Mechanistic Role of Rnd3 in Response to Cardiac Stress

Rnd3 在心脏应激反应中的机制作用

基本信息

批准号：
8755080
负责人：
Jiang Chang
金额：
$ 38.64万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
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/8755080
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 Commit 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 Functional disorder Genes Genetic Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Heart Heart Diseases Heart failure Human Hydrocephalus Hypoxia In Vitro Investigation Knockout Mice Mediating Mediator of activation protein Messenger RNA Molecular Mus Myocardial 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 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 public health relevance receptor research study response rho GTP-Binding Proteins screening

项目摘要

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。它仍然是一个无法治愈的疾病过程，患有晚期疾病的患者估计为30-50％的死亡率为30-50％。尽管我们在心力衰竭的治疗方面取得了长足的进步，但我们对导致心力衰竭的分子机制的理解仍然有限。我的实验室已致力于研究正常心脏向失败过渡的分子机制。在这项研究中，我们专注于对SMAL GTPase RND3的研究。 RND3在心脏中的生物学功能仍未开发。一项微阵列筛查研究显示，人体心肌失败的RND3 mRNA水平显着降低。这项研究的目的是研究心力衰竭中RND3下调的分子机制。在此提案中，我们生成了RND3淘汰小鼠。我们最近报告说，由于缺口信号的过度激活，纯合小鼠在胚胎中具有严重的脑积水。在正常生理条件下，RND3单倍弥补的小鼠（RND3 +/-）是肥沃和可行的，没有明显的异常。然而，在横向主动脉收缩（TAC）之后，RND3 +/-小鼠在压力超负荷后发生了扩张的心肌病（DCM），心力衰竭。我们的初步数据强烈表明，与患者相关的RND3单倍体小鼠对心脏胁迫过敏。直接和挑战性的问题是为什么RND3的下调以及如何导致心力衰竭？过渡到心脏功能障碍的分子机制是什么？我们提出了多种和全身的方法，包括体外蛋白质 - 蛋白质相互作用分析，细胞培养实验以及体内遗传动物评估，并具有解决这些问题的损失和功能障碍策略。动物模型包括RND3单倍弹性小鼠以及RND3过表达转基因小鼠。该提案的发现应提高临床意义。我们将首次建立遗传因素下调与心脏从正常状态过渡到失败状态之间的联系，这将提供潜在的诊断测试和治疗疾病治疗的其他目标。这项研究具有理解人类心力衰竭的基本和临床翻译意义。