Identification of mechanism of FVIII-regulated blood coagulation and development on novel therapeutic drugs for hemophilia A and thrombotic disease
| Project/Area Number |
18K07885
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Nara Medical University |
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Principal Investigator |
NOGAMI KEIJI 奈良県立医科大学, 医学部, 教授 (50326328)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 第VIII因子 / トロンビン / 第VII因子 / 第IX因子 / 凝固 / 遺伝子組み換え / 機能獲得 / 活性化第IX因子 / 結合領域 / 機能獲得型蛋白 / 血液凝固 / 活性型第IX因子 / 組織因子 / 活性型第VII因子 / 結合部位 / 高機能獲得型蛋白 / 結合様式 / 機能獲得型 / 凝固因子 |
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| Outline of Final Research Achievements |
1) We have identified novel thrombin-binding sites of factor VIII (FVIII), which is involved in both hemorrhage and hemostasis in blood coagulation, which regulates FVIII activation due to its cleavage. We successfully generated a gain-of-function FVIII protein with high activity, focused on one thrombin-interactive site responsible for cleavage at Arg372 in A1 of FVIII. 2) In the early phase of the coagulation process, we have clarified that FVIII-FVIIa/tissue factor (TF) mechanism activates the endogenous coagulation process as well simultaneously and in addition have identified the FVIIa/TF-binding region on FVIII. 3) Moreover, we have identified a novel FIXa-binding region on FVIIIa in the intrinsic FX complex on the phospholipid surfaces, and have generated a gain-of-function FVIII protein focused on the FVIIIa A3 domain-FIXa interaction.
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| Academic Significance and Societal Importance of the Research Achievements |
血液凝固第VIII因子は出血と血栓の相反する病態に関わる重要な凝固因子であるため、今回の研究における第VIII因子に関連する機能構造および他の凝固因子との相互反応の解明が、凝固や血栓形成機序の解明と血友病A患者への新規第VIII因子治療製剤開発への応用、また第VIII因子の生体内機能を制御する抗血栓および抗凝固薬の開発に将来的に繋がり、止血血栓学の学問的発展および医療に貢献できると思われる。
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Report
(4 results)
Research Products
(16 results)
