Acyl-CoAs and Lesion Initiation in Diabetes

描述：这些研究旨在确定在高血糖的情况下导致动脉粥样硬化病变加速的机制。我们将重点关注内皮细胞和巨噬细胞——病变发生的两种最重要的细胞类型。实验将在分离的小鼠内皮细胞和巨噬细胞中进行，并在转基因低密度脂蛋白受体缺陷小鼠模型中进行，该模型可由病毒诱导1型糖尿病（LDLR-/-；GP小鼠）。根据初步实验，我们假设高血糖的主要致动脉粥样硬化作用依赖于脂肪酰基辅酶a形成的增加，通过增加长链酰基辅酶a合成酶1 （AcsM）的活性。我们建议通过靶向调节内皮细胞和巨噬细胞中Acsl1的表达水平，直接测试酰基辅酶a合成在葡萄糖和糖尿病对病变发生的影响中的贡献。目标是解决以下三个问题：1)酰基辅酶a的合成在培养的内皮细胞和巨噬细胞的葡萄糖刺激炎症分子的产生中是否至关重要？2)巨噬细胞中酰基辅酶a合成的增加是否模拟糖尿病对炎症介质和LDLR-/-病变起始的影响；GP老鼠呢?;3)抑制内皮细胞或巨噬细胞的酰基辅酶a合成是否会延缓糖尿病动脉粥样硬化小鼠模型的病变发生？这些研究将增加我们对高血糖条件下糖尿病加速病变起始的分子机制的理解。确定这种机制可能用于开发针对1型糖尿病心血管并发症的药物。

DESCRIPTION: The studies proposed aim to identify mechanisms leading to accelerated atherosclerotic lesion initiation in the presence of hyperglycemia. 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 main atherogenic effects of hyperglycemia are dependent on increased formation of fatty acyl-CoAs, through increased activity of long chain acyl-CoA synthetase 1 (AcsM). We propose to directly test the contribution acyl-CoA synthesis in the effects of glucose and diabetes on lesion initiation by targeted modulation of expression levels of Acsl1 in endothelial cells and macrophages. The goal is to address the following three questions: 1) Is acyl-CoA synthesis of central importance in glucose-stimulated production of inflammatory molecules by cultured endothelial cells and macrophages?; 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 under hyperglycemic conditions. Identification of such mechanisms might be used to develop drugs to target cardiovascular complications of type 1 diabetes.