The studies proposed in Project 2 aim to identify mechanisms leading to accelerated initiation ofatherosclerotic lesions in diabetes. We will focus on endothelial cells and macrophages - the two mostimportant cell types in lesion initiation. The experiments will be carried out in isolated mouse endothelialcells and macrophages, and in a transgenic LDL receptor-deficient mouse model in which type 1 diabetescan be induced by a virus (the LDLR-/-;GP mouse). Based on preliminary experiments, we hypothesize thatthe atherogenic and inflammatory effects of diabetes are dependent on formation of fatty acyl-CoAs. Wepropose to directly test the contribution acyl-CoA synthesis in the effects of diabetes on lesion initiation bytargeted modulation of expression levels of one of the principal enzymes involved in acyl-CoA synthesis inendothelial cells and macrophages (long-chain acyl-CoA synthetase 1; AcsM). The goal of Project 2 is toaddress the following three questions: 1) Does acyl-CoA synthesis regulate inflammatory processes inmacrophages and endothelial cells?; 2) Does increased acyl-CoA synthesis in macrophages mimic theeffects of diabetes on inflammatory mediators and lesion initiation in LDLR-/-;GP mice?; 3) Does inhibition ofacyl-CoA synthesis in endothelial cells or macrophages retard lesion initiation in our mouse model ofaccelerated diabetic atherosclerosis? These studies will increase our understanding of the molecularmechanisms involved in diabetes-accelerated lesion initiation. Identification of such mechanisms might beused to develop drugs to target cardiovascular complications of type 1 diabetes.
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