2020 Fiscal Year Final Research Report

Characteriziation of regulatory molecules of platelet integrin function and their clinical application

Research Project

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Project/Area Number	18K08326
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	Tomiyama Yoshiaki 大阪大学, 医学部附属病院, 特任教授(常勤) (80252667)
Co-Investigator(Kenkyū-buntansha)	柏木浩和大阪大学, 医学系研究科, 講師 (10432535) 加藤恒大阪大学, 医学系研究科, 助教 (20705214)
Project Period (FY)	2018-04-01 – 2021-03-31
Keywords	GPIIb-IIIa / 血小板 / inside-outシグナル / 活性化変異 / kindlin-3
Outline of Final Research Achievements	The objective of this project is to identify and characterize regulatory molecules that are involved in αIIbβ3 (GPIIb-IIIa) function, especially αIIbβ3 activation. We focused on investigating human disease or human platelets for this purpose. Firstly, we identified a patient with a unique type of acquired Glanzmann thrombasthenia whose platelets lacked GPIIb-IIIa expression on their platelet surface, but contained significant amounts of GPIIb-IIIa in their inside. We identified autoantibody against GPIIb-IIIa which did not inhibit GPIIb-IIIa function, but may induce GPIIb-IIIa deficiency. Secondarily, we characterized αIIb(R990W) knock-in mice to reveal the molecular defects of human GPIIb-IIIa related macrothrombocytopenia(in human αIIb R995W). Finally, we identified the first Japanese case of kindlin-3 deficiency with sever bleeding tendency from a new born. We demonstrated that kindkin-3 is a prerequisite molecule regarding not only αIIbβ3 but also αLβ2 activation.
Free Research Field	血液内科、血栓止血学
Academic Significance and Societal Importance of the Research Achievements	血管病、特に動脈血栓性疾患の発症抑制およびその制御法の開発は現代医療に課せられた最重要課題の一つであると言える。血小板は動脈血栓発症の中核を形成するだけでなく、動脈硬化進展や血管新生、組織修復に大きく関与していることが明らかとなってきた。このように血小板機能の制御機構を解明し標的分子を同定することは、出血性疾患の解明のみならず、血管病発症を制御する上で必須のことと考えられる。この観点より本研究では、申請者は稀で示唆に富むヒトの血小板インテグリンαIIbβ3(GPIIb-IIIa)異常症を同定しその分子異常を解析した。本研究の成果は、より良い血小板機能制御法の開発に寄与するものと確信する。