LUNG FIBROSIS--MECHANISMS OF COLLAGEN GENE EXPRESSION

肺纤维化--胶原蛋白基因表达机制

• 批准号: 3359138
• 负责人: BARBARA Davis SMITH
• 金额: $ 10.21万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3359138
• 关键词: DNA; acyltransferase; autoradiography; binding proteins; bleomycin; chemical stimulation; collagen; complementary DNA; fibroblasts; gel electrophoresis; gene expression; genetic manipulation; genetic markers; genetic promoter element; genetic transcription; inflammation; laboratory rat; messenger RNA; molecular pathology; nucleic acid hybridization; plasmids; protein biosynthesis; protein structure; pulmonary fibrosis /granuloma; respiratory epithelium; tissue /cell culture; transcription factor; transfection; transforming growth factors; vascular endothelium

The long term goal of this proposal is to gain a better understanding of the mechanisms responsible for increased collagen accumulation in the lung. Injury to either the alveolar epithelium or capillary endothelium leads to a complex interaction of inflammatory cells and effector molecules. Interstitial fibroblasts are activated during this process leading to production of large amounts of extracellular matrix material, including type I and type III collagen. The effect of several inflammatory factors on fibroblast collagen production have been examined in our laboratories. Our data and that of others indicate that transforming growth factor beta (TGF-beta) stimulates fibroblasts to produce significant amounts of collagen. In addition, our results demonstrate that TGF-beta stimulates lung fibroblasts to increase collagen production without increasing proliferation. Steady state mRNA levels of alpha 1(I) and alpha I(III) collagen chains increase during stimulation with TGF-beta. The increase in alpha 2(I) mRNA steady state levels varied depending on cell type. There was no increase in alpha 2(I) mRNA when human lung fibroblasts were stimulated with TGF-beta. In the case of TGF-beta, collagen may be stimulated by increased by a transcriptional and/or a post-transcriptional mechanism. The specific aims of this proposal are to 1) determine the effects of TGF-beta on lung fibroblast expression of collagen type I and type III genes by examining the abundance, transcription, and stability of collagen mRNA, 2) identify and characterize the cis acting regulatory or stabilizing elements of the collagen type I genes, 3) identify and compare DNA binding proteins, in TGF-beta stimulated versus unstimulated fibroblast, and 4) determine whether the regulation of collagen accumlation is altered in fibroblasts derived from bleomycin-treated rat lungs.

该提议的长期目标是获得更好的 了解导致增加的机制 胶原蛋白在肺部积聚。 牙槽伤害 上皮或毛细血管内皮导致复杂的相互作用 炎性细胞和效应分子的膜。 间隙 在此过程中，成纤维细胞被激活 大量细胞外基质材料，包括I型 和III型胶原蛋白。 几种炎症因子对成纤维细胞胶原蛋白的影响 我们的实验室已经检查了生产。 我们的数据和 其他的表明转化生长因子beta （TGF-β）刺激成纤维细胞产生大量 胶原蛋白。 此外，我们的结果表明TGF-beta 刺激肺成纤维细胞增加胶原蛋白的产生 不增加增殖。 稳态mRNA水平 alpha 1（i）和alpha I（iii）胶原蛋白链在期间增加 用TGF-β刺激。 α2（i）mRNA的增加 稳态水平取决于细胞类型。 没有 当人肺成纤维细胞为α2（i）mRNA的增加 用TGF-β刺激。 在TGF-β的情况下，胶原蛋白可能会因增加而刺激 通过转录和/或转录后机制。 这 该建议的具体目的是1）确定 胶原蛋白I型和类型的肺成纤维细胞表达上的TGF-beta III基因通过检查丰度，转录和稳定性 胶原mRNA，2）识别和表征顺式作用 I型基因的调节或稳定元素，3） 在TGF-β中识别和比较DNA结合蛋白 刺激与未刺激的成纤维细胞，4）确定 是否改变了胶原蛋白堆积的调节 来自博来霉素治疗的大鼠肺的成纤维细胞。