Identification of novel therapeutic target for genetic variant-associated vascular disease

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16065
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Keio University
• Principal Investigator: Hiraide Takahiro 慶應義塾大学, 医学部(信濃町), 特任助教 (20897673)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 難治性血管病 / 肺動脈性肺高血圧症 / 遺伝学 / RNF213 / 病態解明研究 / CRISPR-Cas9

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is a poor prognostic disease. Despite the recent advance of pulmonary vasodilators, the cure treatment has not been invented. Ring finger protein 213 (RNF213) R4810K variant is a susceptive gene variant in development of PAH in East-Asia population, and we reported this variant as the independent poor prognostic factor in Japanese patients with PAH. We created the mice with this variant using CRISPR-Cas9 system, and we identified that this variant carrier mice developed significant PAH in hypoxic environment. Microarray analysis demonstrated the elevation of inflammatory chemokines in lung of mice with this variant, and the addition of antagonist ameliorated the severity of PAH. Targeting the chemokine signaling may be a novel therapeutic strategy in patients with RNF213 variant carriers.

Free Research Field

肺高血圧症、脈管学、遺伝学

Academic Significance and Societal Importance of the Research Achievements

本研究では、日本人特有の遺伝子変化に起因する肺動脈性肺高血圧症の発症メカニズムを解明した。従来の肺血管拡張薬への反応性が乏しかった患者群にとっては非常に有意義な研究成果であり、また根治療法開発に向けた将来性もある。肺動脈性肺高血圧症は指定難病であり、高額な肺血管拡張薬を生涯にわたり使用する必要がある。根治療法を開発することで、医療資源の消費を抑える点で社会的に有用である。