Acyl-CoAs and Lesion Initiation in Diabetes

酰基辅酶A和糖尿病病变起始

• 批准号: 7251345
• 负责人: Karin E. Bornfeldt
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-08 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251345
• 关键词: 1,2-diacylglycerol; Acceleration; Acyl Coenzyme A; Address; Adherence; Adhesions; Arterial Fatty Streak; Atherosclerosis; Biochemical Pathway; Biological; Blood Vessels; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; Cardiovascular system; Cell Adhesion Molecules; Cells; Cholesterol Esters; Coenzyme A Ligases; Condition; Confocal Microscopy; Diabetes Mellitus; Diabetic mouse; Diglycerides; Dyslipidemias; Endothelial Cells; Endothelium; Enzymes; Event; Exhibits; Fatty Acids; Foam Cells; Gene Expression; Generations; Glucose; Goals; High Pressure Liquid Chromatography; Histocytochemistry; Hyperglycemia; Hyperglycemic Mice; Hyperlipidemia; IL6 gene; IL8 gene; Immunohistochemistry; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-6; Lead; Lesion; Lipids; Low Density Lipoprotein Receptor; Mammals; Measures; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Muramidase; Mus; Personal Satisfaction; Pharmaceutical Preparations; Plasma; Production; Protein Isoforms; Protein Overexpression; Proteomics; Rate; Relative (related person); Research Personnel; Role; S100A8 gene; System; Testing; Thin Layer Chromatography; Transgenic Organisms; Triglycerides; Vascular Cell Adhesion Molecule-1; Virus; Work; atherogenesis; base; cadherin 5; cell type; diabetic; expression vector; liquid chromatography mass spectrometry; macrophage; monocyte; mouse model; non-diabetic; oxidation; programs; research study; response; size; vector

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.

描述：拟议的旨在确定导致在高血糖存在下加速动脉粥样硬化病变启动的机制。我们将专注于内皮细胞和巨噬细胞 - 病变启动中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LDL受体缺陷的小鼠模型中进行，其中1型糖尿病可以由病毒（LDLR - / - ； GP小鼠）诱导。基于初步实验，我们假设高血糖的主要动脉粥样硬化作用取决于长链酰基-COA合成酶1（ACSM）的活性增加了脂肪酰基-COAS的形成。我们建议直接测试葡萄糖和糖尿病对内皮细胞和巨噬细胞中ACSL1表达水平的靶向调节对病变启动的影响的酰基-COA合成。目的是解决以下三个问题：1）酰基-COA是通过培养的内皮细胞和巨噬细胞通过葡萄糖刺激的炎症分子产生的核心重要性的合成吗？ 2）在巨噬细胞中增加的酰基辅酶A合成是否模仿糖尿病对LDLR - / - ; GP小鼠中炎症介质和病变启动的影响？ 3）在我们的加速糖尿病动脉粥样硬化的小鼠模型中，内皮细胞或巨噬细胞中酰基-COA合成的抑制是否会阻碍病变开始？这些研究将提高我们对高血糖条件下糖尿病加速病变起始涉及的分子机制的理解。这种机制的鉴定可用于开发药物以靶向1型糖尿病的心血管并发症。