Cell Signaling: Macrovascular Complications of Diabetes

细胞信号转导：糖尿病的大血管并发症

• 批准号: 7585690
• 负责人: Karin E. Bornfeldt
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585690
• 关键词: Address; Adipocytes; Advanced Development; Animal Model; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Bone Marrow Transplantation; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cells; Cellular Morphology; Characteristics; Clinical; Coenzyme A Ligases; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic mouse; Diet; Enzymes; Fasting; Fatty Acids; Fatty acid glycerol esters; Gelatinase B; Gene Expression; Goals; Hemorrhage; Hyperglycemia; Hypertriglyceridemia; Knock-out; Lead; Lesion; Lipoproteins; Liver; Metabolic syndrome; Methods; Modeling; Morphology; Mus; Nonesterified Fatty Acids; Peptide Hydrolases; Pharmaceutical Preparations; Plasma; Reaction; Regulation; Research Personnel; Retroviral Vector; Risk Factors; Role; Signal Transduction; Triglycerides; VLDL receptor; Very low density lipoprotein; diabetic; drug development; feeding; gene therapy; helper-dependent adenoviral vector; lipid metabolism; long chain fatty acid; macrophage; macrovascular disease; mortality; non-diabetic; overexpression; particle; prevent; programs; research study; response; vector

A majority of people with diabetes die of cardiovascular disease caused by atherosclerosis. Both hyperglycemia and hypertriglyceridemia are believed to contribute to the increased cardiovascular disease. No animal model to date has been able to distinguish between the contributions of hyperglycemia and hypertriglyceridemia to plaque progression. Accumulation of macrophages in advanced plaques is likely to lead to plaque progression. We hypothesize that the increased fatty acid load associated with hypertriglyceridemia in diabetes causes plaque progression by stimulating macrophage accumulation and secretion of proteases. In this competitive renewal, we propose to address the following questions: 1) Is diabetes-induced hypertriglyceridemia necessary for progression of pre-existing lesions? We have developed a mouse model of diabetes-accelerated atherosclerosis that can be used to separate effects of hyperglycemia and hypertriglyceridemia on plaque progression. The effect of diabetes-induced hypertriglyceridemia on pre-existing plaques will be studied. 2) Does lowering of hypertriglyceridemia in the presence of hyperglycemia prevent diabetes-accelerated plaque progression? We propose to use a helper-dependent adenoviral vector to overexpress the VLDL receptor in livers of diabetic mice, thereby normalizing hypertriglyceridemia. 3) Does increased fatty acid load lead to increased macrophage accumulation and protease secretion ex vivo? We propose to expose isolated macrophages to increased or decreased fatty acid load. 4) Is increased fatty acid load in macrophages necessary and sufficient for plaque progression? We propose use a macrophage-selective retroviral vector to overexpress acyl-CoA synthetase 1 (Acsll) in macrophages, and also to generate a mouse with macrophage-targeted deletion on Acsll. The effect on progression of pre-existing lesions will be investigated. We expect that these studies will significantly increase our understanding of the role of hypertriglyceridemia in plaque progression in diabetes, and may provide the basic information necessary for development of drugs or gene therapies that can prevent or slow down cardiovascular complications of diabetes.

大多数糖尿病患者死于动脉粥样硬化引起的心血管疾病。两 高血糖症和高胆固醇血症被认为是增加心血管疾病的原因。 迄今为止，还没有动物模型能够区分高血糖和高血糖的作用。 高甘油三酯血症至斑块进展。巨噬细胞在晚期斑块中的积聚可能 导致斑块进展。我们假设，与肥胖相关的脂肪酸负荷增加， 糖尿病中的高胆固醇血症通过刺激巨噬细胞积聚而引起斑块进展， 蛋白酶的分泌。在这次竞争性续约中，我们建议解决以下问题： 1)糖尿病诱导的高甘油三酯血症是否是既存病变进展所必需的？我们有 开发了一种糖尿病加速动脉粥样硬化的小鼠模型，可用于分离糖尿病加速动脉粥样硬化的影响 高血糖和高甘油三酯血症对斑块进展的影响。糖尿病引起的 将研究预先存在的斑块上的高胆固醇血症。 2)在高血糖的情况下降低高血糖是否能预防糖尿病加速 斑块进展？我们建议使用辅助依赖性腺病毒载体过表达VLDL 受体，从而使高血糖正常化。 3)脂肪酸负荷增加是否导致巨噬细胞积聚和蛋白酶分泌增加？ 体内？我们建议将分离的巨噬细胞暴露于增加或减少的脂肪酸负荷。 4)巨噬细胞中脂肪酸负荷增加是否是斑块进展所必需和充分的？ 我们建议使用巨噬细胞选择性逆转录病毒载体在大肠杆菌中过表达酰基辅酶A合成酶1（Acsll）。 巨噬细胞，并且还产生在AcsII上具有巨噬细胞靶向缺失的小鼠。的影响 将研究预先存在的病变的进展。 我们期望这些研究将显著增加我们对高胆固醇血症的作用的理解。 在糖尿病斑块进展，并可能提供必要的基本信息， 可以预防或减缓糖尿病心血管并发症的药物或基因疗法。