Genetic and Molecular Signaling in Heart Failure

描述(由申请人提供)： 在美国，心力衰竭是主要的死亡原因，通常表现为多因素疾病进展缓慢，诊断为“特发性”扩张型心肌病。虽然治疗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的差异性，这意味着存在未知的修饰物。我们假设，心力衰竭的易感性和进展的个体间差异是由于环境和遗传应激因素定义不清造成的。我们之前已经定义了关键心脏基因的变异(多态或突变)，它们单独或结合在一起，会改变或导致心力衰竭。由于这些变异中的一些集中在不同的种族群体中，它们可能构成了少数族裔之间心力衰竭患病率和结局的已知差异的机制。这项SCCOR的五个项目将研究心脏肾上腺素能信号通路中自然发生的遗传或转录事件。项目1(Liggett)将扩展他在心力衰竭中对α2-肾上腺素能受体多态的非常成功的调查，重点是不同受体单倍型对心肌收缩能力的组合影响。相关项目2(DORN)将研究α-1肾上腺素能受体的新变种以及心脏表达的RGS和GRK蛋白在心肌肥厚及其进展为心力衰竭中的作用。项目3(Kranias)延续了她最近描述的导致致死性家族性心肌病的磷蛋白突变，并对新发现的作为心力衰竭遗传风险因素的磷蛋白和磷酸酶抑制物1(PPI1)的多态性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，并描述它们对肾上腺素能激动剂对心肌反应性的联合影响。项目5(Robbins)将利用类人兔心脏的转基因来建立改变的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开辟新的天地。

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.