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

• 批准号: 7863886
• 负责人: Maria I Kontaridis
• 金额: $ 43.08万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 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/7863886
• 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 Kinase; 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; receptor; recombinase; research study; rhoA GTP-Binding Protein; statistics; therapeutic target

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. PUBLIC HEALTH RELEVANCE: Information gained from these studies will 1) elucidate the mechanism(s) by which RhoA activity is regulated in the adult myocardium; 2) reveal the manner in which Shp2 regulation of RhoA activity may be cardioprotective, which, in turn, will create new avenues of research for IDC and heart failure; and 3) by elucidating the RhoA-mediated signaling pathways and molecules that regulate cardiac pathogenesis, will 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）：特发性扩张型心肌病 (IDC) 会导致心脏增大且无法正常泵血，是一种常见疾病 (~ 1:2500)，每年死亡率超过 10000 例。这些统计数据强调了开发旨在理解、预防、阻止或逆转进行性心脏功能障碍的新治疗策略的重要性。然而，迄今为止，IDC 的病因尚不清楚，IDC 中异常调节的分子信号传导机制也很大程度上未知。我们的提案将确定蛋白酪氨酸磷酸酶 Shp2 对小 GTP 酶 RhoA 的异常调节是否直接参与介导 IDC 发病机制。我们最近发表的研究表明，心肌细胞特异性缺失 Shp2（大多数（如果不是全部）受体酪氨酸激酶 (RTK) 信号通路中的关键正调节因子）的小鼠心脏会发展为严重的扩张型心肌病 (DCM)。 Shp2 的缺失还揭示了 RhoA 信号通路的过度激活，这表明 Shp2 与心脏中的 RhoA 信号通路之间存在一种新颖但尚未明确的联系。我们假设通过 Shp2 抑制 RhoA 活性具有心脏保护作用，因此从生化角度来说，这是预防 IDC 和心力衰竭所必需的。 RhoA 是一种小型 GTP 结合蛋白，参与重要的细胞功能，包括细胞增殖、迁移和细胞骨架重组。最近的转化研究表明 RhoA 在心血管疾病（包括高血压和动脉粥样硬化）中发挥着重要作用；然而，这里的根本机制也不清楚。在本提案中，我们将阐明 Shp2 调节 RhoA 的机制。该提案解决了有关 RhoA 在心肌细胞疾病中的功能的几个有趣且关键的问题。使用一套综合的生化、细胞生物学、蛋白质组学和遗传学方法，我们计划 (1) 确定成人心肌中 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挽救体内Shp2缺失小鼠的功能性心脏缺陷，以及（3）利用蛋白质组学和体外和离体生化方法来检查RhoA的Shp2调节影响RTK信号传导的机制心肌。该提案的结果将阐明成人心肌中 RhoA 活性的调节机制，揭示 Shp2 对 RhoA 活性的调节可能具有心脏保护作用的方式，并有助于产生新的、基于分子的药理学靶点IDC 患者心力衰竭的治疗。 公共健康相关性：从这些研究中获得的信息将 1) 阐明成人心肌中 RhoA 活性的调节机制； 2）揭示Shp2对RhoA活性的调节可能具有心脏保护作用的方式，这反过来将为IDC和心力衰竭的研究开辟新途径； 3) 通过阐明 RhoA 介导的信号通路和调节心脏发病机制的分子，将有助于产生新的、基于分子的药理学靶点，用于治疗 IDC 患者的心力衰竭。