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: 8496092
• 负责人: Karin E. Bornfeldt
• 金额: $ 41.41万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496092
• 关键词: ASCL1 gene; Acyl Coenzyme A; Address; Affect; Arachidonic Acids; Arterial Fatty Streak; Atherosclerosis; Biology; Bone Marrow Stem Cell; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical Data; Coenzyme A Ligases; Collaborations; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Diabetic mouse; Dinoprostone; Drug Targeting; Event; Glucose; Glucose Transporter; Goals; Human; Hyperglycemia; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Lead; Lesion; Life; Link; Lipids; Low Density Lipoprotein Receptor; Macrophage Activation; Mediating; Modeling; Molecular; Morphology; Mus; Myelogenous; Myeloid Cells; Omega-6 Fatty Acids; PTGS2 gene; Pathway interactions; Peritoneal Macrophages; Phenotype; Plasma; Play; Production; Prostaglandin D2; Prostaglandin E Receptor; Prostaglandin-Endoperoxide Synthase; Research; Risk; SLC2A1 gene; Signal Transduction; Small Interfering RNA; Transgenic Mice; Transplantation; atherogenesis; autocrine; base; cardiovascular disorder risk; cytokine; diabetic; fatty acid modifying enzyme; glucose uptake; glycemic control; human subject; improved; in vivo; insight; interest; knock-down; lipid mediator; macrophage; macrovascular disease; monocyte; mouse model; non-diabetic; novel; overexpression; prevent; promoter; protective effect; research study; treatment strategy; vector

DESCRIPTION (provided by applicant): Diabetes promotes atherosclerosis in humans, greatly increasing the risk of developing cardiovascular disease. Compelling clinical data show that improving glycemic control early in life has long-term beneficial effects on cardiovascular events in human subjects with type 1 diabetes. Macrophages are likely to play a key role in the stimulatory effects of diabetes on atherosclerosis. Our preliminary studies demonstrate that in addition to stimulating a pro-inflammatory response, diabetes and elevated glucose levels lead to an increased expression of an enzyme that esterifies fatty acids (long-chain acyl-CoA synthetase 1; ACSL1) in macrophages, suggesting a close connection between the inflammatory capacity and ACSL1 in macrophages, diabetes and states of hyperglycemia. Strikingly, the stimulatory effects of diabetes on atherosclerotic lesion formation can be completely prevented by deleting ACSL1 in myeloid cells. No such effect is seen in non-diabetic mice, suggesting that the discovered mechanism is selective for diabetes. The protective effect of ACSL1-deficiency correlates with a reduced release of pro-inflammatory mediators from macrophages. The overall hypothesis of this project is that diabetes promotes atherosclerosis largely through increased glucose uptake in macrophages, which promotes an inflammatory macrophage phenotype that requires ACSL1. Our goal for the proposed project is to address two questions: 1). Does increased glucose uptake in macrophages enhance their pro-inflammatory capacity and atherosclerosis through a mechanism that requires ACSL1?; 2). What is the ACSL1-dependent mechanism of glucose-mediated macrophage activation?

描述（由申请人提供）：糖尿病促进人类动脉粥样硬化，大大增加患心血管疾病的风险。令人信服的临床数据表明，在生命早期改善血糖控制对1型糖尿病患者的心血管事件有长期有益的影响。巨噬细胞可能在糖尿病对动脉粥样硬化的刺激作用中发挥关键作用。我们的初步研究表明，除了刺激促炎反应外，糖尿病和葡萄糖水平升高还会导致巨噬细胞中脂肪酸酯化酶（长链酰基辅酶a合成酶1；ACSL1）的表达增加，这表明巨噬细胞的炎症能力和ACSL1、糖尿病和高血糖状态之间存在密切联系。引人注目的是，通过删除髓细胞中的ACSL1，可以完全阻止糖尿病对动脉粥样硬化病变形成的刺激作用。在非糖尿病小鼠中没有发现这种作用，这表明所发现的机制对糖尿病是选择性的。acsl1缺乏的保护作用与巨噬细胞中促炎介质的释放减少有关。本项目的总体假设是糖尿病主要通过增加巨噬细胞的葡萄糖摄取来促进动脉粥样硬化，这促进了需要ACSL1的炎性巨噬细胞表型。我们提议的项目的目标是解决两个问题：1)。巨噬细胞葡萄糖摄取增加是否通过ACSL1的机制增强其促炎能力和动脉粥样硬化？2）. 葡萄糖介导的巨噬细胞活化的acsl1依赖机制是什么？