REGULATION OF MYC GENE EXPRESSION IN CARDIAC HYPERTROPHY

心肌肥厚中 MYC 基因表达的调节

• 批准号: 2223961
• 负责人: PIA S POLLACK
• 金额: $ 10.87万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2223961
• 关键词: DNA binding protein; DNA footprinting; RNase protection assay; biological signal transduction; cats; cell growth regulation; disease /disorder model; gene expression; genetic regulation; heart failure; hemodynamics; immunocytochemistry; messenger RNA; northern blottings; polymerase chain reaction; protooncogene; transcription factor; ventricular hypertrophy

The proto-oncogene c-myc is one of several growth-regulated genes that are induced within the myocardium during the early stages following hemodynamic overload. While it has long been known that c-myc plays an important but undefined role in the regulation of cellular proliferation, recent evidence suggests that c-myc is a transcriptional factor and it would seem likely that the c-myc gene product modulates at least some of the qualitative and quantitative changes in gene expression that characterize the hypertrophying myocyte. We have developed a feline model of gradual and progressive pressure-overload which mimics human disease in its ongoing nature. In contrast to the transient increases in c-myc mRNA that are typical of acute pressure-overload, hearts isolated from these animals show sustained increases in steady-state levels of c-myc mRNA and immuno-reactive myc protein. This unique animal model, which closely mimics the nature and progression of human disease, is highly suitable for the study of factors that regulate c-myc gene expression in hemodynamic overload in vivo. The Specific Aims of this proposal are to: 1 . Characterize the time course of increased levels of c-myc in progressive pressure-overload and determine if the increases in steady-state c-myc mRNA are due to alterations in promoter usage in progressive pressure overload. 2 . Determine if overexpression of c-myc can be associated with an increase in those indices of cell growth considered characteristic of cardiac hypertrophy. 3 . Compare the rates of c-myc transcription in pressure-overloaded myocytes with those of control cells. 4.Begin to identify regulatory regions of the myc gene that modulate c-myc gene expression in response to a hypertrophic stimulus. Heart failure, frequently the end result of chronic hemodynamic overload, remains a significant source of morbidity and mortality in this country. The cellular and molecular mechanisms that regulate the development of hypertrophy in the pressure-overloaded cardiac myocyte are still poorly understood. Determining the mechanisms by which c-myc gene expression is regulated in pressure-overload hypertrophy will be the first step to the accomplishment of the long term aim of this research. This is the identification of the signal transduction mechanisms that are responsible for the linking of a hemodynamic stimulus to the induction of c-myc and other transcriptional regulators.

原癌基因c-myc是几个生长调节基因之一， 在接下来的早期阶段在心肌内被诱导 血流动力学过载。虽然人们很早就知道c-myc扮演着一个 在调节细胞增殖中的重要但未明确的作用， 最近的证据表明，c-myc是一种转录因子，它 似乎c-myc基因产物至少调节了一些 基因表达的质的和量的变化 确定肥大的心肌细胞的特征。我们培育了一种猫科动物 模拟人体的渐进式压力超载模型 疾病本身就是一种疾病。与此形成对比的是， C-myc mRNA是急性压力超负荷的典型表现，心脏离休 从这些动物身上可以看出稳态水平的持续增加 C-myc基因和免疫反应性myc蛋白。这种独特的动物模型， 它非常接近人类疾病的本质和发展过程， 非常适合于c-myc基因调控因素的研究 在体内血流动力学超负荷中的表达。 这项建议的具体目的是： 1.描述c-myc水平升高的时间过程 渐进压力-过载，并确定是否增加 稳定状态的c-myc mRNA是由于启动子在 渐进式压力过载。 2.确定c-myc的过度表达是否与 这些细胞生长指数的增加被认为是 心肌肥厚。 3.压力超负荷时c-myc转录速率的比较 肌细胞数与对照细胞数无显著差异。 4.开始确定myc基因的调控区域 C-myc基因表达对肥大刺激的反应。 心力衰竭，通常是慢性血流动力学超负荷的最终结果， 仍然是这个国家发病率和死亡率的重要来源。 调节血管生成的细胞和分子机制 压力超负荷心肌细胞肥大的情况仍然很差。 明白了。确定c-myc基因表达的机制 调节压力超负荷的肥大将是迈向 完成了本研究的长期目标。这是 确定负责的信号转导机制 将血流动力学刺激与诱导c-myc和 其他转录调控因子。