Acyl-CoAs, Inflammation, and Atherogenesis in Diabetes

项目2中提议的研究旨在确定导致加速启动 糖尿病动脉粥样硬化病变。我们将重点关注内皮细胞和巨噬细胞-这两个最重要的 在病变起始中的重要细胞类型。实验将在离体小鼠内皮细胞中进行。 细胞和巨噬细胞，以及转基因LDL受体缺陷小鼠模型，其中1型糖尿病 可由病毒诱导（LDLR-/-;GP小鼠）。基于初步实验，我们假设， 糖尿病的致动脉粥样硬化和炎症作用依赖于脂肪酰辅酶A的形成。我们 建议通过以下方法直接测试酰基辅酶A合成在糖尿病对病变起始的影响中的作用： 靶向调节参与酰基辅酶A合成的主要酶之一的表达水平 内皮细胞和巨噬细胞（长链酰基辅酶A合成酶1; AcsM）。项目2的目标是 解决以下三个问题：1）酰基辅酶A的合成是否调节炎症过程， 巨噬细胞和内皮细胞？2)巨噬细胞中酰基辅酶A合成的增加是否模拟了 糖尿病对LDLR-/-;GP小鼠炎症介质和病变起始的影响？3)是否抑制了 内皮细胞或巨噬细胞中酰基辅酶A的合成延迟了我们的小鼠模型中的损伤起始， 加速糖尿病动脉粥样硬化？这些研究将增加我们对分子生物学的理解。 参与糖尿病加速损伤起始的机制。确定这种机制可能是 用于开发针对1型糖尿病心血管并发症的药物。

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