Genetic and Molecular Signaling in Heart Failure

描述（由申请人提供）： 在美国，心力衰竭是导致死亡的主要原因，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物。我们推测，个体间心力衰竭的易感性和进展的差异是由定义不清的环境和遗传应激因素造成的。我们以前定义的变异（多态性或突变），在关键的心脏基因，单独或组合，修改或导致心力衰竭。由于这些变异体中的一些聚集在不同的种族群体中，它们可能构成少数民族之间心力衰竭患病率和结局的已知差异的机制。本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）将扩展他非常成功的心力衰竭和α 2-肾上腺素能受体多态性的调查，重点是不同受体单倍型对心肌收缩力的组合效应。相关项目2（多恩）将研究α-1-肾上腺素能受体和心脏表达的RGS和GRK蛋白的新变体对心脏肥大及其进展为心力衰竭的作用。项目3（Kranias）跟进了她最近描述的导致致命性家族性心肌病的受磷蛋白突变体，并对新发现的受磷蛋白和磷酸酶抑制剂1（PPI 1）多态性进行了临床和基础研究，作为心力衰竭的遗传风险因素。相关项目4（Molkentin）将定义PPI 1与蛋白激酶Cot（本身在心力衰竭中转录上调）的相互作用，并描述其对肾上腺素能激动剂心肌反应性的联合作用。项目5（Robbins）将在类人兔心脏中使用转基因技术，以确定α/β-肌球蛋白重链表达改变对心脏对环境应激反应的影响。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理解心力衰竭的发病机制和最佳管理方面开辟新天地。

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.