INITIATION OF CARDIAC HYPERTROPHY IN HYPERTENSION

高血压引起心脏肥大

• 批准号: 6183672
• 负责人: Subha Sen
• 金额: $ 29.39万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183672
• 关键词: biological signal transduction; cardiac myocytes; complementary DNA; disease /disorder etiology; echocardiography; gene expression; genetically modified animals; growth factor; heart function; hypertension; hypertrophic myocardiopathy; immunocytochemistry; in situ hybridization; laboratory mouse; mechanical stress; molecular cloning; muscle proteins; pathologic process; protein biosynthesis; regulatory gene; spontaneous hypertensive rat

DESCRIPTION (Adapted from Investigator's Abstract): In a study designed to elucidate factors other than blood pressure which are responsible for development of cardiac growth and myocardial hypertrophy, the investigator has hypothesized that cardiac hypertrophy is initiated by a mechanical or humoral signal to the myocardium, which in turn produces a soluble factor, previously identified by this laboratory as a 12 kD protein called myotrophin. This substance has been identified in SHR, other rat models of cardiac hypertrophy, and in human dilated cardiomyopathy. When added to isolated cardiac myocytes, myotrophin triggers protein synthesis. Myotrophin has been cloned, stimulates production of hypertrophy markers such as c-myc, c-fos, c-jun, ANF, beta-MHC and connexin and may play a role in myocyte growth. Multiple transcripts have been identified in SHR which all express a 12 kD protein. ECHO methods have been developed to follow functional and morphologic alterations in mice. In the present application, molecular, genetic and functional approaches will be used to understand the mode of action of myotrophin with the following specific aims: a) to elucidate the signal transduction mechanisms by which myotrophin stimulates protein synthesis; b) to study the effect of mechanical stretch on release of myotrophin; c) to localize myotrophin and study its effect on myocyte morphology; d) to use transgenic mice to study the effect of overexpression of myotrophin, determine its effects at the cellular and molecular level, and compare those data with data on cardiac function; e) to evaluate functions in mice by a noninvasive ECHO and Doppler technique to establish whether overexpression of myotrophin results in a physiological or pathophysiological hypertrophy. Long term goals are to elucidate mechanisms for translation of cardiac load and myocardial stress into biochemical messages prompting protein synthesis, and to develop strategies to prevent diseases associated with severe cardiac hypertrophy.

描述（改编自研究者摘要）：在一项旨在 阐明除血压以外的其他因素 心脏生长和心肌肥厚的发展，研究者 假设心脏肥大是由机械或 向心肌发出体液信号，进而产生可溶性因子， 该实验室先前鉴定出一种 12 kD 蛋白质，称为 肌营养蛋白。 该物质已在 SHR 和其他大鼠模型中被鉴定出 心脏肥大和人类扩张型心肌病。 当添加到 分离的心肌细胞，肌营养蛋白触发蛋白质合成。 肌营养蛋白已被克隆，可刺激肥大标记物的产生 例如 c-myc、c-fos、c-jun、ANF、β-MHC 和连接蛋白，可能发挥作用 在心肌细胞生长中。 SHR 中已鉴定出多个转录本 均表达 12 kD 蛋白质。 ECHO 方法的开发遵循 小鼠功能和形态的改变。 在本申请中， 将使用分子、遗传和功能方法来了解 肌营养蛋白的作用方式具有以下具体目标：a) 阐明肌营养蛋白刺激的信号转导机制 蛋白质合成； b) 研究机械拉伸对释放的影响 肌营养蛋白； c) 定位肌营养蛋白并研究其对肌细胞的影响 形态学; d) 使用转基因小鼠研究过度表达的效果 肌营养蛋白，确定其在细胞和分子水平上的作用， 并将这些数据与心脏功能数据进行比较； e) 评估 通过非侵入性 ECHO 和多普勒技术在小鼠中发挥功能，以建立 肌营养蛋白的过度表达是否会导致生理或 病理生理性肥大。 长期目标是阐明机制 将心脏负荷和心肌应激转化为生化指标 促进蛋白质合成的信息，并制定预防策略 与严重心脏肥大相关的疾病。