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世界死亡的主要原因。它仍然是一种无法治愈的疾病，估计晚期患者的两年死亡率为 30-50%。尽管我们在心力衰竭的治疗方面取得了很大进展，但我们对导致心力衰竭的分子机制的了解仍然有限。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。在本研究中，我们重点研究小型 GTPase Rnd3。 Rnd3 在心脏中的生物学功能尚未被探索。一项微阵列筛选研究显示，衰竭的人类心肌中 Rnd3 mRNA 水平显着下降。本研究的目的是探讨 Rnd3 下调在心力衰竭中的分子机制。在这个提案中，我们生成了 Rnd3 敲除小鼠。我们最近报道，由于 Notch 信号过度激活，纯合子小鼠因严重脑积水而导致胚胎死亡。 Rnd3单倍体不足的小鼠(Rnd3+/-)在正常生理条件下具有生育能力并且没有明显异常。然而，在横主动脉缩窄（TAC）后，Rnd3+/-小鼠在压力超负荷后出现扩张型心肌病（DCM）并伴有心力衰竭。我们的初步数据强烈表明，患者相关 Rnd3 单倍体不足的小鼠对心脏应激高度敏感。紧迫且具有挑战性的问题是 Rnd3 下调为何以及如何导致心力衰竭？向心功能障碍转变的分子机制是什么？我们提出了多种系统方法来解决这些问题，包括体外蛋白质-蛋白质相互作用分析、细胞培养实验和体内遗传动物评估以及功能丧失和获得策略。动物模型包括Rnd3单倍体不足的小鼠以及Rnd3过表达的转基因小鼠。该提案的研究结果应该会产生临床意义。我们将首次在遗传因素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目标。该研究对于了解人类心力衰竭具有基础和临床转化意义。