Studies on the mechanisms of activation and inactivation of factor VIII : applications of novel coagulant and anticoagulant therapy

• Project/Area Number: 19591264
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nara Medical University
• Principal Investigator: NOGAMI Keiji Nara Medical University, 医学部, 助教 (50326328)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 血液凝固 / 第VIII因子 / 外因系 / 線溶系 / 凝固抑制系 / 酵素 / 相互作用 / 活性化 / 不活化 / プラスミン / 結合部位 / プロテインS / 活性型第VII因子 / 内因系因子

Research Abstract

血液凝固内因系第VIII因子(FVII)は、欠乏では重篤出血(血友病A)を、逆に増加は血栓形成を惹起する。従来凝固研究は、内因系/外因系/凝固抑制系/線溶系に分けて研究されてきたが、実際の凝固過程は複数系が互いに絡み合い進行していくと支持されつつある。本研究で、凝固反応で最も鍵を握るFVIIが、内因系のみならず、線溶系因子(プラスミン)、凝固抑制因子(プロテインS)、外因系因子(FVII)と相互作用することで凝固血栓が巧みに制御されていることがわかった。

Research Products

• [Journal Article] Identification of plasmin-interactive sites in the light chain of factor VIII responsible for proteolytic cleavage at Lys36 (2009)
  • Author(s): Nogami K, Nishiya K, et.al.(他5名)
  • Journal Title: J Biol Chem 284 Pages: 6934-45
• [Journal Article] The factor VIIIa C2 domain (residues 2228-2240) interacts with the factor IXa Gla domain in the factor Xase complex (2009)
  • Author(s): Soeda T, Nogami K, et.al.(他6名)
  • Journal Title: J Biol Chem 284 Pages: 3379-88
• [Journal Article] Identification of plasmin-interactive sites in the light chain of factor VIII responsible for proteolytic cleavage at Lys36 (2009)
  • Author(s): Nogami K. (1^<st> author), et al.
  • Journal Title: The Journal of Biological Chemistry In press
  • Peer Reviewed
• [Journal Article] The factor VIIIa C2 domain (residues 2228-2240) interacts with the factor IXa Gla domain in the factor xase complex. (2009)
  • Author(s): Soeda T, Nogami K. (corresponding author), et al.
  • Journal Title: The Journal of Biological Chemistry 284 Pages: 3379-3388
  • Peer Reviewed
• [Journal Article] Identification of a plasmin-interactive site within the A2 domain of the factor VIII heavy chain (2008)
  • Author(s): Nogami K, Shima M, et.al.(他5名)
  • Journal Title: Biochim Biophys Acta 1784 Pages: 753-63
• [Journal Article] Protein S down-regulates factor Xase activity independent of activated protein C : specific binding of factor VIII(a) to protein S inhibits interactions with factor IXa (2008)
  • Author(s): Takeyama M, Nogami K, et.al.(他5名)
  • Journal Title: Br J Haematol 143 Pages: 409-20
• [Journal Article] Selective factor VIII and V inactivation by iminodiacetate ion exchange resin through metal ion adsorption (2008)
  • Author(s): Takeyama M, Nogami K, et.al.(他5名)
  • Journal Title: Br J Haematol 142 Pages: 962-70
• [Journal Article] Identification of a thrombin-interactive site within the FVIII A2 domain that is responsible for the cleavage at Arg372 (2008)
  • Author(s): Nogami K, Saenko EL, et.al.(他4名)
  • Journal Title: Br J Haematol 140 Pages: 433-43
• [Journal Article] Identification of a thrombin-interactive site within the factor VIII A2 domain that is responsible for the cleavage at Arg372 (2008)
  • Author(s): Nogami K. (1^<st> author), et al.
  • Journal Title: British Journal of Hematology 140 Pages: 433-443
  • Peer Reviewed
• [Journal Article] Identification of a plasmin-interactive site within the A2 domain of the factor VIII heavy chain (2008)
  • Author(s): Nogami K. (1^<st> author), et al.
  • Journal Title: Biochemical Biochimica et Acta 1784 Pages: 753-763
  • Peer Reviewed
• [Journal Article] Protein S down-regulates factor Xase activity independent of activated protein C : specific binding of factor VIII(a) to protein S inhibits interactions with factor IXa (2008)
  • Author(s): Takeyama M, Nogami K. (corresponding author), et al.
  • Journal Title: British Journal of Hematology 143 Pages: 409-420
  • Peer Reviewed
• [Journal Article] Selective factor VIII and V inactivation by iminodiacetate ion exchange resin through metal ion adsorption (2008)
  • Author(s): Takeyama M, Nogami K. (corresponding author), et al.
  • Journal Title: British Journal of Hematology 142 Pages: 962-970
  • Peer Reviewed
• [Journal Article] Identification of a thrombin-interactive site with in the factor VIII A2 domain that is responsible for the cleavage at Arg372 (2008)
  • Author(s): Nogami K.(1^<st> author), et. al.
  • Journal Title: British Journal of Hematology 140 Pages: 433-443
  • Peer Reviewed
• [Journal Article] Identification of a plasmin-interactive site with in the A2 domain of the factor VIII heavy chain (2008)
  • Author(s): Nogami K.(1^<st> author), et. al.
  • Journal Title: Biochemical Biochimica et Acta In press
  • Peer Reviewed
• [Journal Article] Relationship between the binding sites for von Willebrand factor, phospholipid, and human factor VIII C2 inhibitor alloantibodies within the factor VIII C2 domain (2007)
  • Author(s): Nogami K, Shima M et.al.(他4名)
  • Journal Title: Int J Hematol 85 Pages: 317-22
• [Journal Article] Mechanisms of plasmin-catalyzed inactivation of factor VIII (2007)
  • Author(s): Nogami K, Shima M, et.al.(他4名)
  • Journal Title: J Biol Chem 282 Pages: 5287-95
• [Journal Article] 血友病Aの分子病態. 第VIII因子の分子構造および機能の最近の知見 (2007)
  • Author(s): 野上恵嗣
  • Journal Title: 血栓止血誌 19 Pages: 779-87
  • NAID: 10026116902
• [Journal Article] Mechanisms of plasmin-catallyzed inzctivation of fctor VIII:a crucial role for proteolytic cleavage at Arg336 responsible for plasmin-catalyzed factor VIII inactivation (2007)
  • Author(s): Nogami K. (1^<st> author), et. al.
  • Journal Title: The Journal of Biological Chemistry 282 Pages: 5287-5295
  • Peer Reviewed
• [Journal Article] Relationship between the binding sites for von Willebrand factor, phospholipid, and human factor VIII C2 inhibitor alloantibodies with in the factor VIII C2 domain (2007)
  • Author(s): Nogami K.(1^<st> author), et. al.
  • Journal Title: International Journal of Hematology 85 Pages: 317-322
  • Peer Reviewed
• [Journal Article] Heparin-induced inhibitory effets of a prothrombin complex concentrate on global tests of haemostasis (2007)
  • Author(s): Takeyama M, Sakurai Y, shima M Matsumoto T, Nogami K, et. al.
  • Journal Title: Blood Coagulation & Fibrinolysis 18 Pages: 1-7
  • Peer Reviewed
• [Journal Article] 神経芽細胞腫由来N2a細胞株におけるエストロゲンのヌクレオチド除去修復に対する効果 (2007)
  • Author(s): 吉岡 玲
  • Journal Title: 日本神経精神薬理学雑誌 27 Pages: 77-83
  • Peer Reviewed
• [Presentation] Lysine-binding site-dependent interaction with plasmin and factor Va responsible for plasmin-catalyzed factor Va inactivation (2008)
  • Author(s): Nishiya K, Nogami K, et al
  • Organizer: 50^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-07
• [Presentation] Tissue factor-dependent activation of factor VIII by factor VIIa in the early phase of bloodcoagulation (2008)
  • Author(s): Soeda T, Nogami K, et.al.
  • Organizer: 50^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: San Francisco, CA
  • Year and Date: 2008-12-06
• [Presentation] Identification of a factor IXa-interactive site within the C2 domain of factor VIIIa and a crucial role of these associations for the process of clot formation (2008)
  • Author(s): Soeda T, Nogami K, et.al.
  • Organizer: 50^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: San Francisco, CA
  • Year and Date: 2008-12-06
• [Presentation] Identification of a factor IXa-interactive site within the C2 domain of factor VIIIa and a crucial role of these associations for the process of clot formation (2008)
  • Author(s): Soeda T, Nogami K, et al
  • Organizer: 50^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-06
• [Presentation] Tissue factor-dependent activation of factor VIII by factor VIIa in the early phase of blood coagulation (2008)
  • Author(s): Soeda T, Nogami K, et al
  • Organizer: 50^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-06
• [Presentation] Mechanisms of factor VIII activation by recombinant factor VIIa analog through tissue factor-independent manner (2008)
  • Author(s): Ogiwara K, Nogami K, et al
  • Organizer: 50^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-06
• [Presentation] 6-aminohexanoic acid (6-AHA)の凝固亢進作用 (2008)
  • Author(s): 荻原建一, 野上恵嗣, 他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2008-11-22
• [Presentation] 活性型第VII因子アナログによる組織因子非依存性の第VIII因子制御機構 (2008)
  • Author(s): 荻原建一, 野上恵嗣, 他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2008-11-21
• [Presentation] 活性型第VII因子/組織因子による第VIII因子制御機構 (2008)
  • Author(s): 添田哲弘, 野上恵嗣, 他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2008-11-21
• [Presentation] Plasminogen/Plasminはlysine-binding site依存性に活性型第V因子と結合する (2008)
  • Author(s): 西屋克巳, 野上恵嗣, 他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2008-11-21
• [Presentation] 活性型第IX因子と第VIII因子軽鎖C2ドメイン問特異的阻害ペプチドの抗血栓作用 (2008)
  • Author(s): 添田哲弘, 野上恵嗣, 他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2008-11-21
• [Presentation] 血友病A各種病型の第VIII因子活性とトロンビン生成能 (2008)
  • Author(s): 松本智子, 野上恵嗣, 他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2008-11-21
• [Presentation] 「血友病の分子病態の進歩と臨床応用の展望」 FVIIa、FVIIIを介する止血メカニズムの新たな展開 (2008)
  • Author(s): 荻原建一、野上恵嗣、他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2008-11-20
• [Presentation] 6-aminohexanoic acid(6-AHA)の凝固亢進作用 (2008)
  • Author(s): 荻原建一、野上恵嗣、他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2008-11-20
• [Presentation] 「血友病の分子病態の進歩と臨床応用の展望」 FVIIa、FVIIIを介する止血メカニズムの新たな展開 (2008)
  • Author(s): 荻原建一, 野上恵嗣, 他
  • Organizer: 第31回日本血栓止血学会学術集会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2008-11-20
• [Presentation] 活性型第VIII因子軽鎖C2ドメイン上における活性型第IX因子結合部位の同定 (2008)
  • Author(s): 添田哲弘, 野上恵嗣, 他
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都府京都市
  • Year and Date: 2008-10-11
• [Presentation] Identification of protein S-interactive site on the factor VIII A2 domain (2007)
  • Author(s): Takeyama M, Nogami K, et. al.
  • Organizer: 49^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-10
• [Presentation] Role of direct interaction between factor VIII C2 domain and factor IXa Gla domain in facctor Xase complex (2007)
  • Author(s): Soeda T, Nogami K, et. al.
  • Organizer: 49^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-10
• [Presentation] Localization of factor VIII-interactive site within plasmin/plasminogen which is responsible for plasmin-catalyzed activation and inactivation of factor VIII (2007)
  • Author(s): Nishiya K, Nogami K, et.al.
  • Organizer: 49^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: Atlanta, GA
  • Year and Date: 2007-12-09
• [Presentation] Identification of protein S-interactive site on the factor VIII A2 domain (2007)
  • Author(s): Takeyama M, Nogami K, et.al.
  • Organizer: 49^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: Atlanta, GA
  • Year and Date: 2007-12-09
• [Presentation] Localization of factor VIII-interactive site within plasmin/plasminogen which is responsible for plasmin-catalyzed activation/inactivation of factor VIII (2007)
  • Author(s): Nishiya K, Nogami K, et. al.
  • Organizer: 49^<th> Annual meeting of American Society of Hematology
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-09
• [Presentation] 凝固初期相におけるプラスミンの向凝固作用 (2007)
  • Author(s): 荻原建一、野上恵嗣他
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島市
  • Year and Date: 2007-11-17
• [Presentation] 第VIII因子A2ドメイン上のプロテインS結合部位の同定 (2007)
  • Author(s): 武山 雅博、野上 恵嗣, 他
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島
  • Year and Date: 2007-11-17
• [Presentation] 凝固因子と線溶因子の新たな接点-Plasminogen/Plasminによる第VIII因子制御機構をモデルとして (2007)
  • Author(s): 西屋 克巳、野上 恵嗣, 他
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島
  • Year and Date: 2007-11-17
• [Presentation] 第VIII因子軽鎖C2ドメインは活性型第IX因子Glaドメインに結合する (2007)
  • Author(s): 添田 哲弘、野上 恵嗣, 他
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島
  • Year and Date: 2007-11-17
• [Presentation] 凝固初期相におけるプラスミンの向凝固作用 (2007)
  • Author(s): 荻原 建一、野上 恵嗣, 他
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島
  • Year and Date: 2007-11-17
• [Presentation] インヒビター陽性血友病Aに対する補充療法における凝血学的効果の多様性 (2007)
  • Author(s): 矢田 弘史、吉田 幸一、野上 恵嗣, 他
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島
  • Year and Date: 2007-11-17
• [Presentation] 後天性血友病A type2患者のトロンビン生成能低下の作用機序 (2007)
  • Author(s): 松本 智子、野上 恵嗣, 他
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島
  • Year and Date: 2007-11-16
• [Presentation] 血友病Aインヒビターの免疫生化学的側面 (2007)
  • Author(s): 野上恵嗣
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島市
  • Year and Date: 2007-11-15
• [Presentation] 血友病Aインヒビターの免疫生化学的側面 (2007)
  • Author(s): 野上 恵嗣
  • Organizer: 第30回日本血栓止血学会学術集会
  • Place of Presentation: 三重県賢島
  • Year and Date: 2007-11-15