TGF BETA RECEPTOR SIGNALING IN SCLERODERMA

描述：（改编自申请人的摘要）-总体目标 本研究旨在了解细胞外基质（ECM）的调控， 人成纤维细胞中的产生及其在纤维化疾病中的失调 例如SSc。 TGF-β是最有效的细胞外基质诱导剂之一， 基质蛋白在成纤维细胞中的表达及其在 硬皮病和其它纤维化疾病是有据可查的。 还有 越来越多的证据表明，纤维化病变中活化的成纤维细胞的扩增 可能会导致疾病进展。 在过去的几年里， 首席研究员专注于研究分子机制 成纤维细胞活化的过程。 最近的发现使Trojanowska博士能够 提出了一个假说，即通过增加TGF-β信号传导水平， TGF-β I型和II型受体的过度表达是导致 SSc成纤维细胞的活化。 提出了四个具体目标来检验这一点 假设，以及获得更多的了解TGF-β信号通路 在人类成纤维细胞中。 在具体目标1中，TGF-β信号传导将被阻断， 通过过表达显性负性TGF-β受体突变体， 检查SSc成纤维细胞的表型改变取决于 自分泌TGF-β信号传导。 在具体目标2中，调节TGF-β 将探索其他细胞因子的受体。 在具体目标3中， 研究人员将绘制I型和II型TGF-β的特定结构域， 参与调节TGF-β对人的特异性作用的受体 成纤维细胞（包括调节各种细胞外 基质蛋白，c-myc和c-myb原癌基因，以及对选择的 增长因素）。 在具体的目标4中，相互作用的细胞蛋白质 将开始被表征。

DESCRIPTION: (Adapted from the applicant's abstract) - The overall goal of this research is to understand the regulation of extracellular matrix (ECM) production in human fibroblasts and its dysregulation in fibrotic diseases such as SSc. TGF-beta is one of the most potent inducers of extracellular matrix protein expression in fibroblasts and its presence in the lesions of scleroderma and other fibrotic diseases is well documented. There is also growing evidence that expansion of activated fibroblasts in fibrotic lesions may contribute to the disease progression. For the past several years, the principal investigator has focused on investigating the molecular mechanisms of fibroblast activation. The recent findings enable Dr. Trojanowska to propose the hypothesis that increased level of TGF-beta signaling through overexpression of TGF-beta type I and type II receptors is responsible for activation of SSc fibroblasts. Four specific aims are proposed to test this hypothesis as well as to gain more insight into TGF-beta signaling pathways in human fibroblasts. In specific aim 1, TGF-beta signaling will be blocked by overexpressing the dominant-negative TGF-beta receptor mutant and examining the phenotypic alterations of SSc fibroblasts that depend on autocrine TGF-beta signaling. In specific aim 2, the regulation of TGF-beta receptors by other cytokines will be explored. In specific aim 3, the investigators will map specific domains of the TGF-beta type I and II receptors involved in regulation of specific effects of TGF-beta on human fibroblasts (including regulation of expression of various extracellular matrix proteins, c-myc, and c-myb protooncogenes, and responses to selected growth factors). In specific aim 4, the cellular proteins that interact with TGF-beta receptors will begin to be characterized.