Molecular mechanism of platelet integrin activation and association with vascular lesion

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08813
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Osaka University
• Principal Investigator: Hirokazu Kashiwagi 大阪大学, 医学部附属病院, 准教授 (10432535)
• Co-Investigator(Kenkyū-buntansha): 加藤 恒 大阪大学, 医学系研究科, 講師 (20705214) ; 冨山 佳昭 大阪大学, 医学部附属病院, 特任教授(常勤) (80252667)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: インテグリン

Outline of Final Research Achievements

We established αIIb(R995W) knock-in mice, which show constitutive activation of αIIbβ3, and recealed that the mice showed macrothrombocytopenia like human subjects. There are no difference in morphology and number of megakaryocytes in bone marrow and spleen between KI mice and WT mice. Megakaryocytic differentiation is not impaired in KI mice, either. However, proplatelet formation in cultured megakaryocyte was impaired in KI mice, suggesting that impaired proplatelet formation may responsible for the phenotype. KI mice showed highly impaired platelet function mainly due to reduced αIIbβ3 expression in platelets. We also found novel β3 mutation in macrothrombocytopenic patients. The mutation does not induce constitutive αIIbβ3 activation, and we are now investigating the mechanism of the integrin mutation and platelet production and function

Free Research Field

血液学

Academic Significance and Societal Importance of the Research Achievements

血小板は動脈硬化性血管病変の形成に中心的役割を担う。今回の研究により血小板機能の中で最も重要であるαIIbβ3の恒常的活性化が血小板産生および血小板機能に及ぼす影響を、ノックインマウスを用いることにより明らかにすることができた。さらに直接αIIbβ3,の活性化を誘導しない変異によってもαIIbβ3の変異により血小板産生に影響を与える可能性を示した。今後の更なる分子機構の解明により、血小板機能および血小板産生のメカニズムの一端が明らかにされていくことが期待される。