JP3966819B2 - 毛嚢に存在する新規の第2ケラチノサイト成長因子類似体 - Google Patents
毛嚢に存在する新規の第2ケラチノサイト成長因子類似体 Download PDFInfo
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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Description
乳頭性間葉から出た特定因子(factor)は小胞性上皮の生活史に誘導信号として作用する(Peus, D. & Pittelkow, M. R. (1996) Dermatol. Clin. 14, 559-572)。 具体的には毛嚢の突出部にある上皮幹細胞(epithelial stem cells)が真皮乳頭からの誘導信号に反応可能であると考えられている(Cotsarelis, G., Sun, T. T. & Lavker, R. M.(1990) Cell 61, 1329-1337)。前記の過程によって上皮幹細胞が活性化されると、突出部で幹細胞の増殖が起こり、幹細胞子孫が真皮側に下方に成長し、その後マトリックス細胞(matrix cells)の分化的成長が起こり、複合小胞性上皮(complex follicular product)、シャフト(shaft)及びそれらを取り囲んだシース(sheath)が生成される。
本発明において、アガロースゲル上で確認した蛋白質の分子量は、GST−KGF2Aが約45kDa、KGF−2Aが約20kDaであった。これは予想の分子量と一致するものであった(図2参照)。
正常人と脱毛症患者の頭皮から、形態発生学的に生成期の構造的特性をもつ毛嚢をそれぞれ分離した。
トリゾール(Gibco BRL)を用いて毛嚢から抽出した総RNAをもって逆転写を行った。
序列番号5及び序列番号6のオリゴヌクレオチドプライマーを用いたRT−PCRを行ってKGF−2A mRNAの発現を分析した。
まず、ヒトKGF−2Aの40番から208番までのアミノ酸序列をコーディングするcDNAを増幅するために、ヒトKGF−2A cDNAを鋳型とし、TagDNAポリメラーゼ及び序列番号9と序列番号10のプライマーを用いて25回PCRを行った。増幅された部位は、信号序列の分泌及び切断部位の下流に連結される成熟なKGF−2Aをコーディングする部位に相当するものであった。
前記実施例4の方法でヒトKGF−2A cDNAを増幅し、増幅された産物を制限酵素EcoRI及びBamHIで切断し、発現ベクターpGEX−2T(
Pharmacia)のEcoRI/BamHI位置に連結させて得た
組換えプラスミドpGEX−2T−KGF2Aで大腸菌BL21(DE3)菌株を42℃で30秒間熱衝撃を加えて形質転換させた。
ヒトの頭皮から毛嚢を分離し、100U/mlのペニシリン、10ng/mlのヒドロコルチゾン及び75μg/mlの牛脳下垂体抽出物の補充されたKBM培地(Clonetics)が各ウェル当たり1mlずつ入った24ウェルプレートに仕込み、5%CO2/95%空気の大気下で維持させた。
歯(tooth)或いは羽芽の発生の如き、毛嚢形態発生は、上皮−間葉の相互作用によって左右され、具体的に毛髪板(hair placode)ケラチノサイトと間葉凝縮下部(underlying mesenchymal condensations)の繊維芽細胞間の相互作用によるものと知られている。
本発明に係るKGF−2Aの活性をKGF−1及びKGF−2と比較した。具体的に、脱毛症患者の毛嚢を分離してそれぞれKGF−1、KHG−2及びKGF−2を処理し、実施例6と同様にその細胞増殖活性を測定した(8回反復)。この際、実施例7のように内因性因子の影響を排除するために真皮乳頭を除去した後、同一の実験を行った。
Claims (30)
- 第2ケラチノサイト成長因子のアミノ酸序列で87番アミノ酸がリジンからグルタミン酸に置換された第2ケラチノサイト成長因子類似体。
- 序列番号1の40番から208番までのアミノ酸序列を含む第2ケラチノサイト成長因子類似体。
- N末端にメチオニンをさらに含むことを特徴とする請求項2記載の第2ケラチノサイト成長因子類似体。
- 序列番号1の2番から208番までのアミノ酸序列を含む第2ケラチノサイト成長因子類似体。
- N末端にメチオニンをさらに含むことを特徴とする請求項4記載の第2ケラチノサイト成長因子類似体。
- ヒトの頭皮毛嚢から分離されたことを特徴とする請求項2又は4記載の第2ケラチノサイト成長因子類似体。
- 成熟蛋白質であることを特徴とする請求項1ないし6のいずれか1項に記載の第2ケラチノサイト成長因子類似体。
- 請求項1の第2ケラチノサイト成長因子類似体をコーディングする第2ケラチノサイト成長因子類似体遺伝子。
- 序列番号1の2番から208番までのアミノ酸序列をコーディングする第2ケラチノサイト成長因子類似体遺伝子。
- 序列番号2の4番から627番までの塩基序列を含むことを特徴とする請求項9記載の遺伝子。
- 序列番号1の1番から208番までのアミノ酸序列をコーディングする第2ケラチノサイト成長因子類似体遺伝子。
- 序列番号2の1番から627番までの塩基序列を含むことを特徴とする請求項11記載の遺伝子。
- 序列番号1の40番から208番までのアミノ酸序列をコーディングする第2ケラチノサイト成長因子類似体遺伝子。
- 序列番号2の118番から627番までの塩基序列を含むことを特徴とする請求項13記載の遺伝子。
- 序列番号1の40番から208番までのアミノ酸序列を含み、そのN−末端にメチオニンが結合したアミノ酸序列をコーディングする第2ケラチノサト成長因子類似体遺伝子。
- 序列番号2の118番から627番までの塩基序列を含み、その5’−末端の上流に開始コドンをさらに含むことを特徴とする請求項15記載の遺伝子。
- 前記遺伝子はcDNA型であることを特徴とする請求項8ないし16のいずれか1項に記載の遺伝子。
- 前記遺伝子はgDNA型であることを特徴とする請求項8ないし16のいずれか1項に記載の遺伝子。
- 第2ケラチノサイト成長因子のアミノ酸序列で87番アミノ酸がリジンからグルタミン酸に置換された第2ケラチノサイト成長因子類似体をコーディングする第2ケラチノサイト成長因子類似体遺伝子をベクターにクローニングした後、宿主細胞に形質転換させて形質転換体を得、前記形質転換体を培養することを特徴とする第2ケラチノサイト成長因子類似体の製造方法。
- 前記第2ケラチノサイト成長因子類似体遺伝子は序列番号1の2番から208番までのアミノ酸序列をコーディングすることを特徴とする請求項19記載の製造方法。
- 第2ケラチノサイト成長因子類似体遺伝子は序列番号1の40番から208番までのアミノ酸序列をコーティングすることを特徴とする請求項19記載の製造方法。
- 前記第2ケラチノサイト成長因子類似体遺伝子は、序列番号2の第2ケ ラチノサイト成長因子類似体遺伝子の全部、序列番号2の4番から627番までの塩基序列、又は序列番号2の118番から627番までの塩基序列を含み、付加的なDNA序列をさらに含んでいる融合遺伝子の形態であることを特徴とする請求項19記載の製造方法。
- 第2ケラチノサイト成長因子のアミノ酸序列で87番アミノ酸がリジンからグルタミン酸に置換された第2ケラチノサイト成長因子類似体又は該第2ケラチノサイト成長因子類似体をコーディングする第2ケラチノサイト成長因子類似体遺伝子を有効成分とする脱毛症予防及び治療又は毛髪成長及び毛嚢再活促進用薬学的組成物。
- 第2ケラチノサイト成長因子類似体は序列番号1の40番から208番までのアミノ酸序列を含むことを特徴とする請求項23記載の薬学的組成物。
- 第2ケラチノサイト成長因子類似体は序列番号1の2番から208番までのアミノ酸序列を含むことを特徴とする請求項23記載の薬学的組成物。
- 前記第2ケラチノサイト成長因子類似体のアミノ酸序列それぞれのN−末端にメチオニンをさらに含むことを特徴とする請求項24又は25記載の薬学的組成物。
- 第2ケラチノサイト成長因子のアミノ酸序列で87番アミノ酸がリジンからグルタミン酸に置換された第2ケラチノサイト成長因子類似体は成熟蛋白質形態であることを特徴とする請求項23記載の薬学的組成物。
- 第2ケラチノサイト成長因子類似体遺伝子は序列番号1の2番から208番までのアミノ酸序列をコーディングすることを特徴とする請求項23記載の薬学的組成物。
- 第2ケラチノサイト成長因子類似体遺伝子は序列番号1の40番から208番までのアミノ酸序列をコーディングすることを特徴とする請求項23記載の薬学的組成物。
- 第2ケラチノサイト成長因子類似体遺伝子は序列番号2の第2ケラチノサイト成長因子類似体遺伝子の全部、序列番号2の4番から627番までの塩基序列、又は序列番号2の118番から627番までの塩基序列を含み、付加的なDNA序列をさらに含んでいる融合遺伝子の形態であることを特徴とする請求項23記載の薬学的組成物。
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KR20030022094A (ko) | 2003-03-15 |
US7094569B2 (en) | 2006-08-22 |
EP1404713A4 (en) | 2004-09-22 |
WO2002094871A1 (en) | 2002-11-28 |
JP2005504515A (ja) | 2005-02-17 |
EP1404713A1 (en) | 2004-04-07 |
US7335641B2 (en) | 2008-02-26 |
US20060251604A1 (en) | 2006-11-09 |
US20030036174A1 (en) | 2003-02-20 |
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