2021 Fiscal Year Final Research Report

Identification of molecular mechanisms of RNF213-related occlusive cerebrovascular diseases and development of new treatment strategies

Research Project

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Project/Area Number	19H03770
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 56010:Neurosurgery-related
Research Institution	Kyoto University
Principal Investigator	Miyamoto Susumu 京都大学, 医学研究科, 教授 (70239440)
Co-Investigator(Kenkyū-buntansha)	高橋淳京都大学, iPS細胞研究所, 教授 (10270779) 片岡大治国立研究開発法人国立循環器病研究センター, 病院, 部長 (40359815) 山下潤京都大学, iPS細胞研究所, 教授 (50335288) 峰晴陽平京都大学, 医学研究科, 特定准教授 (50716602) 小泉昭夫京都大学, 医学研究科, 名誉教授 (50124574)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	moyamoya / genetics / iPS cells / cerebrovascular disease / atherosclerosis
Outline of Final Research Achievements	(1) We compared the characteristics of endothelial cells differentiated from patient-derived mutant iPS cells and their genetically repaired cell lines, and identified molecules that are responsible for differential tube formation capacity. (2) We compared gene expression in blood from patients and carriers with the RNF213 p.R4810K mutation and identified molecules that facilitate the progression of moyamoya disease. (3) We identified daily alcohol drinking as a risk factor for contralateral progression of unilateral moyamoya disease and clarified the association of several environmental factors including viral infection. (4) We clarified the effect of p.R4810K mutation on the morphology and hemodynamics of intracranial arteries in patients with moyamoya disease. These findings will facilitate the development of disease models, which is critical to understand the pathogenesis of the disease.
Free Research Field	Neurosurgery
Academic Significance and Societal Importance of the Research Achievements	RNF213 p.R4810K変異は東アジアのもやもや病患者で最も多く認められる変異にも関わらず、その詳細な機能は不明であった。本研究で樹立したiPS細胞の遺伝子修復株はその詳細な機能解明に貢献できると考えられる。実際に、内皮細胞における変異の影響が本研究で明らかになり、今後は疾患モデル樹立により、病態解明の他、治療法開発にも繋がると期待される。p.R4810K変異は、もやもや病以外にも数多くの頭蓋内外の血管障害に関与しており、その機能解明は、非動脈硬化性血管障害の病態解明と治療開発にも貢献できると考えられる。