Beta 1 Integrins and Cellular Responses to TGFbeta

描述(由申请人提供)：整合素除了在细胞黏附中的传统作用外，在细胞信号传递中显然也很重要。通过这些功能，整合素参与了多种生物学过程，如炎症、基质重塑、纤维化和恶性肿瘤。整合素可以启动细胞内信号传递或调节其他信号受体的功能。我们的初步结果表明，β1整合素可以放大成纤维细胞中的转化生长因子β信号。该项目的长期目标是确定整合素输入细胞对TGFbeta的反应的分子机制，并确定这些整合素信号的调节是否具有治疗潜力。短期内，我们将重点关注三个具体目标。(1)我们将研究在Beta1缺失的成纤维细胞中表达的Beta1胞外区与Beta1胞内区的嵌合体，以确定介导TGFbeta信号所需的Beta1区。(2)我们将通过RNA干扰改变几个已知与Beta1相关的整合素α链的基因表达，以确定特定的α-Beta1异二聚体是否负责介导TGFbeta信号。(3)我们将通过研究整合素与特定配体结合的影响，确定整合素在这一新角色中激活的决定因素。

DESCRIPTION (provided by applicant): In addition to their traditional role in cell adhesion, integrins are clearly important in cell signaling. Through these functions, integrins have been implicated in diverse biological processes, such as inflammation, matrix remodeling, fibrosis and malignancy. Integrins can initiate intracellular signaling or regulate the function of other signaling receptors. Our preliminary results suggest that beta1 integrins can amplify TGFbeta signaling in fibroblasts. The long term goals of the project are to define the molecular mechanisms underlying the input of integrins into the cellular response to TGFbeta and to determine if regulation of these integrin signals has therapeutic potential. In the short term, we will focus on three specific aims. (1) We will study a chimeric of the beta1 extra cellular domain fused to the cytoplasmic domain of betaS expressed in beta1-null fibroblasts to determine the beta1 domain necessary to mediate TGFbeta signaling. (2) We will alter gene expression of several integrin alpha chains known to associate with beta1 by RNA interference to determine if a specific alpha-beta1 heterodimer is responsible for mediating TGFbeta signaling. (3) We will identify the determinants of integrin activation in this novel role by studying the effects of integrin engagement with specific ligands.