Genetic and Molecular Signaling in Heart Failure

心力衰竭的遗传和分子信号传导

• 批准号: 7564000
• 负责人: Evangelia G Kranias
• 金额: $ 395.87万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564000
• 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）：

项目成果

Beta-blockade in heart failure: adding SENIORS to the mix.

心力衰竭中的β受体阻滞剂：将老年人加入其中。

• DOI: 10.1093/eurheartj/ehi693
• 发表时间: 2006
• 期刊: European heart journal
• 影响因子: 39.3
• 作者: Lindsey,MerryL;Freeman,GregoryL
• 通讯作者: Freeman,GregoryL

Hypertrophy-associated polymorphisms ascertained in a founder cohort applied to heart failure risk and mortality.

在创始人队列中确定的肥厚相关多态性应用于心力衰竭风险和死亡率。

• DOI: 10.1111/j.1752-8062.2010.00251.x
• 发表时间: 2011-02
• 期刊: Clinical and translational science
• 作者: Parsa A;Chang YP;Kelly RJ;Corretti MC;Ryan KA;Robinson SW;Gottlieb SS;Kardia SL;Shuldiner AR;Liggett SB
• 通讯作者: Liggett SB

Tight control of adrenal medulla catecholamine release by alpha 2C-adrenergic receptors influences susceptibility to heart failure.

α2C-肾上腺素能受体严格控制肾上腺髓质儿茶酚胺的释放会影响心力衰竭的易感性。

• DOI: 10.1016/j.cardiores.2007.07.005
• 发表时间: 2007
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Petrashevskaya,Natalia;Liggett,StephenB
• 通讯作者: Liggett,StephenB

Pharmacogenetic profiling in the treatment of heart disease.

在心脏病治疗中的药物遗传学分析。

• DOI: 10.1016/j.trsl.2009.07.010
• 发表时间: 2009-12
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Dorn GW 2nd