There is a direct relationship between the development of atherosclerosis and the serum levels of native low-density lipoprotein (LDL). Further, there is a long-term ameliorative effect on the arterial vasculature with the lowering of LDL. Both effects are, in part, explained by the actions of LDL on the vascular endothelium. Consequentially, the PI proposes to comprehensively examine the hypothesis that LDL directly perturbs endothelial cells (EC) by modulating these cells to a pro-inflammatory condition. To carry out these investigations, three specific aims have been designed, based on their previous publications and current preliminary data.
Specific Aim I is directed toward examining that portion of LDL that appears to be primarily responsible for EC activation. Studies are targeted toward examination of the interaction of cholesterol with caveolin-1 in caveolae. It is their contention that caveolae are likely affected by cholesterol enrichment. This enrichment appears to initiate intracellular signaling by the activation of kinases, in particular, Ras. This process may occur by the uncoupling of Ras from caveolin- I or by accumulation of Ras in caveolae.
Specific Aim 2 is a logical extension of this process and examines the ensuing specific intracellular signaling. This intracellular signaling pathway distinguishes itself from the traditional pathway, described for activation of EC by cytokines, which initiates transcription through NF-KB. In the case of LDL-induced EC activation, the process occurs via an AP-1 pathway. In conjunction with the detailed examination of this pathway, Specific Aim 3 is designed to fully examine the regulation of ICAM-1, which is directly involved in the pro-inflammatory change of EC. These studies use a novel adenoviral-mediated gene transfer system. This system permits transduction efficiencies approximating 100%, and allows an in-depth study of the regulatory effects of AP-1. Such studies have substantial therapeutic implications since interruption of this signaling pathway should contribute toward halting atherogenesis. This proposal will develop unique fundamental knowledge of the nature of EC activation by LDL, much of which may provide novel rationales for future patient treatment.
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