| Project/Area Number |
18K07798
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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 |
Yada Koji 奈良県立医科大学, 医学部, 助教 (30635785)
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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) |
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: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 血友病A / インヒビター / 分子異常症 / F8遺伝子変異 / 凝固機能 |
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| Outline of Final Research Achievements |
Hemophilia(H) A is bleeding disorder caused by quantitative and qualitative factor (F)VIII deficiency, and is classified as severe, moderate and mile type by residual FVIII level in the plasma. The severity and development of inhibitor in the patients with HA are considered to be associated with F8 genotype. In the present study, F8 genotypes were investigated in the patients with moderate/mild HA, and the FVIII mutants with the identified F8 missense variants in the patients with moderate/mild HA were produced by a stable human FVIII expression system utilizing BHK or HEK cells. The functional and structural characteristics of the FVIII mutants were investigated and it was found that mutant FVIII could be catalyzed and activated by FVIIa/TF as well as wild-type FVIII in the early phase of coagulation reaction. The results in the present study will help development of a novel hemostatic therapy for the patients with moderate/mild HA.
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| Academic Significance and Societal Importance of the Research Achievements |
当教室の多彩な手法を駆使した生化学的アプローチによるFVIIIの構造・機能、病態解析やインヒビター研究は、国内では唯一であり、国際的にもトップの一つに挙げられている。本研究の結果、中等症・軽症血友病Aの凝血学的特性とF8遺伝子変異との関連が明らかとなり、F8遺伝子変異によりその特性を分類・評価し得ることが示され、遺伝子解析の重要性を示すものであった。さらに、外因系凝固と内因系凝固のクロストークに関しては、最近、世界的に注目されており、本研究で明らかとなった、中等症・軽症血友病A患者の有するF8変異型FVIIIの外因系凝固因子による活性化反応は、新たな治療開発の上で極めて有意義である。
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