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）： 在美国死亡的主要原因，心力衰竭通常代表了多因素疾病的缓慢进展，被诊断为“特发性”扩张的心肌病。尽管治疗的心力衰竭的预后仍然比大多数恶性肿瘤差，但发病率和临床过程中存在很大的患者变异性，这意味着存在未知的修饰剂。我们假设，由于环境和遗传压力较差，对心力衰竭的敏感性和心力衰竭进展的个体间差异。我们以前已经定义了关键心脏基因的变异（多态性或突变），这些变化（单独或组合都会改变或引起心力衰竭）。由于这些变体中的一些聚集在不同的族裔群体中，因此它们可能构成一种机制，即少数族裔患病率和心力衰竭结果的已知差异。该SCCOR的五个项目将检查心脏肾上腺素能信号通路内的自然遗传或转录事件。项目1（Liggett）将扩展他对心力衰竭中对A2-肾上腺素能受体多态性的非常成功的调查，重点是不同受体单倍型对心肌收缩力的组合作用。相关项目2（DORN）将研究α-1-肾上腺素能受体和心脏表达的RGS和GRK蛋白在心脏肥大中的新型变体的作用，以及其发展为心力衰竭。项目3（Kranias）跟进了她最近对磷脂突变体的描述，该突变体引起致命的家族性心肌病，并对新发现的磷酸兰巴兰和磷酸酶抑制剂1（PPI1）的临床和基本研究作为心脏失败的遗传危险因素。相关项目4（Molkentin）将定义PPI1与蛋白激酶COT的相互作用，心力衰竭本身在转录上上调，并描述了它们对肾上腺素能激动剂的心肌反应性的综合作用。项目5（Robbins）将在类似人类的兔子心中使用转基因来建立改变α/β-肌球蛋白重链链反应对心脏应激源对心脏压力的影响的影响。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，干细胞操纵和临床研究技能开发的核心的支持。我们认为，这个主题联系，多学科中心将继续为理解心力衰竭的发病机理和最佳管理而开展新的基础。