Elucidation of molecular mechanism and treatment application of heart failure by transcription factor and DNA damage response factor

Research Project

Project/Area Number	15K09145
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Cardiovascular medicine
Research Institution	Jichi Medical University
Principal Investigator	Aizawa Kenichi 自治医科大学, 医学部, 准教授 (70436484)
Co-Investigator(Kenkyū-buntansha)	永井良三自治医科大学, 医学部, 学長 (60207975)
Project Period (FY)	2015-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000) Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords	循環器内科学 / 分子心臓学
Outline of Final Research Achievements	The heart causes myocardial remodeling as an adaptation to load. Although many cardiac hypertrophy inducers are already known, the mechanism of adaptive failure leading to heart failure has not been fully elucidated. We have previously shown that the cardiac stromal cell transcription factor KLF5 is important for load adaptation, and that acetylation of KLF5 is involved in cell proliferation in vitro. In this study, we focused on the acetylation of KLF5 molecule and DNA repair factor (ATM etc.) and clarified the role in adaptation and failure of the heart at individual level. It has been revealed that KLF5 non-acetylated mutant mice and ATM deficient mice produce abnormalities in cardiac development and hypertrophy. Furthermore, we isolated factors that interact with them and identified new therapeutic targets.
Academic Significance and Societal Importance of the Research Achievements	心不全は近年増加しつつある高血圧性心疾患、虚血性心疾患の最終病態であり、この問題を解決することは臨床的のみならず社会的にも重要である。これまでの心不全の薬物治療は心不全状態で活性化される細胞外の神経・体液性因子を標的としたものであった。本研究は動脈硬化、心肥大が転写因子とその相互作用因子により制御されることを明らかにし、その鍵分子である転写因子KLF5とDNA損傷応答機構が、心肥大・心不全の発症機序の鍵となる可能性を示した。すなわち、本研究は心筋リモデリングにおける病態生理の解明、ひいては新規治療薬開発につながると期待される。