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。 人成纤维细胞的产生及其在纤维化疾病中的调节失调 例如SSC。转化生长因子-β是最有效的细胞外诱导物之一 基质蛋白在成纤维细胞中的表达及其在皮损中的表达 硬皮病和其他纤维性疾病都有很好的文献记载。还有就是 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张 可能会导致疾病的进展。在过去几年里， 首席研究员一直专注于研究分子机制。 成纤维细胞的激活。最近的发现使Trojanowska博士能够 提出一种假说，即转化生长因子-β信号水平通过 转化生长因子-βI型和II型受体的过度表达是 SSC成纤维细胞活化。为了检验这一点，我们提出了四个具体目标 假说以及对转化生长因子-β信号通路的更多了解 在人类成纤维细胞中。在特定的目标1中，转化生长因子-β信号将被阻断 通过过度表达显性阴性的转化生长因子-β受体突变体和 检测SSC成纤维细胞的表型变化 自分泌转化生长因子-β信号。在特定目标2中，转化生长因子-β的调节 还将探索其他细胞因子的受体。在具体目标3中， 研究人员将绘制转化生长因子-βI和II的特定结构域 参与调节转化生长因子-β对人体特异性作用的受体 成纤维细胞(包括调节各种胞外因子的表达 基质蛋白、c-myc和c-myb原癌基因，以及对选定的 增长因素)。在特定的目标4中，相互作用的细胞蛋白质 有了转化生长因子-β受体，人们将开始对其进行表征。

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.