Identification and functional analysis of novel susceptibility genes for the development of pulmonary arterial hypertension

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K08154
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kyorin University
• Principal Investigator: Inami Takumi 杏林大学, 医学部, 学内講師 (80580381)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 肺動脈性肺高血圧症

Outline of Final Research Achievements

BMPR2 has been reported as a causative gene for pulmonary arterial hypertension (PAH), but the pathogenic mechanism of PAH due to BMPR2 mutations has not been elucidated. We also identified RNF213 as a new susceptibility gene for PAH. In this study, we generated genetically modified mice with hot-spot mutations in BMPR2 and RNF213, respectively. Single-cell analysis using BMPR2 mutant mice has led to the elucidation of the pathogenic mechanism of PAH onset due to changes in gene expression levels of cells in lung tissue. In addition, verification using RNF213 mutant mice has led to the elucidation of the downstream signal pathway of RNF213 leading to the onset of angiopathy.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究では、難病疾患である肺動脈性肺高血圧症(PAH)の発症機序全容解明に繋がる研究成果を得ることができた。これらの成果はPAH患者の早期診断や早期治療介入による予後改善に繋がることが期待される。また、患者で認めるhot-spot変異を再現した遺伝子改変マウスを用いた本研究成果は、難病疾患領域における病態解明研究のモデルケースとして他難病疾患へも応用可能であり、学術的意義および社会的意義が高いものと考えられる。