Vascular injury promotes the influx of inflammatory cells and induces apoptosis in vascular smooth muscle cells and endothelial cells. Our studies will examine the mechanisms that control the viability of both inflammatory and vascular cells and assess the consequences of these processes on vascular lesion formation. As in the original grant, studies will predominantly focus on the Fas/Fas ligand regulatory system. This research involves the construction of new animal models and performing mechanistic studies to delineate the signaling mechanisms that control the expression of apoptosis-regulatory molecules. To more fully understand the regulation and role of apoptosis in vessel wall lesion formation we propose the following specific aims: 1) Characterize a new mouse line that lacks functional Fas ligand and apolipoprotein E genes and serves as a model of accelerated atherosclerosis that is associated with autoimmune disease. 2) Characterize a new mouse line that over expresses Fas ligand on the vascular endothelium 3) Produce and characterize new mouse models of atherosclerosis where Fas is disrupted in specific cell types. 4) Perform mechanistic analyses on the signaling and transcriptional regulators that control the sensitivity of vascular endothelial cells to Fas-mediated apoptosis.
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