| Project/Area Number |
17K10125
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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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| Research Field |
Pediatrics
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| Research Institution | Nara Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
野上 恵嗣 奈良県立医科大学, 医学部, 准教授 (50326328)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 血友病 / 第VIII因子 / プロテインS / 活性型プロテインC / 血液凝固 / 抗凝固 / 活性化プロテインC |
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| Outline of Final Research Achievements |
Factor (F) VIII functions as a cofactor in the tenase complex responsible for phospholipid (PL) surface-dependent conversion of FX to FXa by FIXa. On the other hand, protein S (PS) functions as a cofactor of activated protein C (APC) that inactivates FVIII(a) and FV(a). In this study, several approaches were employed to assess APC-FVIII A2 interaction and PS-FVIII LC interaction. Amino acid residues 420-429 in FVIII A2 domain might be the new APC binding site. On the other hand, FVIII mutant, S488A/S489A/R490A/K2239A, showed the low affinity to PS comparing to wild type FVIII. However, this FVIII mutant had a moderate affinity to FIXa. Therefore, FVIII mutant, S488A/S489A/R490A/K2239A, could be new FVIII concentrate which has the longer half-life.
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| Academic Significance and Societal Importance of the Research Achievements |
血友病Aは凝固第VIII因子（FVIII）の欠乏によっておこる。治療に用いるFVIII製剤は半減期が短く頻回な投与が必要である。FVIIIは活性型プロテインC (APC)及びプロテインS (PS) により不活化される。従って、FVIIIとAPC/PSの結合を制御することは、新規FVIII製剤の開発につながる。 FVIIIのAPC/PS結合部位のアミノ酸を置換することで、APC/PSとの結合能が弱い変異FVIIIを作製した。この変異FVIIIによる新規製剤はAPC/PSに不活化されにくいため、従来の製剤より安定性が高く、長時間作用すると考えられ、患者のQOLの向上に役立つものと期待できる。
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