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Role of ROCK isoform-mediated actin cytoskeleton modification in the pathogenesis of heart disease

ROCK亚型介导的肌动蛋白细胞骨架修饰在心脏病发病机制中的作用

基本信息

批准号：
10542786
负责人：
Jianjian Shi
金额：
$ 44.5万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542786
关键词：
Actins Adult Aging Animal Model Autophagocytosis Cardiac Cardiac Myocytes Cardiac health Cardiovascular Diseases Cause of Death Cell physiology Cerebrovascular Spasm Cessation of life Clinical Research Clinical Trials Compensation Complex Cytoskeletal Modeling Cytoskeleton Disease Etiology Extracellular Matrix Proteins F-Actin FRAP1 gene Family Fibroblasts Fibrosis Functional disorder Genes Genetic Processes Goals Grant Guanosine Triphosphate Phosphohydrolases Heart Heart Diseases Heart Hypertrophy Heart Injuries Heart failure Human Hypertrophy Japan Knock-out Knockout Mice Knowledge LIM Domain Kinase 1 Mediating Modification Molecular Mus Muscle Contraction Myocardial Ischemia Myocardium Myofibroblast Myosin Light Chains Names Nature Nuclear Translocation Organelles Outcome Study Oxidative Stress Pathogenesis Pathologic Pathway interactions Phosphotransferases Prevention Process Production Protein Isoforms ROCK1 gene Regulation Research Rho-associated kinase Role Serum Response Factor Signal Pathway Signal Transduction Smooth Muscle Myocytes Stress Stress Fibers Subarachnoid Hemorrhage Testing Therapeutic Therapeutic Effect Time Ventricular Work age related biological adaptation to stress cell type coronary fibrosis experimental study fasudil heart function human disease human model in vivo inducible Cre inhibition of autophagy inhibitor interstitial ischemic injury member misfolded protein myocardin myosin phosphatase new therapeutic target novel therapeutic intervention pressure response senescence therapeutic target transcription factor treatment trial

项目摘要

PROJECT ABSTRACT The prevention and treatment of heart disease remain challenging. Rho kinase (also named ROCK) has recently emerged as a potential therapeutic target for various cardiovascular diseases. A long-term goal of our past twenty years of research on ROCK pathophysiology is to define the roles and underlying mechanisms of ROCK-mediated signal pathway in regulating cardiac remodeling. The two members of the ROCK family, ROCK1 and ROCK2, have both shared and distinct cellular functions and can compensate each other in numerous single isoform knockout conditions. The majority of our knowledge on the cellular and molecular function of ROCKs comes from research on proliferative cell types in which ROCKs modulate actin cytoskeleton organization through promoting actomyocin contraction and F-actin stabilization. Cardiomyocytes stand apart from other cell types because they contain both sarcomeric and non-sarcomeric cytoskeleton. There is a gap in our knowledge on how ROCKs regulate sarcomeric and non-sarcomeric F-actin in cardiomyocytes and how these processes contribute to overall heart function. Recently, for the first time to use inducible approach to delete both ROCK isoforms in cardiomyocytes, we have discovered that although ROCKs are not required for maintaining sarcomeric cytoskeleton in adult hearts, they do participate in the regulation of non-sarcomeric F-actin organization, inhibit autophagy by promoting mammalian target of rapamycin (mTOR) activity and contribute to age-related cardiac fibrosis. In contrast, the non-sarcomeric F- actin dynamics are able to be maintained with the presence of either isoform in the cardiomyocytes where the other isoform has been deleted; this might be attributed to compensatory over-activation of the remaining isoform in cardiomyocytes having single ROCK isoform deletion. The proposed research aims to further elucidate the pathophysiological roles and downstream pathways of ROCK-mediated actin cytoskeleton changes in cardiomyocytes and fibroblasts under pathological stress sceneries. Aim 1 will determine if deletion of both ROCK1 and ROCK2 from adult cardiomyocytes limits the progression of heart failure in pathological hypertrophy and myocardial ischemic injury through activating autophagy and facilitating autophagic flux by inhibiting mTOR signaling. Aim 2 will determine if deletion of both ROCK1 and ROCK2 from adult fibroblasts limits the activation of myofibroblasts and fibrotic response through inhibition of F-actin regulated transcription factor activation including the serum response factor (SRF) and myocardin-related transcription factors (MRTFs); the direct contribution of ROCKs/F-actin/MRTFs/SRF axis in fibroblasts to cardiac fibrosis has never been demonstrated in vivo, and our preliminary results indicate that the inducible approach is required for double ROCK knockout in fibroblasts. The biomedical significance of this work is to provide the cutting-edge concepts for understanding pathophysiological roles of ROCKs in heart failure. The ultimate goal is to develop new therapeutic intervention to ameliorate compromised cardiac function.

项目摘要