Engineering an Atherosclerosis-Resistant Endothelium

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DESCRIPTION (provided by applicant): Atherosclerosis occurs at regions of the vasculature where flow patterns depart from the normal laminar mode. Atherogenic hemodynamic forces activate the endothelium to recruit monocytes and decrease barrier unction, which in the presence of systemic risk factors leads to atherosclerosis. Recent data show that the composition of the subendothelial extracellular matrix plays an important role in this process. Fluid flow activates NF-KB, PAK and JNK in endothelia! cells on fibronectin (FN) or fibrinogen but not on basement membrane proteins due to differential signaling by the integrins that bind these extracellular matrix proteins. Furthermore, FN is found at atherosclerosis-prone sites in vivo prior to other indications of disease, suggesting that deposition of FN may contribute to initiation of atherosclerosis in vivo. Our in vitro studies have shown that FN matrix can be modified to suppress NF-KB and JNK, suggesting a possible method to Drevent or treat atherosclerosis. The project will be performed by a team of researchers at the University of Virginia consisting of Drs. Martin Schwartz, who works on mechanotransduction and integrin signaling; Brian Helmke, a bioengineer who works on mechanotransduction and image analysis; Brett Blackman, a bioengineer expert in endothelial biology and measuring and modeling flow patterns; and Ian Sarembock, a cardiologist and expert in animal models of atherosclerosis and immunohistochemistry. To take advantage of the opportunity created by the above findings, we will use flow and strain patterns from an atherosclerosis- prone site in the vasculature to study effects of atherogenic forces in vitro. These profiles will be used to elucidate mechanisms of signaling that give rise to sustained activation of atherogenic pathways in athero- prone regions. This information will be used to engineer transfected endothelial cell lines that do not activate these pathways. To test the relevance of the results in in vivo, transgenic mice expressing similar constructs in the endothelium will be constructed and crossed with apolipoproteinE"'" mice to evaluate their ability to suppress atherosclerosis. Together, these studies will provide insight into mechanisms of atherogenesis and test novel therapeutic strategies for treatment.