Vascular Consequences of Insulin Resistance and Obesity

描述（由申请人提供）： 患有肥胖相关现象（如胰岛素抵抗、代谢综合征和2型糖尿病）的患者发生动脉粥样硬化血栓形成的风险显著增加。研究人员现在认识到这些疾病是对公共卫生的重大威胁，我们目前对这些疾病的理解和管理策略是不够的。研究表明，过量的热量摄入和缺乏身体活动会导致神经体液失衡，从而促进肥胖和胰岛素抵抗，并伴有全身炎症和血脂异常。在血管壁中，全身因素和局部胰岛素抵抗联合收割机改变细胞能量和线粒体功能，激活先天免疫，并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临床导向研究专门中心（SCCOR），该中心将采用多学科方法来确定这种情况下血管损伤的机制。我们将检验肥胖和胰岛素抵抗诱导炎症和异位脂质沉积在血管系统中损害血管功能并促进动脉粥样硬化血栓形成的总体假设。项目1（Vita博士）将检验AMP依赖性蛋白激酶活性降低、脑源性活性氧产生增加和先天免疫激活的相互作用导致早期胰岛素抵抗受试者血管功能障碍的假设。项目2（Dr. Ramachandran）将在Fracket心脏研究中检验循环脂肪因子和神经内分泌及肠源性激素损害血管功能的假设，并将前瞻性预测肥胖、高血压、血脂异常和代谢综合征的风险。项目3（Gokce博士）将检验脂肪组织作为炎症细胞因子的主要来源的假设，这些炎症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脂肪组织中血管功能和炎症的影响。项目4（Freedman博士）将通过检查人类受试者和肥胖小鼠模型的白细胞和血小板中toll样受体（TLR）介导的信号传导机制，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，即异位脂质沉积是肥胖和代谢综合征患者血管功能障碍和加速动脉粥样硬化的标志。该项目利用了波士顿大学医学院研究人员和研究资源的独特专业知识，包括强大的统计支持，基础血管生物学研究的优秀计划，新颖的成像资源，肥胖管理的临床计划和心脏病研究。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，并可能为患者管理确定新的方法。

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.