 Leu Asn Ala Gly Glu Ile Val Ile Gly Asp Gly Gly Phe Val Phe Ala 20 25 30 Leu Glu Lys Arg Gly Tyr Val Lys Ala Gly Pro Trp Thr Pro Glu Ala 35 40 45 Ala Val Glu His Pro Glu Ala Val Arg Gln Leu His Arg Glu Phe Leu 50 55 60 Arg Ala Gly Ser Asn Val Met Gln Thr Phe Thr Phe Tyr Ala Ser Glu 65 70 75 80 Asp Lys Leu Glu Asn Arg Gly Ala Ser Ile Ile Gly Val Asn Cys His 85 90 95 Phe Asp Pro Thr Ile Ser Leu Lys Thr Val Lys Leu Met Lys Glu Gly 100 105 110 Leu Glu Ala Ala Arg Leu Lys Ala His Leu Met Ser Gln Pro Leu Ala 115 120 125 Tyr His Thr Pro Asp Cys Asn Lys Gln Gly Phe Ile Asp Leu Pro Glu 130 135 140 Phe Pro Phe Gly Leu Glu Pro Arg Val Ala Thr Arg Trp Asp Ile Gln 145 150 155 160 Lys Tyr Ala Arg Glu Ala Tyr Asn Leu Gly Val Arg Tyr Ile Gly Gly 165 170 175 Cys Cys Gly Phe Glu Pro Tyr His Ile Arg Ala Ile Ala Glu Glu Leu 180 185 190 Ala Pro Glu Arg Gly Phe Leu Pro Pro Ala Ser Glu Lys His Gly Ser 195 200 205 Trp Gly Ser Gly Leu Asp Met His Thr Lys Pro Trp Val Arg Ala Arg 210 215 220 Ala Arg Lys Glu Tyr Trp Glu Asn Leu Arg Ile Ala Ser Gly Arg Pro 225 230 235 240 Tyr Asn Pro Ser Met Ser Lys Pro Asp Gly Trp Gly Val Thr Lys Gly 245 250 255 Thr Ala Glu Leu Met Gln Gln Lys Glu Ala Thr Thr Glu Gln Gln Leu 260 265 270 Lys Glu Leu Phe Glu Lys Gln Lys Phe Lys Ser Gln 275 280 <210> 11 <211> 117 <212> PRT <213> Homo sapiens <400> 11 Met Ala Ser Phe Pro Leu Leu Leu Thr Leu Leu Thr His Cys Ala Gly 1 5 10 15 Ser Trp Ala Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 20 25 30 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile 35 40 45 Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 50 55 60 Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp 65 70 75 80 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 85 90 95 Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp 100 105 110 Asp Ser Leu Asn Gly 115 <210> 12 <211> 335 <212> PRT <213> Homo sapiens <400> 12 Met Gly Lys Val Lys Val Gly Val Asn Gly Phe Gly Arg Ile Gly Arg 1 5 10 15 Leu Val Thr Arg Ala Ala Phe Asn Ser Gly Lys Val Asp Ile Val Ala 20 25 30 Ile Asn Asp Pro Phe Ile Asp Leu Asn Tyr Met Val Tyr Met Phe Gln 35 40 45 Tyr Asp Ser Thr His Gly Lys Phe His Gly Thr Val Lys Ala Glu Asn 50 55 60 Gly Lys Leu Val Ile Asn Gly Asn Pro Ile Thr Ile Phe Gln Glu Arg 65 70 75 80 Asp Pro Ser Lys Ile Lys Trp Gly Asp Ala Gly Ala Glu Tyr Val Val 85 90 95 Glu Ser Thr Gly Val Phe Thr Thr Met Glu Lys Ala Gly Ala His Leu 100 105 110 Gln Gly Gly Ala Lys Arg Val Ile Ile Ser Ala Pro Ser Ala Asp Ala 115 120 125 Pro Met Phe Val Met Gly Val Asn His Glu Lys Tyr Asp Asn Ser Leu 130 135 140 Lys Ile Ile Ser Asn Ala Ser Cys Thr Thr Asn Cys Leu Ala Pro Leu 145 150 155 160 Ala Lys Val Ile His Asp Asn Phe Gly Ile Val Glu Gly Leu Met Thr 165 170 175 Thr Val His Ala Ile Thr Ala Thr Gln Lys Thr Val Asp Gly Pro Ser 180 185 190 Gly Lys Leu Trp Arg Asp Gly Arg Gly Ala Leu Gln Asn Ile Ile Pro 195 200 205 Ala Ser Thr Gly Ala Ala Lys Ala Val Gly Lys Val Ile Pro Glu Leu 210 215 220 Asp Gly Lys Leu Thr Gly Met Ala Phe Arg Val Pro Thr Ala Asn Val 225 230 235 240 Ser Val Val Asp Leu Thr Cys Arg Leu Glu Lys Pro Ala Lys Tyr Asp 245 250 255 Asp Ile Lys Lys Val Val Lys Gln Ala Ser Glu Gly Pro Leu Lys Gly 260 265 270 Ile Leu Gly Tyr Thr Glu His Gln Val Val Ser Ser Asp Phe Asn Ser 275 280 285 Asp Thr His Ser Ser Thr Phe Asp Ala Gly Ala Gly Ile Ala Leu Asn 290 295 300 Asp His Phe Val Lys Leu Ile Ser Trp Tyr Asp Asn Glu Phe Gly Tyr 305 310 315 320 Ser Asn Arg Val Val Asp Leu Met Ala His Met Ala Ser Lys Glu 325 330 335 <210> 13 <211> 137 <212> PRT <213> Homo sapiens <400> 13 Met Ser Ser Leu Ile Arg Arg Val Ile Ser Thr Ala Lys Ala Pro Gly 1 5 10 15 Ala Ile Gly Pro Tyr Ser Gln Ala Val Leu Val Asp Arg Thr Ile Tyr 20 25 30 Ile Ser Gly Gln Ile Gly Met Asp Pro Ser Ser Gly Gln Leu Val Ser 35 40 45 Gly Gly Val Ala Glu Glu Ala Lys Gln Ala Leu Lys Asn Met Gly Glu 50 55 60 Ile Leu Lys Ala Ala Gly Cys Asp Phe Thr Asn Val Val Lys Thr Thr 65 70 75 80 Val Leu Leu Ala Asp Ile Asn Asp Phe Asn Thr Val Asn Glu Ile Tyr 85 90 95 Lys Gln Tyr Phe Lys Ser Asn Phe Pro Ala Arg Ala Ala Tyr Gln Val 100 105 110 Ala Ala Leu Pro Lys Gly Ser Arg Ile Glu Ile Glu Ala Val Ala Ile 115 120 125 Gln Gly Pro Leu Thr Thr Ala Ser Leu 130 135 <210> 14 <211> 1005 <212> PRT <213> Homo sapiens <400> 14 Leu Leu Ser Arg Met Pro Ser Thr Asn Arg Ala Gly Ser Leu Lys Asp 1 5 10 15 Pro Glu Ile Ala Glu Leu Phe Phe Lys Glu Asp Pro Glu Lys Leu Phe 20 25 30 Thr Asp Leu Arg Glu Ile Gly His Gly Ser Phe Gly Ala Val Tyr Phe 35 40 45 Ala Arg Asp Val Arg Thr Asn Glu Val Val Ala Ile Lys Lys Met Ser 50 55 60 Tyr Ser Gly Lys Gln Ser Thr Glu Lys Trp Gln Asp Ile Ile Lys Glu 65 70 75 80 Val Lys Phe Leu Gln Arg Ile Lys His Pro Asn Ser Ile Glu Tyr Lys 85 90 95 Gly Cys Tyr Leu Arg Glu His Thr Ala Trp Leu Val Met Glu Tyr Cys 100 105 110 Leu Gly Ser Ala Ser Asp Leu Leu Glu Val His Lys Lys Pro Leu Gln 115 120 125 Glu Val Glu Ile Ala Ala Ile Thr His Gly Ala Leu Gln Gly Leu Ala 130 135 140 Tyr Leu His Ser His Thr Met Ile His Arg Asp Ile Lys Ala Gly Asn 145 150 155 160 Ile Leu Leu Thr Glu Pro Gly Gln Val Lys Leu Ala Asp Phe Gly Ser 165 170 175 Ala Ser Met Ala Ser Pro Ala Asn Ser Phe Val Gly Thr Pro Tyr Trp 180 185 190 Met Ala Pro Glu Val Ile Leu Ala Met Asp Glu Gly Gln Tyr Asp Gly 195 200 205 Lys Val Asp Val Trp Ser Leu Gly Ile Thr Cys Ile Glu Leu Ala Glu 210 215 220 Arg Lys Pro Pro Leu Phe Asn Met Asn Ala Met Ser Ala Leu Tyr His 225 230 235 240 Ile Ala Gln Asn Glu Ser Pro Thr Leu Gln Ser Asn Glu Trp Ser Asp 245 250 255 Tyr Phe Arg Asn Phe Val Asp Ser Cys Leu Gln Lys Ile Pro Gln Asp 260 265 270 Arg Pro Thr Ser Glu Glu Leu Leu Lys His Ile Phe Val Leu Arg Glu 275 280 285 Arg Pro Glu Thr Val Leu Ile Asp Leu Ile Gln Arg Thr Lys Asp Ala 290 295 300 Val Arg Glu Leu Asp Asn Leu Gln Tyr Arg Lys Met Lys Lys Leu Leu 305 310 315 320 Phe Gln Glu Ala His Asn Gly Pro Ala Val Glu Ala Gln Glu Glu Glu 325 330 335 Glu Glu Gln Asp His Gly Val Gly Arg Thr Gly Thr Val Asn Ser Val 340 345 350 Gly Ser Asn Gln Ser Ile Pro Ser Met Ser Ile Ser Ala Ser Ser Gln 355 360 365 Ser Ser Ser Val Asn Ser Leu Pro Asp Val Ser Asp Asp Lys Ser Glu 370 375 380 Leu Asp Met Met Glu Gly Asp His Thr Val Met Ser Asn Ser Ser Val 385 390 395 400 Ile His Leu Lys Pro Glu Glu Glu Asn Tyr Arg Glu Glu Gly Asp Pro 405 410 415 Arg Thr Arg Ala Ser Asp Pro Gln Ser Pro Pro Gln Val Ser Arg His 420 425 430 Lys Ser His Tyr Arg Asn Arg Glu His Phe Ala Thr Ile Arg Thr Ala 435 440 445 Ser Leu Val Thr Arg Gln Met Gln Glu His Glu Gln Asp Ser Glu Leu 450 455 460 Arg Glu Gln Met Ser Gly Tyr Lys Arg Met Arg Arg Gln His Gln Lys 465 470 475 480 Gln Leu Met Thr Leu Glu Asn Lys Leu Lys Ala Glu Met Asp Glu His 485 490 495 Arg Leu Arg Leu Asp Lys Asp Leu Glu Thr Gln Arg Asn Asn Phe Ala 500 505 510 Ala Glu Met Glu Lys Leu Ile Lys Lys His Gln Ala Ala Met Glu Lys 515 520 525 Glu Ala Lys Val Met Ser Asn Glu Glu Lys Lys Phe Gln Gln His Ile 530 535 540 Gln Ala Gln Gln Lys Lys Glu Leu Asn Ser Phe Leu Glu Ser Gln Lys 545 550 555 560 Arg Glu Tyr Lys Leu Arg Lys Glu Gln Leu Lys Glu Glu Leu Asn Glu 565 570 575 Asn Gln Ser Thr Pro Lys Lys Glu Lys Gln Glu Trp Leu Ser Lys Gln 580 585 590 Lys Glu Asn Ile Gln His Phe Gln Ala Glu Glu Glu Ala Asn Leu Leu 595 600 605 Arg Arg Gln Arg Gln Tyr Leu Glu Leu Glu Cys Arg Arg Phe Lys Arg 610 615 620 Arg Met Leu Leu Gly Arg His Asn Leu Glu Gln Asp Leu Val Arg Glu 625 630 635 640 Glu Leu Asn Lys Arg Gln Thr Gln Lys Asp Leu Glu His Ala Met Leu 645 650 655 Leu Arg Gln His Glu Ser Met Gln Glu Leu Glu Phe Arg His Leu Asn 660 665 670 Thr Ile Gln Lys Met Arg Cys Glu Leu Ile Arg Leu Gln His Gln Thr 675 680 685 Glu Leu Thr Asn Gln Leu Glu Tyr Asn Lys Arg Arg Glu Arg Glu Leu 690 695 700 Arg Arg Lys His Val Met Glu Val Arg Gln Gln Pro Lys Ser Leu Lys 705 710 715 720 Ser Lys Glu Leu Gln Ile Lys Lys Gln Phe Gln Asp Thr Cys Lys Ile 725 730 735 Gln Thr Arg Gln Tyr Lys Ala Leu Arg Asn His Leu Leu Glu Thr Thr 740 745 750 Pro Lys Ser Glu His Lys Ala Val Leu Lys Arg Leu Lys Glu Glu Gln 755 760 765 Thr Arg Lys Leu Ala Ile Leu Ala Glu Gln Tyr Asp His Ser Ile Asn 770 775 780 Glu Met Leu Ser Thr Gln Ala Leu Arg Leu Asp Glu Ala Gln Glu Ala 785 790 795 800 Glu Cys Gln Val Leu Lys Met Gln Leu Gln Gln Glu Leu Glu Leu Leu 805 810 815 Asn Ala Tyr Gln Ser Lys Ile Lys Met Gln Ala Glu Ala Gln His Asp 820 825 830 Arg Glu Leu Arg Glu Leu Glu Gln Arg Val Ser Leu Arg Arg Ala Leu 835 840 845 Leu Glu Gln Lys Ile Glu Glu Glu Met Leu Ala Leu Gln Asn Glu Arg 850 855 860 Thr Glu Arg Ile Arg Ser Leu Leu Glu Arg Gln Ala Arg Glu Ile Glu 865 870 875 880 Ala Phe Asp Ser Glu Ser Met Arg Leu Gly Phe Ser Asn Met Val Leu 885 890 895 Ser Asn Leu Ser Pro Glu Ala Phe Ser His Ser Tyr Pro Gly Ala Ser 900 905 910 Gly Trp Ser His Asn Pro Thr Gly Gly Pro Gly Pro His Trp Gly His 915 920 925 Pro Met Gly Gly Pro Pro Gln Ala Trp Gly His Pro Met Gln Gly Gly 930 935 940 Pro Gln Pro Trp Gly His Pro Ser Gly Pro Met Gln Gly Val Pro Arg 945 950 955 960 Gly Ser Ser Met Gly Val Arg Asn Ser Pro Gln Ala Leu Arg Arg Thr 965 970 975 Ala Ser Gly Gly Arg Thr Glu Gln Gly Met Ser Arg Ser Thr Ser Val 980 985 990 Thr Ser Gln Ile Ser Asn Gly Ser His Met Ser Tyr Thr 995 1000 1005 <210> 15 <211> 1411 <212> PRT <213> Homo sapiens <400> 15 Met Ser Leu Ser Ser Gly Ala Ser Gly Gly Lys Gly Val Asp Ala Asn 1 5 10 15 Pro Val Glu Thr Tyr Asp Ser Gly Asp Glu Trp Asp Ile Gly Val Gly 20 25 30 Asn Leu Ile Ile Asp Leu Asp Ala Asp Leu Glu Lys Asp Gln Gln Lys 35 40 45 Leu Glu Met Ser Gly Ser Lys Glu Val Gly Ile Pro Ala Pro Asn Ala 50 55 60 Val Ala Thr Leu Pro Asp Asn Ile Lys Phe Val Thr Pro Val Pro Gly 65 70 75 80 Pro Gln Gly Lys Glu Gly Lys Ser Lys Ser Lys Arg Ser Lys Ser Gly 85 90 95 Lys Asp Thr Ser Lys Pro Thr Pro Gly Thr Ser Leu Phe Thr Pro Ser 100 105 110 Glu Gly Ala Ala Ser Lys Lys Glu Val Gln Gly Arg Ser Gly Asp Gly 115 120 125 Ala Asn Ala Gly Gly Leu Val Ala Ala Ile Ala Pro Lys Gly Ser Glu 130 135 140 Lys Ala Ala Lys Ala Ser Arg Ser Val Ala Gly Ser Lys Lys Glu Lys 145 150 155 160 Glu Asn Ser Ser Ser Lys Ser Lys Lys Glu Arg Ser Glu Gly Val Gly 165 170 175 Thr Cys Ser Glu Lys Asp Pro Gly Val Leu Gln Pro Val Pro Leu Gly 180 185 190 Gly Arg Gly Gly Gln Tyr Asp Gly Ser Ala Gly Val Asp Thr Gly Ala 195 200 205 Val Glu Pro Leu Gly Ser Ile Ala Ile Glu Pro Gly Ala Ala Leu Asn 210 215 220 Pro Leu Gly Thr Lys Pro Glu Pro Glu Glu Gly Glu Asn Glu Cys Arg 225 230 235 240 Leu Leu Lys Lys Val Lys Ser Glu Lys Met Glu Ser Pro Val Ser Thr 245 250 255 Pro Ala Val Leu Pro Ile His Leu Leu Val Pro Val Val Asn Asn Asp 260 265 270 Ile Ser Ser Pro Cys Glu Gln Ile Met Val Arg Thr Arg Ser Val Gly 275 280 285 Val Asn Thr Cys Asp Val Ala Leu Ala Thr Glu Pro Glu Cys Leu Gly 290 295 300 Pro Cys Glu Pro Gly Thr Ser Val Asn Leu Glu Gly Ile Val Trp Gln 305 310 315 320 Glu Thr Glu Asp Gly Met Leu Val Val Asn Val Thr Trp Arg Asn Lys 325 330 335 Thr Tyr Val Gly Thr Leu Leu Asp Cys Thr Arg His Asp Trp Ala Pro 340 345 350 Pro Arg Phe Cys Asp Ser Pro Thr Ser Asp Leu Glu Met Arg Asn Gly 355 360 365 Arg Gly Arg Gly Lys Arg Met Arg Pro Asn Ser Asn Thr Pro Val Asn 370 375 380 Glu Thr Ala Thr Ala Ser Asp Ser Lys Gly Thr Ser Asn Ser Ser Lys 385 390 395 400 Thr Arg Ala Gly Ala Asn Ser Lys Gly Arg Arg Gly Ser Gln Asn Ser 405 410 415 Ser Glu His Arg Pro Pro Ala Ser Ser Thr Ser Glu Asp Val Lys Ala 420 425 430 Ser Pro Ser Ser Ala Asn Lys Arg Lys Asn Lys Pro Leu Ser Asp Met 435 440 445 Glu Leu Asn Ser Ser Ser Glu Asp Ser Lys Gly Ser Lys Arg Val Arg 450 455 460 Thr Asn Ser Met Gly Ser Ala Thr Gly Pro Leu Pro Gly Thr Lys Val 465 470 475 480 Glu Pro Thr Val Leu Asp Arg Asn Cys Pro Ser Pro Val Leu Ile Asp 485 490 495 Cys Pro His Pro Asn Cys Asn Lys Lys Tyr Lys His Ile Asn Gly Leu 500 505 510 Lys Tyr His Gln Ala His Ala His Thr Asp Asp Asp Ser Lys Pro Glu 515 520 525 Ala Asp Gly Asp Ser Glu Tyr Gly Glu Glu Pro Ile Leu His Ala Asp 530 535 540 Leu Gly Ser Cys Asn Gly Ala Ser Val Ser Gln Lys Gly Ser Leu Ser 545 550 555 560 Pro Ala Arg Ser Ala Thr Pro Lys Val Arg Leu Val Glu Pro His Ser 565 570 575 Pro Ser Pro Ser Ser Lys Phe Ser Thr Lys Gly Leu Cys Lys Lys Lys 580 585 590 Leu Ser Gly Glu Gly Asp Thr Asp Leu Gly Ala Leu Ser Asn Asp Gly 595 600 605 Ser Asp Asp Gly Pro Ser Val Met Asp Glu Thr Ser Asn Asp Ala Phe 610 615 620 Asp Ser Leu Glu Arg Lys Cys Met Glu Lys Glu Lys Cys Lys Lys Pro 625 630 635 640 Ser Ser Leu Lys Pro Glu Lys Ile Pro Ser Lys Ser Leu Lys Ser Ala 645 650 655 Arg Pro Ile Ala Pro Ala Ile Pro Pro Gln Gln Ile Tyr Thr Phe Gln 660 665 670 Thr Ala Thr Phe Thr Ala Ala Ser Pro Gly Ser Ser Ser Gly Leu Thr 675 680 685 Ala Thr Val Ala Gln Ala Met Pro Asn Ser Pro Gln Leu Lys Pro Ile 690 695 700 Gln Pro Lys Pro Thr Val Met Gly Glu Pro Phe Thr Val Asn Pro Ala 705 710 715 720 Leu Thr Pro Ala Lys Asp Lys Lys Lys Lys Asp Lys Lys Lys Lys Glu 725 730 735 Ser Ser Lys Glu Leu Glu Ser Pro Leu Thr Pro Gly Lys Val Cys Arg 740 745 750 Ala Glu Glu Gly Lys Ser Pro Phe Arg Glu Ser Ser Gly Asp Gly Met 755 760 765 Lys Met Glu Gly Leu Leu Asn Gly Ser Ser Asp Pro His Gln Ser Arg 770 775 780 Leu Ala Ser Ile Lys Ala Glu Ala Asp Lys Ile Tyr Ser Phe Thr Asp 785 790 795 800 Asn Ala Pro Ser Pro Ser Ile Gly Gly Ser Ser Arg Leu Glu Asn Thr 805 810 815 Thr Pro Thr Gln Pro Leu Thr Pro Leu His Val Val Thr Gln Asn Gly 820 825 830 Ala Glu Ala Ser Ser Val Lys Thr Asn Ser Pro Ala Tyr Ser Asp Ile 835 840 845 Ser Asp Ala Gly Glu Asp Gly Glu Gly Lys Val Asp Ser Val Lys Ser 850 855 860 Lys Asp Ala Glu Gln Leu Val Lys Glu Gly Ala Lys Lys Thr Leu Phe 865 870 875 880 Pro Pro Gln Pro Gln Ser Lys Asp Ser Pro Tyr Tyr Gln Gly Phe Glu 885 890 895 Ser Tyr Tyr Ser Pro Ser Tyr Ala Gln Ser Ser Pro Gly Ala Leu Asn 900 905 910 Pro Ser Ser Gln Ala Gly Val Glu Ser Gln Ala Leu Lys Thr Lys Arg 915 920 925 Asp Glu Glu Pro Glu Ser Ile Glu Gly Lys Val Lys Asn Asp Ile Cys 930 935 940 Glu Glu Lys Lys Pro Glu Leu Ser Ser Ser Ser Gln Gln Pro Ser Val 945 950 955 960 Ile Gln Gln Arg Pro Asn Met Tyr Met Gln Ser Leu Tyr Tyr Asn Gln 965 970 975 Tyr Ala Tyr Val Pro Pro Tyr Gly Tyr Ser Asp Gln Ser Tyr His Thr 980 985 990 His Leu Leu Ser Thr Asn Thr Ala Tyr Arg Gln Gln Tyr Glu Glu Gln 995 1000 1005 Gln Lys Arg Gln Ser Leu Glu Gln Gln Gln Arg Gly Val Asp Lys Lys 1010 1015 1020 Ala Glu Met Gly Leu Lys Glu Arg Glu Ala Ala Leu Lys Glu Glu Trp 1025 1030 1035 1040 Lys Gln Lys Pro Ser Ile Pro Pro Thr Leu Thr Lys Ala Pro Ser Leu 1045 1050 1055 Thr Asp Leu Val Lys Ser Gly Pro Gly Lys Ala Lys Glu Pro Gly Ala 1060 1065 1070 Asp Pro Ala Lys Ser Val Ile Ile Pro Lys Leu Asp Asp Ser Ser Lys 1075 1080 1085 Leu Pro Gly Gln Ala Pro Glu Gly Leu Lys Val Lys Leu Ser Asp Ala 1090 1095 1100 Ser His Leu Ser Lys Glu Ala Ser Glu Ala Lys Thr Gly Ala Glu Cys 1105 1110 1115 1120 Gly Arg Gln Ala Glu Met Asp Pro Ile Leu Trp Tyr Arg Gln Glu Ala 1125 1130 1135 Glu Pro Arg Met Trp Thr Tyr Val Tyr Pro Ala Lys Tyr Ser Asp Ile 1140 1145 1150 Lys Ser Glu Asp Glu Arg Trp Lys Glu Glu Arg Asp Arg Lys Leu Lys 1155 1160 1165 Glu Glu Arg Ser Arg Ser Lys Asp Ser Val Pro Lys Glu Asp Gly Lys 1170 1175 1180 Glu Ser Thr Ser Ser Asp Cys Lys Leu Pro Thr Ser Glu Glu Ser Arg 1185 1190 1195 1200 Leu Gly Ser Lys Glu Pro Arg Pro Ser Val His Val Pro Val Ser Ser 1205 1210 1215 Pro Leu Thr Gln His Gln Ser Tyr Ile Pro Tyr Met His Gly Tyr Ser 1220 1225 1230 Tyr Ser Gln Ser Tyr Asp Pro Asn His Pro Ser Tyr Arg Ser Met Pro 1235 1240 1245 Ala Val Met Met Gln Asn Tyr Pro Gly Ser Tyr Leu Pro Ser Ser Tyr 1250 1255 1260 Ser Phe Ser Pro Tyr Gly Ser Lys Val Ser Gly Gly Glu Asp Ala Asp 1265 1270 1275 1280 Lys Ala Arg Ala Ser Pro Ser Val Thr Cys Lys Ser Ser Ser Glu Ser 1285 1290 1295 Lys Ala Leu Asp Ile Leu Gln Gln His Ala Ser His Tyr Lys Ser Lys 1300 1305 1310 Ser Pro Thr Ile Ser Asp Lys Thr Ser Gln Glu Arg Asp Arg Gly Gly 1315 1320 1325 Cys Gly Val Val Gly Gly Gly Gly Ser Cys Ser Ser Val Gly Gly Ala 1330 1335 1340 Ser Gly Gly Glu Arg Ser Val Asp Arg Pro Arg Thr Ser Pro Ser Gln 1345 1350 1355 1360 Arg Leu Met Ser Thr His His His His His Leu Gly Tyr Ser Leu 1365 1370 1375 Leu Pro Ala Gln Tyr Asn Leu Pro Tyr Ala Ala Gly Leu Ser Ser Thr 1380 1385 1390 Ala Ile Val Ala Ser Gln Gln Gly Ser Thr Pro Ser Leu Tyr Pro Pro 1395 1400 1405 Pro Arg Arg 1410
Claims (8)
Chaperonin having the amino acid sequence of SEQ ID NO: 1; Beta actin having the amino acid sequence of SEQ ID NO: 3; Transketolase having the amino acid sequence of SEQ ID NO: 4; Carbamyl phosphate synthetase I having the amino acid sequence of SEQ ID NO: 5; Transketolase variants having the amino acid sequence of SEQ ID NO: 6; Heat shock 70kDa protein 9 precursor having the amino acid sequence of SEQ ID NO: 7; UDP-glucose phosphorylase 2 isoform a having the amino acid sequence of SEQ ID NO: 8; Aldehyde dehydrogenase 4A1 precursor having the amino acid sequence of SEQ ID NO: 9; Betaine-homocysteine methyltransferase (isoform CRA b) having the amino acid sequence of SEQ ID NO: 10; Ig γ light chain having the amino acid sequence of SEQ ID NO: 11; Glyceraldehyde-3-phosphate dehydrogenase having the amino acid sequence of SEQ ID NO: 12; Heat-responsive protein 12 having the amino acid sequence of SEQ ID NO: 13; KIAA1361 protein having the amino acid sequence of SEQ ID NO: 14; And zinc finger protein 609 having an amino acid sequence of SEQ ID NO: 15, further comprising at least one protein selected from the group consisting of Aspirin Intolerant Asthma (AIA) for diagnosis. Biomarker Compositions.
(Ii) measuring the expression level of the protein of FABP1 (Fatty acid binding protein 1) having the amino acid sequence of SEQ ID NO: 2 from nasal polyps tissue, and chaperonin having the amino acid sequence of SEQ ID NO: 1 ; Beta actin having the amino acid sequence of SEQ ID NO: 3; Transketolase having the amino acid sequence of SEQ ID NO: 4; Carbamyl phosphate synthetase I having the amino acid sequence of SEQ ID NO: 5; Transketolase variants having the amino acid sequence of SEQ ID NO: 6; Heat shock 70kDa protein 9 precursor having the amino acid sequence of SEQ ID NO: 7; UDP-glucose phosphorylase 2 isoform a having the amino acid sequence of SEQ ID NO: 8; Aldehyde dehydrogenase 4A1 precursor having the amino acid sequence of SEQ ID NO: 9; Betaine-homocysteine methyltransferase (isoform CRA b) having the amino acid sequence of SEQ ID NO: 10; Ig γ light chain having the amino acid sequence of SEQ ID NO: 11; Glyceraldehyde-3-phosphate dehydrogenase having the amino acid sequence of SEQ ID NO: 12; Heat-responsive protein 12 having the amino acid sequence of SEQ ID NO: 13; KIAA1361 protein having the amino acid sequence of SEQ ID NO: 14; and zinc finger protein 609 having the amino acid sequence of SEQ ID NO: 15; Further measuring the expression level of one or more proteins selected from the group consisting of; And
b) a method for detecting a protein for providing information necessary for diagnosing aspirin-sensitive asthma by analyzing the expression level of the protein measured in step a).
The measurement in step a) is a method for detecting a protein, characterized in that the measurement using an antibody that specifically binds to the two-dimensional electrophoresis, biochip or protein.
Chaperronin having an amino acid sequence of SEQ ID NO: 1 in step b); Fatty acid binding protein 1 (FABP1) having the amino acid sequence of SEQ ID NO: 2; Carbamyl phosphate synthetase I having the amino acid sequence of SEQ ID NO: 5; Aldehyde dehydrogenase 4A1 precursor having the amino acid sequence of SEQ ID NO: 9; Betaine-homocysteine methyltransferase (isoform CRA b) having the amino acid sequence of SEQ ID NO: 10; Ig γ light chain having the amino acid sequence of SEQ ID NO: 11; And glyceraldehyde-3-phosphate dehydrogenase having the amino acid sequence of SEQ ID NO: 12; If the expression level of one or more proteins selected from the group consisting of aspirin-resistant asthma patients, the expression of aspirin-sensitive asthma is confirmed that the high risk of protein detection method.
Beta actin having the amino acid sequence of SEQ ID NO: 3 in step b); Transketolase having the amino acid sequence of SEQ ID NO: 4 Transketolase variant having the amino acid sequence of SEQ ID NO: 6; Heat shock 70kDa protein 9 precursor having the amino acid sequence of SEQ ID NO: 7; UDP-glucose phosphorylase 2 isoform a having the amino acid sequence of SEQ ID NO: 8; Heat-responsive protein 12 having the amino acid sequence of SEQ ID NO: 13; KIAA1361 protein having the amino acid sequence of SEQ ID NO: 14; And zinc finger protein 609 having the amino acid sequence of SEQ ID NO: 15; If the expression level of at least one protein selected from the group consisting of aspirin-resistant asthma is less than the expression level of aspirin-sensitized protein detection method characterized in that it is confirmed that the risk of aspirin hypersensitivity asthma.
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