MYOCARDIAL COLLAGEN GENE EXPRESSION--HORMONAL REGULATION

心肌胶原蛋白基因表达--激素调节

• 批准号: 2445185
• 负责人: Mahboubeh Eghbali-Webb
• 金额: $ 13.72万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2445185
• 关键词: DNA footprinting; collagen; connective tissue metabolism; disease /disorder model; extracellular matrix; fibroblasts; gel mobility shift assay; gene expression; genetic manipulation; genetic promoter element; genetic regulatory element; hormone regulation /control mechanism; immunofluorescence technique; laboratory rabbit; myocardium; protooncogene; thyroid hormones; transfection; ventricular hypertrophy; western blottings

DESCRIPTION: (Adapted from the Investigator's Abstract) It is now well recognized that the remodeling of the fibrillar collagen matrix that occurs in ventricular hypertrophy may adversely alter myocardial stiffness and lead to heart failure. The investigators have established that in ventricular hypertrophy induced by hemodynamic and hormonal stimuli the remodeling of collagen matrix is linked to alterations in collagen gene expression. They discovered that in contrast to animal models of ventricular hypertrophy induced by abdominal aortic banding and infusion of hypertensive doses of norepinephrine, thyroid hormone induced ventricular hypertrophy is not associated with cardiac fibrosis and is characterized by decrease in collagen type I gene expression. In vitro studies have demonstrated that thyroid hormone induced inhibition of the activity of collagen type I promoter occurs in cardiac fibroblast and changes in the stability of collagen type I mRNA take place. The hypothesis is that the thyroid hormone induced inhibition of collagen type I gene expression in cardiac fibroblast is mediated by the interaction of thyroid hormone induced nuclear proteins with thyroid hormone response elements on collagen type I promoter and that the activator proteins (AP-1) participates in the negative regulation of collagen gene expression by thyroid hormones. The objective, therefore, is to identify the cis-acting elements and the trans-acting factors involved in thyroid hormone induced inhibition of collagen type I gene expression in cardiac fibroblast. The results are expected to help in elucidation of the thyroid hormone sensitive pathways involved in the remodeling of the heart collagen matrix in pathological conditions and during development and growth.

描述：(改编自《调查者摘要》)现在很好 认识到纤维状胶原基质的重塑 心肌肥厚可能会对心肌僵硬和导联产生不利影响 心力衰竭。研究人员已经证实，在脑室 血流动力学和激素刺激诱导的心肌肥厚 胶原基质与胶原基因表达的改变有关。他们 发现与心肌肥厚的动物模型相比 腹主动脉缩窄和输注高血压剂量的 去甲肾上腺素、甲状腺激素引起的心室肥厚不是 与心脏纤维化有关，其特征是 I型胶原基因表达。体外研究表明， 甲状腺激素对I型胶原活性的抑制作用 启动子出现在心脏成纤维细胞中并改变其稳定性 I型胶原基因的表达发生了。假设是甲状腺激素 心肌成纤维细胞I型胶原基因表达的诱导抑制 是由甲状腺激素诱导的核蛋白相互作用所介导的 在I型胶原启动子上带有甲状腺激素反应元件 激活蛋白(AP-1)参与细胞的负性调节。 甲状腺激素对胶原基因表达的影响。因此，目标是 确定涉及的顺式作用元件和反式作用因素 甲状腺激素抑制血管内皮细胞I型胶原基因表达 心脏成纤维细胞。这一结果有望有助于阐明 甲状腺激素敏感通路参与心脏重塑 病理状态和发育过程中的胶原基质 成长。