The role of DNA damage in development of abdominal aortic aneurysm

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17585
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamagata University
• Principal Investigator: Takahashi Tetsuya 山形大学, 医学部, 客員研究員 (40825775)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 腹部大動脈瘤 / DNA傷害 / DNA傷害応答

Outline of Final Research Achievements

Abdominal aortic aneurysm is an asymptomatically progressive disease with a mortality rate of over 60% at the time of aortic aneurysm rupture. Aortic wall weakening due to inflammation and atherosclerosis is associated with the development of aortic aneurysms. Recently, it has been reported that DNA damage of vascular smooth muscle cells causes cellular senescence, apoptosis, and inflammation and promotes the development of atherosclerosis. However, the relationship between DNA damage and aortic aneurysm formation remains unclear. In this study, we generate mouse models of abdominal aortic aneurysms and examine the relationship between DNA damage and the DNA damage response and the formation and progression of aortic aneurysms, as well as the effect of inhibitors of ATM, a regulator of the DNA damage response, on the formation of abdominal aortic aneurysms.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

腹部大動脈瘤は、動脈硬化と危険因子が共通するが、大動脈瘤形成および瘤破裂を抑制する治療法は確立していない。動脈硬化進展に血管平滑筋細胞のDNA傷害およびDNA傷害応答が関与することが報告された(Circ Res 2015;116:816-826)。しかし腹部大動脈瘤の進展に細胞のDNA傷害およびDNA傷害応答の関係は不明である。本研究は、腹部大動脈瘤の形成と進展におけるDNA傷害およびDNA傷害応答の役割を解明することで新たな治療標的になるかを検討する。また、抗癌剤として発展してきた抗DNA傷害応答薬 (ATM阻害剤)をドラッグリポジショニングとして腹部大動脈瘤の治療に応用できるか検討を行う。