2022 Fiscal Year Final Research Report

Elucidation of the molecular mechanism of hemostasis and search for novel functions of CalDAG-GEF1

Research Project

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Project/Area Number	20K07808
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 52010:General internal medicine-related
Research Institution	Kagoshima University
Principal Investigator	Kojo Tsuyoshi 鹿児島大学, 鹿児島大学病院, 臨床検査技師 (30837282)
Co-Investigator(Kenkyū-buntansha)	山口宗一鹿児島大学, 医歯学域医学系, 准教授 (20325814) 大山陽子鹿児島大学, 鹿児島大学病院, 医員 (20583470) 竹之内和則鹿児島大学, 医歯学域医学系, 助教 (30646758) 小浜祐行鹿児島大学, 鹿児島大学病院, 臨床検査技師 (50837276) 橋口照人鹿児島大学, 医歯学域医学系, 教授 (70250917)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	CalDAG-GEFI / RasGRP2 / Rap1
Outline of Final Research Achievements	Whole exome analysis was performed in a family of patients with platelet dysfunction with hemostasis abnormalities to identify mutations in the RASGRP2 gene encoding CalDAG-GEFI. Compared to healthy controls, platelet aggregation (ADP, collagen, and ristocetin) was reduced and platelet activation marker αIIbβ3 expression was decreased in cases with RASGRP2 gene mutations. Western blotting confirmed that RASGRP2 gene abnormalities prevented the maintenance and persistence of the Rap1 activation. These results suggest that CalDAG-GEFI is a central molecule in platelet activation and is expected to be a potential target for future therapy and drug discovery.
Free Research Field	分子生物学
Academic Significance and Societal Importance of the Research Achievements	CalDAG-GEFIは血小板活性化の統合的役割をもち、主には血小板凝集反応を司る分子として知られているが、そのRASGRP2遺伝子異常による血小板機能異常の詳細な検討は、新たな血小板の役割解明に繋がる可能性がある。また、原因不明の出血傾向の患者の原因の一つとしてCalDAG-GEFIを精査する意義があり、今後の医療に貢献できる。更に、このCalDAG-GEFI分子の血小板以外の組織や細胞における働きなどを明らかにしていく予定である。