INITIATION OF CARDIAC HYPERTROPHY IN HYPERTENSION

描述(改编自《调查者摘要》)：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，调查者 曾假设心肌肥厚是由机械性或 体液信号传递给心肌，进而产生一种可溶性因子， 此前该实验室鉴定为一种12kD的蛋白质，名为 肌营养素。这种物质已经在SHR、其他大鼠模型中被发现 心肌肥厚，在人类扩张型心肌病中。添加到时 分离的心肌细胞，肌营养因子触发蛋白质合成。 肌营养素已被克隆，可刺激肥大标志物的产生 例如c-myc、c-fos、c-jun、ANF、β-MHC和连接蛋白 在肌细胞生长过程中。在自发性高血压病中发现了多个转录本 它们都表达一个12kD的蛋白。Echo方法已经开发出来，以遵循 小鼠的功能和形态改变。在本申请中， 将使用分子、遗传和功能方法来理解 肌营养因子的作用方式，具体目标如下：a) 阐明肌营养因子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 C)定位肌营养因子并研究其对心肌细胞的作用 形态学；d)使用转基因小鼠研究过表达的影响 肌营养素，在细胞和分子水平上确定其作用， 并将这些数据与心脏功能数据进行比较；e)评估 利用无创性超声和多普勒技术建立小鼠的功能 肌营养素的过度表达是否会导致生理性或 病理生理性肥大。长期目标是阐明机制 用于将心脏负荷和心肌应激转化为生化 促使蛋白质合成的信息，并制定预防策略 与严重的心肌肥大相关的疾病。

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.