Elucidation of the molecular pathology of pulmonary arterial hypertension using murine model with hot-spot mutation of related genes

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17161
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: University of Occupational and Environmental Health, Japan (2021); Kyorin University (2020)
• Principal Investigator: Yuichi Momose 産業医科大学, 医学部, 非常勤医師 (60795798)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 肺動脈性肺高血圧症 / 遺伝子変異 / 遺伝子改変マウス

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is a cardiovascular intractable disease, and BMPR2 has been reported as the causative gene of PAH. However, the mechanism by which the BMPR2 mutation leads to the onset of PAH remains unclear. We also found a hot-spot mutation of RNF213, which is a common susceptibility gene for other intractable vasculopathies, in PAH patients. Therefore, in order to elucidate the pathological mechanism, mice with Hot-Spot mutantations of BMPR2 and RNF213 genes were generated using the CRISPR/Cas9 system. We obtained results that led to the elucidation of the pathological mechanism by single-cell analysis using mice with BMPR2 Hot-Spot mutantion. In addition, we obtained results that led to the elucidation of the downstream signal pathway of RNF213 leading to the onset of vasculopathies.

Free Research Field

循環器病学

Academic Significance and Societal Importance of the Research Achievements

本研究は、BMPR2やRNF213といった遺伝子全体のノックアウトマウスを用いた研究ではなく、実際のPAH患者で認めるHot-Spot変異部位を再現したマウスを用いた研究である。実際の患者の遺伝子状態を模倣したマウスを用いることによって、より実臨床に近い発症病態を正確に解明することができ、学術的意義が高いと考える。また、このような実臨床に近い発症病態解明によって新しい治療標的分子発掘に繋がる成果を得ており、難病患者の予後改善と難病医療界への貢献において、社会的意義も高いものと考えられる。