Acyl-CoAs, Inflammation, and Atherogenesis in Diabetes

糖尿病中的酰基辅酶A、炎症和动脉粥样硬化

• 批准号: 7548831
• 负责人: Karin E. Bornfeldt
• 金额: $ 40.76万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7548831
• 关键词: Acceleration; Acyl Coenzyme A; Address; Adherence; Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Cardiovascular system; Cells; Cholesterol; Coenzyme A Ligases; Condition; Diabetes Mellitus; Diabetic mouse; Endothelial Cells; Endothelium; Enzymes; Fatty Acids; Fatty acid glycerol esters; Goals; Histocytochemistry; Hyperglycemia; Immunohistochemistry; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Lesion; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Measures; Mediator of activation protein; Modeling; Molecular; Mus; Nonesterified Fatty Acids; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasma; Play; Principal Investigator; Process; Production; Property; Protein Overexpression; Proteomics; Rate; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; System; Testing; Transgenic Organisms; Triglycerides; Unsaturated Fatty Acids; Virus; atherogenesis; base; cell type; cytokine; diabetic; feeding; macrophage; monocyte; mouse model; programs; research study; response; size; type I diabetic

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.

项目2中提出的研究旨在确定导致加速启动的机制 糖尿病的动脉粥样硬化病变。我们将专注于内皮细胞和巨噬细胞 - 两个 病变启动中的重要细胞类型。实验将在孤立的小鼠内皮中进行 细胞和巨噬细胞，以及转基因LDL受体缺陷的小鼠模型，其中1型糖尿病 可以由病毒（LDLR - / - ; GP小鼠）诱导。基于初步实验，我们假设 糖尿病的动脉粥样硬化和炎症作用取决于形成脂肪酰基-COA。我们 提议直接测试糖尿病对糖尿病对病变启动的影响的贡献 针对参与酰基-COA合成的主要酶的表达水平的靶向调节 内皮细胞和巨噬细胞（长链酰基-COA合成酶1; ACSM）。项目2的目标是 解决以下三个问题：1）酰基-COA合成是否调节炎症过程 巨噬细胞和内皮细胞？ 2）在巨噬细胞中增加酰基辅酶A的合成 LDLR - / - ; GP小鼠对糖尿病对炎症介质和病变启动的影响？ 3）抑制 在我们的小鼠模型中，内皮细胞或巨噬细胞中的酰基-COA合成延迟病变启动 加速糖尿病动脉粥样硬化？这些研究将增加我们对分子的理解 参与糖尿病加速病变启动的机制。这种机制的识别可能是 用于开发靶向1型糖尿病的心血管并发症的药物。