REGULATION OF GENE EXPRESSION IN HYPERTENSIVE HEARTS

高血压心脏基因表达的调节

• 批准号: 6311666
• 负责人: LAURENCE H KEDES
• 金额: $ 26.29万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-25 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6311666
• 关键词: actins; biological signal transduction; cellular pathology; cytokine; endothelin; familial hypertension; gene expression; genetic enhancer element; genetic regulation; laboratory rat; molecular genetics; northern blottings; polymerase chain reaction; protein kinase C; renin angiotensin system; site directed mutagenesis; tissue /cell culture; transcription factor; transfection; troponin; ventricular hypertrophy; western blottings

Cardiac hypertrophy and remodeling is a common sequela of hypertension and myocardial infarction. These events often culminate in irreversible heart muscle disease similar to congestive cardiomyopathy of a variety of etiologies. The histopathological findings of hypertrophic cardiomyocytes generally includes a characteristic picture of increased cell size and increased cell content of myofibrils. Although the precise subcellular mechanisms of hypertension-induced cardiac hypertrophy is not defined, some of the pathogenic mechanisms include increased RNA and protein synthesis. The induction of these events may be triggered by cytokine stimulation that may involve members of the renin-angiotensin system (RAS), their modulators, and intracellular signaling cascades that alter the levels of gene expression in myocardiocytes. The experiments proposed are designed to test the hypothesis that hypertension leads, in part, to specific effects on the transcriptional regulatory machinery of tissue-specific genes. The studies proposed involve molecular genetic analysis of events related to cytokine effects in cells in culture and in heart muscle in vivo. Some of these experiments are of relatively high risk but have the possibility of providing major understanding of critical mechanisms involved in hypertension induced cardiomyopathy and leading to methods that could ameliorate or prevent it. A long term objective of this proposal is to develop rational therapeutic approaches to cardiac hypertrophy and remodeling, by taking advantage of the knowledge gained from the study of cultured heart cells and myocardium exposed to cytokines. These studies may lead to prevention or reduction of this serious sequela of hypertension. To this end, it is essential to understand the precise molecular mechanisms by which hypertension causes cardiac hypertrophy.

心脏肥大和重塑是高血压的常见后遗症 和心肌梗塞。这些事件通常在不可逆的 心肌疾病类似于多种多样的多种多样的心肌病 病因。肥厚的组织病理学发现 心肌细胞通常包括增加的特征图片 细胞大小和肌原纤维的细胞含量增加。虽然是确切的 高血压引起的心脏肥大的亚细胞机制不是 定义，某些致病机制包括增加的RNA和 蛋白质合成。这些事件的诱导可能是由 可能涉及肾素 - 血管紧张素成员的细胞因子刺激 系统（RAS），它们的调节器和细胞内信号级联 改变心肌细胞中基因表达的水平。 提出的实验旨在检验以下假设。 高血压部分导致对转录的特定影响 组织特异性基因的调节机制。研究提出 涉及与细胞因子作用有关的事件的分子遗传分析 在体内培养和心肌中的细胞中。其中一些 实验的风险相对较高，但有可能 提供对涉及的关键机制的重大理解 高血压诱导的心肌病，并导致可能 改善或防止它。 该提议的长期目标是开发理性的治疗 通过利用 从研究培养的心脏细胞和 心肌暴露于细胞因子。这些研究可能导致预防或 减少了严重的高血压后遗症。为此，是 了解确切的分子机制必不可少的必不可少的 高血压会导致心脏肥大。