Studies on the structure and function of new vascular endothelial growth factors

• Project/Area Number: 18370048
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: MORITA Takashi Meiji Pharmaceutical University, 薬学部, 教授 (90128108)
• Co-Investigator(Kenkyū-buntansha): YAMAZAKI Yasuo 明治薬科大学, 薬学部, 助教 (30308621)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥17,920,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥3,120,000); Fiscal Year 2008: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2007: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2006: ¥4,400,000 (Direct Cost: ¥4,400,000)
• Keywords: 血管内皮増殖因子 / VEGF / 血管透過性 / 生体生命情報学 / 分子認識 / 蛋白質 / ゲノム / 生体分子

Research Abstract

申請者は、VEGFの分子作用機序の解明を目標に、ヘビ毒腺に発現する毒型VEGF (VEGF-F) に焦点を当て、生化学的および生物学的な解析を行った。その結果、毒ヘビに発現する毒型VEGFは機能的に重要な領域の構造 (受容体結合ループおよびC末端領域) を多様化させることで、その機能を多様化していることを明らかにした。次に、vamminをはじめとする異なるリガンド特性を持つVEGFを用いた超微形態学的解析より、VEGFの血管透過性の亢進に伴う血管壁の超微構造変化 (VVOおよびfenestrae形成) は、リガンドの受容体選択性によって異なることを示した。さらに、種々のヘビ毒よりVEGFとは異なる新しいVEGF受容体結合タンパク質、KDR-bp (Lys49-PLA2) を同定した。VEGFの血管透過性亢進作用は癌性浮腫や腹水、炎症細胞・癌細胞浸潤の原因となることから、本研究の成果は、それら病態機序の解明および分子治療に貢献することと期待している。さらに、KDR-bpの発見はKDRの新たな機能探索ならびにVEGFおよびVEGF受容体分子標的物質の開発研究において有用なツールとなると考える。

Research Products

• [Journal Article] VEGF-A and VEGF-F evoke distinct changes in vascular ultrastructure. (2009)
  • Author(s): Matsunaga Y, Yamazaki Y, Suzuki H, Morita T
  • Journal Title: Biochem. Biophys. Res. Commun. 379 Pages: 872-875
  • Peer Reviewed
• [Journal Article] VEGF-A and VEGF-F evoke distinct changes in vascular ultrastructure. (2009)
  • Author(s): Matsunaga Y
  • Journal Title: Biochem. Biophys. Res. Commun. 379 Pages: 872-875
  • Peer Reviewed
• [Journal Article] Snake venom vascular endothelial growth factors (VEGF-Fs) exclusively vary their structures and functions among species. (2009)
  • Author(s): Yamazaki Y
  • Journal Title: J. Biol. Chem. (in press)
  • Peer Reviewed
• [Journal Article] Catalytically inactive phospholipase A2 homologue binds to vcascular endothelial growth factor receptor-2 via a C-terminal loop region. (2008)
  • Author(s): Fujisawa D, Yamazaki Y, Lomonte B, Morita T
  • Journal Title: Biochem. J. 411 Pages: 515-522
  • Peer Reviewed
• [Journal Article] Adenovirus serotype 5 hexon mediates liver gene transter. (2008)
  • Author(s): Waddington SN, McVey JH, Bhella D, Parker AL, Barker K, Atoda H, Pink R, Buckley SMK, Greig JA, Denby L, Custers J, Morita T, Francischetti IMB, Monteiro RQ, Barouch DH, Rooijen NV, Napoli C, Havenga MJE, Nicklin SA, Baker AH
  • Journal Title: Cell 132 Pages: 397-409
  • Peer Reviewed
• [Journal Article] Adenovirus serotype 5 hexon mediates liver gene transter. (2008)
  • Author(s): Waddington SN
  • Journal Title: Cell 132 Pages: 397-409
  • Peer Reviewed
• [Journal Article] Catalytically inactive phospholipase A_2 homologue binds to vcascular endothelial growth factor receptor-2 via a C-teminal loop region. (2008)
  • Author(s): Fujisawa D
  • Journal Title: Biochem.J. 411 Pages: 515-522
  • Peer Reviewed
• [Journal Article] Augmentation of vascular permeability of VEGF is enhanced by KDR-binding proteins. (2007)
  • Author(s): Yamazaki Y, Nakano Y, Imamura T, Morita T
  • Journal Title: Biochem. Biophys. Res. Commun. 355 Pages: 693-699
  • Peer Reviewed
• [Journal Article] Augmentation of vascular permeability of VEGF is enhanced by KDR-binding proteins. (2007)
  • Author(s): Yamazaki Y
  • Journal Title: Biochem.Biophys.Res.Commun1 355 Pages: 693-699
  • Peer Reviewed
• [Journal Article] Age-and gender-related differences of plasma prothrombin activity levels. (2007)
  • Author(s): Sakata T
  • Journal Title: Thromb.Haemost 97 Pages: 1052-1053
  • Peer Reviewed
• [Journal Article] Snake venom components affecting blood coagulation and the vascular system:Structural similarities and marked diversity (2007)
  • Author(s): Yamazaki Y
  • Journal Title: Current Pharmaceutical Design 13 Pages: 2872-2886
  • Peer Reviewed
• [Journal Article] 血管内皮増殖因子ファミリー-その多様な構造と機能- (2007)
  • Author(s): 山崎 泰男
  • Journal Title: 日本血栓止血学会誌 18 Pages: 3-15
  • NAID: 10026114149
• [Journal Article] PIVKA-IIの生化学 (2007)
  • Author(s): 森田 隆司
  • Journal Title: 肝胆膵 54 Pages: 459-463
• [Journal Article] The vascular endothelial growth factor VEGF165 induces perlecan synthesis via VEGF receptor-2 in cultured human brain microvascular endothelial cells. (2006)
  • Author(s): Kaji T, Yamamoto C, Oh-i M, Fujiwara Y, Yamazaki Y, Morita T, Plaas AH, Wight TN
  • Journal Title: Biochim. Biophys. Acta. 1760 Pages: 1465-1474
  • Peer Reviewed
• [Journal Article] Localization of heparin- and neuropilin-1-recognition sites of viral VEGFs. (2006)
  • Author(s): Tokunaga Y, Yamazaki Y, Morita T
  • Journal Title: Biochem. Biophys. Res. Commun. 348 Pages: 957-962
  • Peer Reviewed
• [Journal Article] Characterization of a monoclonal antibody B1 that recognizes phosphorylated Ser-158 in the activation peptide region of human coagulation factor IX. (2006)
  • Author(s): Atoda H, Yokota E, Morita T
  • Journal Title: J. Biol. Chem. 281 Pages: 9314-9320
  • Peer Reviewed
• [Journal Article] A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. (2006)
  • Author(s): Suzuki-Inoue K, Fuller GLJ, Garcia A, Eble JA, Pohlmann S, Inoue O, Gartner TK, Hughan SC, Pearce AC, Laing GD, Theakston RD, Schweighoffer E, Zitzmann N, Morita T, Tybulewicz VLJ, Ozaki Y, Watson SP
  • Journal Title: Blood 107 Pages: 542-549
  • Peer Reviewed
• [Journal Article] Different contributions of polymorphism in VKORC1 and CYP2C9 to intra- and inter- population differences in maintenance dose of warfarin in Japanese, Caucasians and African- Americans. (2006)
  • Author(s): Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG, Pengo V, Barban M, Padrini R, Ieiri I, Otsubo K, Kashima T, Kimura S, Kijima S, Echizen H
  • Journal Title: Pharmacogenetics Genomics 16 Pages: 101-110
  • Peer Reviewed
• [Journal Article] Characterization of a monoclonal antibody B1 that recognizes phosphorylated Ser-158 in the activation peptide region of human coagulation factor IX. (2006)
  • Author(s): 阿刀田 英子ら
  • Journal Title: J. Biol. Chem. 281(14) Pages: 9314-9320
• [Journal Article] Localization of heparin- and neuropilin-1-recognition sites of viral VEGFs. (2006)
  • Author(s): 徳永 優子ら
  • Journal Title: Biochem. Biophys. Res. Commun. 348 Pages: 957-962
• [Journal Article] The vascular endothelial growth factor VEGF165 induces perlecan synthesis via VEGF receptor-2 in cultured human brain microvascular endothelial cells. (2006)
  • Author(s): 鍛冶 利幸ら
  • Journal Title: Biochem. Biophys. Acta. 1760 Pages: 1465-1474
• [Journal Article] Snake venom vascular endothelial growth factors (VEGF-Fs) exclusively vary their structures and functions among species.
  • Author(s): Yamazaki Y, Matsunaga Y, Tokunaga Y, Obayashi S, Saito M and Morita T
  • Journal Title: J. Biol. Chem. in press Pages: 0-0
  • Peer Reviewed
• [Presentation] 血液凝固IX因子と抗凝固タンパク質(IX/X-bpおよびIX-bp)の相互作用に対するMg^<2+>の影響 (2008)
  • Author(s): 石川みどり、山崎泰男、森田隆司
  • Organizer: 第55回毒素シンポジウム
  • Place of Presentation: 山梨
• [Presentation] 組織型および毒型VEGF(血管内皮増殖因子)のゲノム構造解析 (2008)
  • Author(s): 山崎泰男、齋藤麻衣、徳永優子、森田隆司
  • Organizer: 第55回毒素シンポジウム
  • Place of Presentation: 山梨
• [Presentation] 血液凝固IX因子と抗凝固タンパク質(IX/X-bpおよびIX-bp)の相互作用の速度論的解析 (2008)
  • Author(s): 石川みどり、山崎泰男、森田隆司
  • Organizer: 日本薬学会128年会
  • Place of Presentation: 横浜
• [Presentation] 異なるC末端ドメインを持つVEGFキメラの創製とその生物活性 (2008)
  • Author(s): 夘月博和、山崎泰男、森田隆司
  • Organizer: 日本薬学会128年会
  • Place of Presentation: 横浜
• [Presentation] 組織型と毒型の血管内皮増殖因子のゲノム構造解析とその進化論的考察 (2008)
  • Author(s): 齋藤麻衣、徳永優子、長谷川芳裕、山崎泰男、森田隆司
  • Organizer: 日本薬学会128年会
  • Place of Presentation: 横浜
• [Presentation] 血液・血管研究の新しい視点-毒タンパク質研究から何がわかるのか?- (2007)
  • Author(s): 山崎 泰男
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会合同大会(BMB2008)、ワークショップ「ベノミクス:毒生物ゲノムプロジェクト」
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] ハブ由来の組織型および毒型VEGF(血管内皮増殖因子)のゲノム構造解析 (2007)
  • Author(s): 齋藤 麻衣
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会合同大会(BMB2008)
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] ニューロピリン-1およびヘパリン結合性の異なる血管内皮増殖因子組換え体の調製 (2007)
  • Author(s): 夘月 博和
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会合同大会(BMB2008)
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-12
• [Presentation] 抗凝固活性を有すると報告された_L-アミノ酸参加酵素の抗凝固メカニズムの解析 (2007)
  • Author(s): 藤澤 大輔
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重
  • Year and Date: 2007-11-16
• [Presentation] Inactive Phospholipase A_2 Homologue Binds to VEGF Receptor-2 Via Its C-Terminal Loop Regon (2007)
  • Author(s): Fuisawa D
  • Organizer: The lst Seminar on Bioactive Natural Products from Marine Organisms/EndophyticFungi amd The JSPS 2nd Medicinal Chemistry Seminar of Asia/Africa Science Platform Program
  • Place of Presentation: Phuket,Thailand
  • Year and Date: 2007-10-27
• [Presentation] Use of Snake Venom Proteins in Studies of the Structure and Function of Coagulation Factors (2007)
  • Author(s): Morita T
  • Organizer: The Ist Seminar on Bioactive Natural Products from Marine Organisms/EndophyticFungi and The JSPS 2nd Medicinal ChemistrySeminar of Asia/Africa Science Platform Program
  • Place of Presentation: Phuket,Thailand
  • Year and Date: 2007-10-26
• [Presentation] Trimeresurus flavoviridis毒腺cDNAライブラリーの網羅的解析 (2007)
  • Author(s): 長谷川 芳裕
  • Organizer: 第54回毒素シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2007-09-05
• [Presentation] Echis pyramidum毒由来の非ヘパリン結合性VEGFの単離とその性質 (2007)
  • Author(s): 乙部 清香
  • Organizer: 第54回毒素シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2007-09-05
• [Presentation] ヘビ毒には多様な構造と性質をもつVEGFが含まれている (2007)
  • Author(s): 松永 幸子
  • Organizer: 第54回毒素シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2007-09-05
• [Presentation] Augmentation of Vascular Permeability of Vascular Endothelial Growth Factor(VEGF)is Enhanced by VEGF Recetor 2-bindingProteins (2007)
  • Author(s): Yamazaki Y
  • Organizer: XXIst Congress of the International Society on Thrombosis and Haemostasis, 53rd Annual SSC Meeting
  • Place of Presentation: Geneva,Switzerland
  • Year and Date: 2007-07-08
• [Presentation] Molecular and Functional Diversity of Snake Venom VEGFS (2007)
  • Author(s): Matsunaga Y
  • Organizer: XXIstCongress of the International Society on Thrombosis and Haemostasis, 53rd Annual SSC Meeting
  • Place of Presentation: Geneva,Switzerland
  • Year and Date: 2007-07-08
• [Presentation] Identification of VEGF Receptor-binding Sites of KDR-binding Protein (2007)
  • Author(s): Fujisawa D
  • Organizer: XXIst Congress of the International Society on Thrombosis and Haemostasis, 53rd Annual SSC Meeting
  • Place of Presentation: Geneva,Switzerland
  • Year and Date: 2007-07-08
• [Presentation] KDR結合タンパク質はVEGFの血管透過性元進作用を増強する (2007)
  • Author(s): 山崎 泰男
  • Organizer: 第8回Phamlaco-Hematologyシンポジウム
  • Place of Presentation: 金沢
  • Year and Date: 2007-06-08
• [Book] Snake Venoms and Other Toxic Components Affecting Thrombosis and Hemostasis. In: Recent Advances in Thrombosis and Hemostasis 2008. (Tanaka K, Davie EW eds) (2008)
  • Author(s): Yamazaki Y, Morita T
  • Publisher: Springer
• [Book] Recent Advances in Thrombosis and Hemostasis 2008 (2008)
  • Author(s): Yamazaki Y
  • Publisher: Snake Venoms and Other Toxic Components Affecting Thrombosis and Hemostasis
• [Book] Xa阻害薬のすべて (2007)
  • Author(s): 山崎 泰男
  • Publisher: 株式会社先端医学社
• [Book] Molecular and functional diversity of vascular endothelial growth factors (2006)
  • Author(s): Yamazaki Y, Morita T
  • Publisher: Mol. Divers.