Genetic and Molecular Signaling in Heart Failure

心力衰竭的遗传和分子信号传导

• 批准号: 7338024
• 负责人: Evangelia G Kranias
• 金额: $ 378.09万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-22 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338024
• 关键词: Genetic; Molecular; Signaling; Heart; Failure

DESCRIPTION (provided by applicant): The leading cause of death in the USA, heart failure most often represents slow progression of multi-factorial disease, diagnosed as "idiopathic" dilated cardiomyopathy. While the prognosis of treated heart failure continues to be poorer than for most malignancies, there is substantial patient variability in incidence and clinical course that implies the existence of unknown modifiers. We hypothesize that inter-individual differences in susceptibility to and progression of heart failure result from poorly defined environmental and genetic stressors. We have previously defined variations (polymorphisms or mutations) in critical cardiac genes that, alone or in combination, modify or cause heart failure. As some of these variants cluster in distinct ethnic groups, they may constitute a mechanism for known differences in prevalence and outcome of heart failure among ethnic minorities. The five Projects of this SCCOR will examine naturally-occurring genetic or transcriptional events within cardiac adrenergic signaling pathways. Project 1 (Liggett) will extend his highly successful survey of and a2-adrenergic receptor polymorphisms in heart failure, focusing on combinatorial effects of different receptor haplotypes on myocardial contractility. Related Project 2 (Dorn) will examine the roles of novel variants of alpha-1-adrenergic receptors and cardiac-expressed RGS and GRK proteins on cardiac hypertrophy and its progression to heart failure. Project 3 (Kranias) follows up her recent description of a phospholamban mutant that causes lethal familial cardiomyopathy with clinical and basic investigations of newly discovered polymorphisms for phospholamban and phosphatase inhibitor 1 (PPI1) as genetic risk factors for heart failure. Related Project 4 (Molkentin) will define the interactions of PPI1 with protein kinase Cot, itself transcriptionally upregulated in heart failure, and delineate their combined effects on myocardial responsiveness to adrenergic agonists. Project 5 (Robbins) will use transgenesis in human-like rabbit hearts to establish the effects of altered alpha/beta-myosin heavy chain expression on cardiac responses to environmental stressors. Studies will be performed in human subjects, genetically modified animal models, and cultured cells, and are supported by Cores for Genomics, Biostatistics, Stem Cell Manipulation, and Clinical Research Skills Development. We believe this thematically linked, multidisciplinary Center will continue to break new ground in understanding the pathogenesis and optimal management of heart failure.

描述（由申请人提供）： 心力衰竭是美国死亡的主要原因，通常代表多因素疾病的缓慢进展，被诊断为“特发性”扩张型心肌病。虽然治疗后的心力衰竭的预后仍然比大多数恶性肿瘤差，但患者的发病率和临床病程存在很大差异，这意味着存在未知的修饰因素。我们假设心力衰竭易感性和进展的个体间差异是由于环境和遗传压力源定义不明确造成的。我们之前已经定义了关键心脏基因的变异（多态性或突变），这些变异单独或组合起来会改变或导致心力衰竭。由于其中一些变异集中在不同的种族群体中，因此它们可能构成了少数民族心力衰竭患病率和结果已知差异的机制。该 SCCOR 的五个项目将检查心脏肾上腺素信号通路内自然发生的遗传或转录事件。项目 1 (Liggett) 将扩展他对心力衰竭中 α2-肾上腺素受体多态性的高度成功的调查，重点关注不同受体单倍型对心肌收缩力的组合效应。相关项目 2 (Dorn) 将研究 α-1-肾上腺素能受体的新变体以及心脏表达的 RGS 和 GRK 蛋白对心脏肥大及其进展为心力衰竭的作用。项目 3 (Kranias) 跟进了她最近对导致致命性家族性心肌病的受磷蛋白突变体的描述，并对新发现的受磷蛋白和磷酸酶抑制剂 1 (PPI1) 多态性作为心力衰竭的遗传危险因素进行了临床和基础研究。相关项目 4 (Molkentin) 将定义 PPI1 与蛋白激酶 Cot 的相互作用，蛋白激酶 Cot 本身在心力衰竭中转录上调，并描述它们对心肌对肾上腺素能激动剂反应的综合影响。项目 5 (Robbins) 将在类人兔心脏中使用转基因技术，以确定改变的 α/β-肌球蛋白重链表达对心脏对环境应激源反应的影响。研究将在人类受试者、转基因动物模型和培养细胞中进行，并得到基因组学、生物统计学、干细胞操作和临床研究技能开发核心的支持。我们相信，这个主题相关的多学科中心将继续在了解心力衰竭的发病机制和最佳治疗方面取得新的突破。