MITOCHONDRIAL DYSFUNCTION IN THE DIABETIC ENDOTHELIUM

糖尿病内皮线粒体功能障碍

• 批准号: 8109656
• 负责人: Joseph A. Vita
• 金额: $ 58.83万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109656
• 关键词: Accounting; Address; Age; Agonist; Alabama; American; Atherosclerosis; Bioavailable; Biogenesis; Biological Availability; Biopsy; Blood; Blood Vessels; Caloric Restriction; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical Research; Cross-Over Studies; DNA Damage; Development; Diabetes Mellitus; Diabetic Angiopathies; Diagnosis; Diagnostic and Statistical Manual; Endothelial Cells; Endothelium; Evaluation; Event; Exercise; Experimental Models; Fatty acid glycerol esters; Forearm; Functional disorder; Future; Gene Expression; Genes; Glucose; Health Expenditures; Human; Inflammatory; Injury; Instruction; Intervention; Link; Measures; Metabolic Control; Methodology; Mitochondria; Mitochondrial DNA; Mononuclear; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional; Organ; Pathogenesis; Pathology; Patient Care; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Placebo Control; Preparation; Prevalence; Prevention; Production; Public Health; Randomized; Reactive Oxygen Species; Reporting; Resveratrol; Risk; Risk Factors; Role; Skeletal Muscle; Testing; Tissues; Translations; United States; Universities; Vascular Diseases; Vasodilation; Vasodilator Agents; Venous; Video Microscopy; Wisconsin; Work; arteriole; blood glucose regulation; cardiovascular risk factor; cellular imaging; diabetic; diabetic patient; experience; high risk; human subject; improved; medical schools; mitochondrial dysfunction; novel; novel strategies; professor; programs; research study; subcutaneous; therapy design; treatment strategy

PROJECT SUIVIMARY (See instructions): Type 2 diabetes mellitus is a major and increasingly prevalent risk factor for cardiovascular disease. Risk persists despite intensive risk factor and glucose control. A key mechanism in diabetic vascular disease is the development of endothelial dysfunction. An improved understanding ofthe mechanisms of endothelial dysfunction in diabetes could stimulate new approaches for patient management. Prior experimental studies link mitochondrial dysfunction to the pathogenesis of diabetic vascular disease. Elevated glucose and free fatty acid levels stimulate mitochondrial production of reactive oxygen species (ROS) and impair biogenesis and dynamics. These conditions reduce nitric oxide availability and activate endothelial cells. Although abnormalities of mitochondrial function have been observed in skeletal muscle from patients, the connections between mitochondrial dysfunction and vascular disease remain pooriy understood in human diabetes. We have developed methodology to study specific aspects of mitochondrial function in freshly isolated vascular tissue (venous endothelial cells and arterioles from subcutaneous fat) and in more accessible blood mononuclear cells. Our preliminary studies show increased mitochondrial ROS, decreased mitochondrial mass, and loss of mitochondrial networks that relate to endothelial dysfunction. In Aim 1, we will correlate mitochondrial function in isolated endothelial cells and mononuclear cells to endothelial function in the forearm of 200 patients and controls. In Aim 2, we will investigate the mechanistic links between mitochondrial and endothelial dysfunction by isolating arterioles from subcutaneous fat and use organ chamber methodology and video microscopy to measure the effects of specific mitochondrial agonists/antagonists on endothelium-dependent vasodilation. In Aim 3, we will determine whether an intervention designed to increase mitochondrial biogenesis and dynamics (resveratrol) has favorable effects on our measures of endothelial and mitochondrial function in a randomized, placebo-controlled crossover study in 50 patients with diabetes mellitus. Our proposed studies fit well with the overall theme ofthe Program Project, and we expect to obtain novel information about the contribution of mitochondrial dysfunction to vascular injury that will bring us closer to identifying optimal treatment strategies to reduce cardiovascular risk in diabetes.

Suivimary项目（请参阅说明）： 2型糖尿病是心血管疾病的主要且日益普遍的风险因素。尽管有密集的危险因素和葡萄糖控制，风险仍然存在。糖尿病血管疾病的关键机制是内皮功能障碍的发展。对糖尿病内皮功能障碍的机制有了改进的理解，可以刺激患者管理的新方法。 先前的实验研究将线粒体功能障碍与糖尿病血管疾病的发病机理联系起来。 升高的葡萄糖和游离脂肪酸水平刺激了活性氧（ROS）的线粒体产生，并损害了生物发生和动力学。这些条件降低了一氧化氮的可用性并激活内皮细胞。尽管已经在患者的骨骼肌中观察到线粒体功能的异常，但是在人类糖尿病中，线粒体功能障碍与血管疾病之间的联系仍然很差。我们已经开发了研究新鲜分离的血管组织（静脉内皮细胞和来自皮下脂肪的小动脉）以及更容易获得的血液单核细胞中线粒体功能的特定方面的方法。我们的初步研究表明，线粒体ROS增加，线粒体质量降低以及与内皮功能障碍有关的线粒体网络的丧失。 在AIM 1中，我们将在分离的内皮细胞和单核细胞中的线粒体功能相关联，以在200例和对照组的前臂中的内皮功能。在AIM 2中，我们将通过从皮下脂肪中分离小动脉来研究线粒体和内皮功能障碍之间的机械联系，并使用器官室方法论和视频显微镜来测量特定的线粒体激动剂/拮抗剂对内皮依赖性血管静脉的影响。在AIM 3中，我们将确定旨在增加线粒体生物发生和动力学（白藜芦醇）的干预措施是否具有有利的影响 在50例糖尿病患者的随机，安慰剂对照的跨界研究中，我们对内皮和线粒体功能的衡量标准。 我们提出的研究非常符合计划项目的整体主题，我们希望获得有关线粒体功能障碍对血管损伤的贡献的新信息，这将使我们更加接近确定最佳治疗策略，以减少糖尿病中心血管风险。