LUNG FIBROSIS--MECHANISMS OF COLLAGEN GENE EXPRESSION

该提案的长期目标是获得更好的 提高对造成这一现象的机制的认识 肺中胶原蛋白的积累。 无论是牙槽骨损伤 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。 间质 成纤维细胞在此过程中被激活， 大量的细胞外基质物质，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的影响 我们的产品在我们的实验室进行了测试。 我们的数据和 其他研究表明转化生长因子β （TGF-β）刺激成纤维细胞产生大量的 胶原蛋白。 此外，我们的研究结果表明，TGF-β 刺激肺成纤维细胞增加胶原蛋白的产生 而不增加扩散。 稳态mRNA水平 α 1（I）和α I（III）胶原蛋白链在 用TGF-β刺激。 α 2（I）mRNA的增加 稳态水平根据细胞类型而变化。 没有 当人肺成纤维细胞被 用TGF-β刺激。 在TGF-β的情况下，胶原蛋白可以通过增加的胶原蛋白来刺激。 通过转录和/或转录后机制。 的 该提案的具体目标是：（1）确定 TGF-β对肺成纤维细胞I型和II型胶原表达的影响 III基因的丰度、转录和稳定性 2）鉴定和表征胶原蛋白mRNA的顺式作用， I型胶原基因的调节或稳定元件，3） 鉴别和比较TGF-β中DNA结合蛋白 刺激的与未刺激的成纤维细胞，和4）确定 胶原蛋白的调节是否改变， 来源于博来霉素处理的大鼠肺的成纤维细胞。

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.