ARRA: Integrin Signaling in Vascular Cells

This application requests funds for an administrative supplement to HL074219 "Integrin signalin in vascular cells". As described in the original application, the broad goal of the research program is to understand how integrin alphaVbeta3-dependent signaling influences vascular smooth muscle cell (SMC) growth and migration. Abnormal vascular SMC growth and migration contributes to hypertension, atherosclerosis, and restenosis. SMC function is controlled by complex regulatory mechanisms, which are governed in part by interactions with the extracellular matrix. Integrins, the predominant receptors for the extracellular matrix, activate adhesion-dependent signaling pathways, and cross-talk with growth factor and G-protein coupled receptors to influence cellular functions. As described in a non-competing renewal, we have exciting new data that integrin alphaVbeta3, when activated, may serve to localize the plasma enzyme autotaxin to sites of vascular injury. Autotaxin's primary function is to generate the bioactive lipid lysophosphatidic acid (LPA), which is a potent inducer of phenotypic modulation of SMC. In this administrative supplement, we proposed to continue the aims of the parent grant by providing important insight into how activation of alphaVbeta3 on SMC may promote the generation of LPA. We will test the hypothesis that recruitment of autotaxin to the SMC surface by activated integrins increases local LPA generation, which in turn interacts with G-protein coupled receptors to trigger SMC migration and proliferation. Most importantly, this administrative supplement will provide a vehicle to employ a recent college graduate from the University of Kentucky and so clearly this request will result in broad economic benefits consistent with the goals of the American Recovery and Reinvestment Act.