CARDIAC GROWTH REGULATION

心脏生长调节

• 批准号: 6388433
• 负责人: Kaie Margareeta OJAMAA
• 金额: $ 11.11万
• 依托单位: NORTH SHORE UNIVERSITY HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-05 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388433
• 关键词: biological signal transduction; cardiac myocytes; cell growth regulation; genetic library; genetic regulatory element; genetic transcription; heart contraction; heart transplantation; hemodynamics; laboratory rat; molecular cloning; molecular pathology; prognosis; protein binding; protein kinase C; tissue /cell culture; transcription factor; transfection; transfection /expression vector; ventricular hypertrophy

DESCRIPTION (Adapted from applicants' abstract) The heart responds to various hemodynamic and humoral stimuli by changes in myocyte size and function. Left ventricular hypertrophy such as arises from hypertension or valvular disease is a sensitive predictor for morbidity and mortality due to myocardial dysfunction. The purpose of the present study is test the hypothesis that myocyte contractile activity per se is a major stimulus of cardiomyocyte growth and function. The experimental approach is designed to identify the molecular mechanisms involved in the transduction of the contractile signal to the nucleus. Data from previous in vitro and in vivo studies that examined the transcriptional regulation of the alpha-myosin heavy chain (alpha-MHC) gene allow them to integrate the nuclear changes within the overall cellular response to the changes in hemodynamic load. This application addresses four specific aims: (1) identification of a transcription factor(s) that binds to a cis-acting element at -47 bp of the transcriptional start site of the alpha-MHC gene, designated hemodynamic response element (HME), that is both necessary and sufficient to confer contractile responsiveness to this promoter in cardiac myocytes. This nuclear protein (designated HRP) will be cloned from a cardiomyocyte expression library by its ability to bind to the HME sequence and to activate the alpha-MHC promoter; (2) study the mechanisms by which the contractile stimulus regulates the transcriptional activity of HRP by determining whether its activity is modulated by phosphorylation, determine its DNA binding characteristics, and its dimerization properties in response to the contractile stimulus; (3) study the contractile-induced signaling pathway in which protein kinase C-zeta plays a role in the phosphorylation and activation of HRP; and (4) determine the in vivo function of HRP by using viral vector systems to deliver the gene into the hemodynamically unloaded, heterotopically transplanted heart, that undergoes atrophy and decreased alpha-MHC expression. These studies will advance the understanding of the molecular pathways by which workload regulates cardiac growth and function, and potentially lead to novel genetic therapies of disorders of cardiac growth leading to pathologic hypertrophy. (End of Abstract)

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