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)

描述 （改编自申请人的摘要）心脏对各种 肌细胞大小和功能的变化，血液动力学和体液刺激。 左心室肥大，例如由高血压或瓣膜引起 疾病是由于 心肌功能障碍。 本研究的目的是测试 假设肌细胞收缩活动本身是一个主要刺激 心肌细胞的生长和功能。 实验方法设计为 确定参与转导的分子机制 收缩信号向细胞核。 来自先前体外和体内的数据 研究了α-肌球蛋白的转录调控的研究 重链（Alpha-MHC）基因使它们能够整合核变化 在整体细胞对血液动力学负荷变化的反应中。 该申请解决了四个具体目的：（1）识别 与在-47 bp的顺式作用元件结合的转录因子 α-MHC基因的转录起始位点，指定为血液动力学 响应元素（HME），既需要又足以授予 收缩的反应性在心肌细胞中对该启动子。 这 核蛋白（指定的HRP）将从心肌细胞克隆 表达式文库通过其与HME序列结合的能力和与 激活α-MHC启动子； （2）研究的机制 收缩刺激调节HRP的转录活性 确定其活性是否通过磷酸化调节，确定 它的DNA结合特性及其二聚化特性 到收缩刺激； （3）研究收缩诱导的信号传导 蛋白激酶C-zeta在磷酸化中起作用的途径 和HRP的激活； （4）通过 使用病毒载体系统将基因输送到血流动力学中 卸载的，异位移植的心脏，经历萎缩和 α-MHC表达降低。 这些研究将推动 了解工作量调节心脏的分子途径 生长和功能，并有可能导致新的基因疗法 心脏生长的疾病导致病理肥大。 （结束 抽象的）