Inflammation and Vascular Dysfunction in Obesity

描述(申请人提供)：肥胖可以说已经成为这个国家最严重的公共健康问题，目前近65%的美国人口被归类为超重或肥胖。不断增长的疫情给这个国家带来了毁灭性的医疗负担，而且没有放缓的迹象。空前数量的个人暴露在心血管风险增加的环境中。炎症机制在动脉粥样硬化和心血管疾病事件的所有阶段都是至关重要的。本研究的目的是描述脂肪储存中的炎症作为肥胖者代谢和血管功能障碍的协调者的作用。该项目与申请者研究肥胖心血管疾病机制的长期目标是一致的。除了作为能量储存的主要场所外，脂肪库越来越被认为是代谢和炎症活动的重要温床，以及导致动脉粥样硬化和促炎症的脂肪因子的重要合成来源，这些脂肪因子协调了肥胖中血管功能障碍、损伤和心血管疾病进展的机制。脂肪组织炎症和脂肪细胞功能障碍的不适应状态在多大程度上与肥胖个体的血管表型有关，而靶向药物干预对这些参数的影响严重缺乏。本项目在特定目标1中提出：利用血管内皮功能的非侵入性测量，将人类脂肪活检标本中的组织炎症活动与肥胖患者受损的血管表型联系起来；在特定目标2中，确定人类脂肪组织中的炎症活动是否与脂肪细胞通过RT-PCR定量的促动脉粥样硬化脂肪因子的表达有关；在特定目标3中：确定抗炎药物柳氮磺吡啶治疗是否改善肥胖患者的血管功能障碍，以及这些变化是否与脂肪组织中的炎症水平有关。该项目提出了一种非常新颖的调查方法，并利用独特的多学科合作伙伴关系，在日益增长的重大公共卫生问题领域审查与肥胖相关的血管疾病的机制。这些拟议的研究极有可能产生关于肥胖血管疾病机制的重要新信息，并使我们更接近于确定与超重和肥胖患者的未来管理密切相关的最佳治疗策略。

DESCRIPTION (provided by applicant): Obesity has arguably emerged as the most serious public health problem in this country with nearly 65% of the US population currently classified as overweight or obese. The growing epidemic imposes a devastating health care burden on the nation, and there are no signs of slowing. Unprecedented numbers of individuals are exposed to increased cardiovascular risk. Inflammatory mechanisms are critical to all stages of atherosclerosis and cardiovascular disease events. The goal of the present proposal is to characterize the role of inflammation in adipose stores as a coordinator of metabolic and vascular dysfunction in obese individuals. The project is consistent with the long-term goal of the applicant to investigate mechanisms of cardiovascular disease in obesity. In addition to serving as the primary site for energy stores, fat depots are increasingly recognized as an important hotbed of metabolic and inflammatory activity, and significant synthetic source of proatherogenic and proinflammatory adipokines that orchestrate mechanisms of vascular dysfunction, injury, and cardiovascular disease progression in obesity. The extent to which a maladaptive state of inflammation in adipose tissue and adipocyte dysfunction relates to individual vascular phenotype across a wide range of obese individuals, and the effects of targeted pharmacological intervention on these parameters are critically lacking. This project proposes in specific aim 1: to relate histological inflammatory activity in human fat biopsy specimens to impaired vascular phenotype in obesity using non-invasive measures of vascular endothelial function, in specific aim 2: to determine whether inflammatory activity in human adipose tissue relates to adipocyte expression of proatherogenic adipokines quantified by rt-PCR, and in specific aim 3: to determine whether treatment with the anti-inflammatory drug sulfasalazine improves vascular dysfunction in obese patients and whether these changes relate to the level of inflammation in adipose tissue. This project proposes a highly novel approach of investigation and takes advantage of a unique multidisciplinary partnership examining mechanisms of obesity-related vascular disease in a growing area of major public health concern. These proposed studies are highly likely to yield important novel information with regard to mechanisms of vascular disease in obesity and bring us closer to identifying optimal treatment strategies firmly relevant to the future management of overweight and obese patients.