Beta 1 Integrins and Cellular Responses to TGFbeta

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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.