The Role of RhoA in the Molecular Pathogenesis of Heart Disease

RhoA 在心脏病分子发病机制中的作用

基本信息

批准号：
8440361
负责人：
Maria I Kontaridis
金额：
$ 41万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440361
关键词：
Address Adult Affect Atherosclerosis Biochemical Biological Cardiac Cardiac Myocytes Cardiomegaly Cardiovascular Diseases Cell Proliferation Cell physiology Cells Cessation of life Complex Congenital Heart Defects Cytoskeletal Modeling Data Developmental Therapeutics Program Dilated Cardiomyopathy Disease Functional disorder GTP-Binding Proteins Generations Genetic Heart Heart Diseases Heart failure Homeostasis Human Hypertension In Vitro Link Mass Spectrum Analysis Mediating Molecular Monomeric GTP-Binding Proteins Mus Myocardial Myocardium Pathogenesis Pathway interactions Patients Physiological Primary idiopathic dilated cardiomyopathy Protein Tyrosine Phosphatase Proteins Proteomics Publishing Pump Receptor Protein-Tyrosine Kinases Regulation Research Role Sampling Series Signal Pathway Signal Transduction Signaling Molecule Testing Work base in vivo inhibitor/antagonist interest migration mortality mouse Cre recombinase novel novel therapeutics prevent protein complex protein expression public health relevance recombinase research study rhoA GTP-Binding Protein statistics therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Idiopathic dilated cardiomyopathy (IDC), resulting in an enlarged heart that does not pump properly, is a common disease (~ 1:2500) associated with an annual mortality rate of greater than 10000 deaths. These statistics underscore the significance for developing new therapeutic strategies aimed at understanding, preventing, arresting or reversing progressive cardiac dysfunction. However, to date, the cause(s) of IDC is (are) unclear and the molecular signaling mechanisms that are aberrantly regulated in IDC are largely unknown. Our proposal will determine whether aberrant regulation of the small GTPase RhoA by the protein tyrosine phosphatase Shp2 is directly involved in mediating IDC pathogenesis. Our recently published work shows that hearts from mice with cardiomyocyte-specific deletion of Shp2, a key positive regulator in most, if not all, receptor tyrosine kinase (RTK) signaling pathways, develop a severe dilated cardiomyopathy (DCM). This loss of Shp2 also revealed a hyper-activation in the RhoA signaling pathway, implicating a novel, yet undefined, connection between Shp2 and the RhoA signaling pathway in the heart. We hypothesize that suppression of RhoA activity, via Shp2, is cardioprotective and, as such, is biochemically required to prevent IDC and heart failure. RhoA is a small GTP binding protein involved in important cellular functions including cell proliferation, migration and cytoskeletal reorganization. Recent translational work has demonstrated a significant role for RhoA in cardiovascular disease, including hypertension and atherosclerosis; however, here too, the underlying mechanisms are unclear. In this proposal, we will elucidate the mechanisms by which RhoA is regulated by Shp2. This proposal addresses several interesting and key questions with regards to the function of RhoA in cardiomyocyte disease. Using a combined, comprehensive set of biochemical, cell biological, proteomic and genetic approaches, we plan to (1) determine the physiological significance of loss of RhoA activity in the adult myocardium (2) determine whether loss of RhoA expression and/or activity can rescue the functional cardiac defects in Shp2 deleted mice in vivo, and (3) utilize proteomic and in vitro and ex vivo biochemical approaches to examine the mechanism by which Shp2 regulation of RhoA affects RTK signaling in the myocardium. Results of this proposal will elucidate the mechanism(s) by which RhoA activity is regulated in the adult myocardium, reveal the manner in which Shp2 regulation of RhoA activity may be cardioprotective, and assist in the generation of novel, molecular-based pharmacological targets for the treatment of heart failure in patients with IDC.

描述（由申请人提供）：特发性扩张的心肌病（IDC），导致心脏扩大，无法正确泵送，是一种常见疾病（〜1：2500），与年死亡率大于10000人死亡。这些统计数据强调了制定旨在理解，预防，逮捕或逆转进步性心脏功能障碍的新的治疗策略的重要性。但是，迄今为止，IDC的原因尚不清楚，并且在IDC中受到异常调节的分子信号传导机制在很大程度上尚不清楚。我们的建议将确定蛋白质酪氨酸磷酸酶SHP2对小GTPase RhoA的异常调节直接参与介导IDC发病机理。我们最近发表的工作表明，来自心肌细胞特异性缺失的小鼠的心脏SHP2是大多数（如果不是全部）受体酪氨酸激酶（RTK）信号传导途径的关键阳性调节剂，会发展出严重的扩张性心肌病（DCM）。 SHP2的这种损失还显示出RhoA信号通路中的过度激活，这暗示了SHP2与心脏中RhoA信号通路之间的一种新颖但未定义的联系。我们假设通过SHP2抑制RhoA活性是心脏保护性的，因此，在生化上需要进行预防IDC和心力衰竭。 RhoA是一种参与重要细胞功能的小型GTP结合蛋白，包括细胞增殖，迁移和细胞骨架重组。最近的翻译工作表明，RhoA在心血管疾病中的重要作用，包括高血压和动脉粥样硬化。但是，在这里，基本机制也不清楚。在此提案中，我们将阐明RhoA受SHP2调节的机制。该提案解决了关于RhoA在心肌细胞疾病中的功能方面的几个有趣和关键问题。使用一组全面的生化，细胞生物学，蛋白质组学和遗传方法，我们计划（1）确定成年心肌（2）RhoA活性丧失的生理意义（2）确定RhoA表达和/或活性的丧失是否可以营救SHP2中的功能性心脏缺陷在体内删除小鼠，（3）利用蛋白质组学和体外和实体生物化学方法来检查SHP2调节RhoA的机制，该机制会影响RhoA的RHOA会影响心肌心肌的RTK信号。该提案的结果将阐明在成年心肌中调节RhoA活性的机制，揭示RhoA活性可能受到心脏保护的方式，并有助于产生新型的基于分子的药理靶标的。 IDC患者心力衰竭的治疗。