Vascular Consequences of Insulin Resistance and Obesity

描述(由申请人提供)： 有肥胖相关现象的患者，如胰岛素抵抗、代谢综合征和2型糖尿病，患动脉粥样硬化血栓的风险显著增加。调查人员现在认识到，这些疾病是对公共健康的重大威胁，我们目前对这些疾病的了解和管理战略是不够的。研究表明，过多的卡路里摄入和缺乏运动会导致神经-体液失衡，从而促进肥胖和胰岛素抵抗，并与全身炎症和血脂异常相关。在血管壁上，全身因子和局部胰岛素抵抗共同改变细胞能量和线粒体功能，激活先天免疫，损害内皮源性一氧化氮的生物利用度。我们建议在波士顿大学医学院建立一个专门的临床导向研究中心(SCCOR)，该中心将采取多学科方法来确定这种情况下血管损伤的机制。我们将测试肥胖和胰岛素抵抗导致炎症和血管内异位脂肪沉积，从而损害血管功能和促进动脉粥样硬化血栓形成的总体假设。项目1(Vita博士)将测试这一假设，即AMP依赖的蛋白激酶活性降低、线粒体衍生的活性氧物种的产生增加以及天然免疫激活的相互关联效应导致早期胰岛素抵抗受试者的血管功能障碍。项目2(Ramachandran博士)将在Framingham心脏研究中测试循环脂肪因子、神经内分泌和肠源性激素损害血管功能的假设，并将前瞻性地预测肥胖、高血压、血脂异常和代谢综合征的风险。项目3(Gokce博士)将测试脂肪组织作为炎性细胞因子的主要来源的假设，这些炎性细胞因子损害肥胖患者的血管功能，并将检查特定减肥策略对血管功能和脂肪组织炎症的影响。项目4(弗里德曼博士)将通过研究人类受试者和肥胖小鼠模型中白细胞和血小板中Toll样受体(TLR)介导的信号机制来检验先天免疫有助于动脉粥样硬化血栓形成和对血管损伤的急性反应的假设。项目5(汉密尔顿博士)将使用新的磁共振成像和光谱技术来检验这一假设，即异位脂肪沉积是肥胖和代谢综合征患者血管功能障碍和动脉粥样硬化加速的标志。该项目利用了波士顿大学医学院研究人员的独特专业知识和研究资源，包括强大的统计支持、基础血管生物学方面的杰出研究计划、新颖的成像资源、肥胖管理的临床计划以及Framingham心脏研究。这项工作将提高我们对胰岛素抵抗和肥胖中血管损伤的理解，并可能找到新的患者管理方法。

DESCRIPTION (provided by applicant): Patients with obesity-related phenomena such as insulin resistance, the metabolic syndrome, and Type 2 diabetes mellitus, have a markedly increased risk for atherothrombosis. Investigators now recognize these conditions as representing a major threat to public health and that our current understanding and management strategies of these disorders are inadequate. Studies suggest that excess caloric intake and physical inactivity lead to a neuro-humoral imbalance that promotes obesity and insulin resistance in association with systemic inflammation and dyslipidemia. In the vascular wall, systemic factors and local insulin resistance combine to alter cellular energetics and mitochondrial function, activate innate immunity, and impair the bioavailability of endothelium-derived nitric oxide. We propose to establish a Specialized Center of Clinically-Oriented Research (SCCOR) at Boston University School of Medicine that will take a multi-disciplinary approach to define mechanisms of vascular injury in this setting. We will test the overall hypothesis that obesity and insulin resistance induce inflammation and ectopic lipid deposition in vasculature that impairs vascular function and promotes atherothrombosis. Project 1 (Dr. Vita) will test the hypothesis that inter-related effects of reduced activity of AMP-dependent protein kinase, increased production of mitochondrial-derived reactive oxygen species, and activation of innate immunity contribute to vascular dysfunction in human subjects with early insulin resistance. Project 2 (Dr. Ramachandran) will test the hypothesis that circulating adipokines and neuroendocrine and gut-derived hormones impair vascular function and will prospectively predict risk for developing obesity, hypertension, dyslipidemia, and the metabolic syndrome in the Framingham Heart Study. Project 3 (Dr. Gokce) will test the hypothesis that adipose tissue serves as a primary source of inflammatory cytokines that impair vascular function in obese patients and will examine the impact of specific weight loss strategies on vascular function and inflammation in adipose tissue. Project 4 (Dr. Freedman) will test the hypothesis that innate immunity contributes to atherothrombosis and the acute response to vascular injury by examining toll-like receptor (TLR)-mediated signaling mechanisms in leukocytes and platelets from human subjects and mouse models of obesity. Project 5 (Dr. Hamilton) will use novel magnetic resonance imaging and spectroscopy techniques to test the hypothesis that ectopic lipid deposition is a marker of vascular dysfunction and accelerated atherosclerosis in obesity and the metabolic syndrome. This project takes advantage of the unique expertise of the investigators and research resources at the Boston University Medical Campus, including strong statistical support, outstanding programs of research in basic vascular biology, novel imaging resources, clinical programs for the management of obesity, and the Framingham Heart Study. This work will improve our understanding of vascular injury in insulin resistance and obesity and may identify new approaches for patient management.