Mechanistic Role of Rnd3 in Response to Cardiac Stress

Rnd3 在心脏应激反应中的机制作用

• 批准号: 8890878
• 负责人: Jiang Chang
• 金额: $ 42.23万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890878
• 关键词: Address; Agonist; Animal Genetics; Animal Model; Animals; Area; Biological Process; Blood capillaries; Brain; CREB-binding protein; Cardiac; Cardiac Myocytes; Cause of Death; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Complex; Congestive Heart Failure; Coronary; Culture Media; Data; Defect; Development; Diagnostic tests; Dilated Cardiomyopathy; Disease; Down-Regulation; EP300 gene; Endothelial Cells; Endothelium; Epithelial Cells; Failure; Feedback; Genes; Genetic; Genetic Transcription; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Heart; Heart Diseases; Heart failure; Human; Hydrocephalus; Hypoxia; In Vitro; Investigation; Knockout Mice; Mediating; Mediator of activation protein; Messenger RNA; Molecular; Mus; Myocardial; Myocardial dysfunction; Myocardium; Nutrient; Oxygen; Paracrine Communication; Pathway interactions; Patients; Physiological; Process; Procollagen-Proline Dioxygenase; Protein Isoforms; Proteins; Reporting; Rnd3 protein; Role; Signal Transduction; Source; Staging; Stress; Testing; Therapeutic; Time; Transgenic Mice; Translations; Tube; Ubiquitination; Umbilical vein; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; advanced disease; angiogenesis; attenuation; biological adaptation to stress; capillary; cardiac angiogenesis; constriction; gain of function; human CREBBP protein; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; innovation; insight; mortality; neovascularization; notch protein; novel; overexpression; paracrine; pressure; programs; protein degradation; protein protein interaction; receptor; research study; response; rho GTP-Binding Proteins; screening

DESCRIPTION (provided by applicant): Congestive heart failure is a leading cause of death worldwide. It remains an incurable disease process with an estimated two-year mortality rate of 30-50% for patients with the advanced disease. Although we have made great advances in the treatment for heart failure, our understanding of the molecular mechanism leading to heart failure is still limited. My lab has been committed to study the molecular mechanism involved in the transition of a normal heart to failure. In this study, we focus on the investigation of a smal GTPase Rnd3. The biological function of Rnd3 in the heart remains unexplored. One microarray screening study showed a significant decrease in the Rnd3 mRNA levels in failing human myocardium. The goal of this study is to investigate the molecular mechanisms of Rnd3 downregulation in heart failure. In this proposal, we generated Rnd3 knockout mice. We recently reported that the homozygous mice were embryonically lethal with severe hydrocephalus due to the hyperactivation of Notch signaling. The Rnd3 haploinsufficient mice (Rnd3+/-) are fertile and viable without obvious abnormalities under normal physiological conditions. However, following transverse aortic constriction (TAC), the Rnd3+/- mice developed dilated cardiomyopathy (DCM) with heart failure after the pressure overload. Our preliminary data strongly suggest that the patient-relevant Rnd3 haploinsufficient mice are hypersensitive to cardiac stress. The immediate and challenging questions are why and how does the downregulation of Rnd3 result in heart failure? What is the molecular mechanism involved in the transition to cardiac dysfunction? We propose multiple and systemic approaches including in vitro protein-protein interaction analysis, cell culture experiments, and in vivo genetic animal assessments with loss- and gain-of-function strategies to address these questions. The animal models include Rnd3 haploinsufficient mice as well as Rnd3 overexpression transgenic mice. The findings from this proposal should raise clinical implications. We will, for the first time, establish a connection between the downregulation of a genetic factor and the transition of the heart from a normal to a failing state This will provide a potential diagnostic test and additional target for the treatment of the diseas. The study has basic and clinical translational significance for the understanding of human heart failure.

描述（由申请人提供）：充血性心力衰竭是全球死亡的主要原因。它仍然是一种无法治愈的疾病过程，估计晚期疾病患者的两年死亡率为30-50%。虽然我们在心力衰竭的治疗方面取得了很大的进展，但我们对导致心力衰竭的分子机制的理解仍然有限。我的实验室一直致力于研究正常心脏向衰竭转变的分子机制。在这项研究中，我们专注于调查的一个小的GT3 Rnd 3。Rnd 3在心脏中的生物学功能尚未探索。一项微阵列筛选研究显示，在衰竭的人类心肌中，Rnd 3 mRNA水平显著降低。本研究的目的是探讨Rnd 3在心力衰竭中下调的分子机制。在这个提议中，我们产生了Rnd 3敲除小鼠。我们最近报道称，由于Notch信号过度激活，纯合小鼠具有胚胎致死性，并伴有严重脑积水。Rnd 3单倍不足小鼠（Rnd 3 +/-）在正常生理条件下可生育且存活，无明显异常。然而，在横向主动脉缩窄（TAC）后，Rnd 3 +/-小鼠在压力超负荷后发生扩张型心肌病（DCM）伴心力衰竭。我们的初步数据有力地表明，患者相关的Rnd 3单倍不足小鼠对心脏应激过敏。目前最紧迫和最具挑战性的问题是，Rnd 3的下调为什么以及如何导致心力衰竭？向心功能不全转变的分子机制是什么？我们提出了多个和系统的方法，包括在体外蛋白质-蛋白质相互作用分析，细胞培养实验，并在体内遗传动物评估与损失和获得的功能策略，以解决这些问题。动物模型包括Rnd 3单倍不足小鼠以及Rnd 3过表达转基因小鼠。这项提议的发现应该会引起临床上的影响。我们将首次在遗传因子的下调与心脏从正常状态向衰竭状态的转变之间建立联系，这将为疾病的治疗提供潜在的诊断测试和额外的靶点。本研究对认识人类心力衰竭具有基础和临床转化意义。