The pathophysiological mechanisms and causative genetic mutations of familial aortic aneusyrm/dissection and patent ductus arteriosus

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08083
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Imai Yasushi 自治医科大学, 医学部, 教授 (20359631)
• Co-Investigator(Kenkyū-buntansha): 永井 良三 自治医科大学, 医学部, 学長 (60207975) ; 相澤 健一 自治医科大学, 医学部, 准教授 (70436484) ; 高橋 政夫 自治医科大学, 医学部, 講師 (00447418)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 大動脈解離 / 大動脈瘤 / 動脈管開存症 / 遺伝子改変マウス / 臨床遺伝子診断 / Myh11

Outline of Final Research Achievements

We generated gene-engineered mice carrying a MYH11 causative mutation, which was detected in a Japanese pedigree with familial aortic dissection. We demonstrated that the heterozygous mice tended to suffer from aortic dissection in the Angiotensin II infusion model and the homozygous mice were complicated with aortic dissection and patent ductus arteriosus. Therefore, this mutant mouse is a promising animal model for hereditary aortic dissection in the field of cardiovascular medicine and pharmacology. In addition, we also performed genetic analyses for the patients with aortic aneurysm/dissection. We could detect causative genetic mutations in most of the cases, suggesting feasibility and importance of clinical genome sequencing for the aforementioned diseases.

Free Research Field

遺伝性・先天性心疾患

Academic Significance and Societal Importance of the Research Achievements

家族性大動脈解離・瘤について予防・治療における管理・薬物療法は未確立である。そのため、ヒト家系に見出された遺伝子変異を組み入れ、表現型を再現する動物モデルを構築し得たことの意義は大きく、難病の治療解明へ大きく寄与することが期待される。さらに大動脈解離・瘤症例における臨床的遺伝子診断も我々の小規模の検討においては有用であった。大動脈疾患への基礎・臨床両面からのアプローチが今後も求められる。