Inflammation and Vascular Dysfunction in Obesity

描述（由申请人提供）：肥胖可以说是这个国家最严重的公共卫生问题，近65%的美国人口目前被归类为超重或肥胖。这种日益增长的流行病给全国带来了毁灭性的医疗负担，而且没有减缓的迹象。越来越多的人面临心血管疾病的风险。炎症机制对动脉粥样硬化和心血管疾病事件的所有阶段都至关重要。本提案的目的是表征炎症在脂肪储存中的作用，作为肥胖个体代谢和血管功能障碍的协调者。该项目与申请人研究肥胖中心血管疾病的机制的长期目标是一致的。除了作为能量储存的主要部位外，脂肪库越来越被认为是代谢和炎症活动的重要温床，也是促动脉粥样硬化和促炎症脂肪因子的重要合成来源，这些脂肪因子协调了肥胖血管功能障碍、损伤和心血管疾病进展的机制。脂肪组织炎症的不适应状态和脂肪细胞功能障碍在多大程度上与肥胖个体的个体血管表型相关，以及靶向药物干预对这些参数的影响严重缺乏。本项目提出具体目标1：利用血管内皮功能的非侵入性测量将人脂肪活检标本中的组织学炎症活动与肥胖血管表型受损联系起来；具体目标2：确定人脂肪组织中的炎症活动是否与通过rt-PCR量化的促动脉粥样硬化脂肪因子的脂肪细胞表达有关；具体目标3：确定抗炎药物磺胺氮嗪治疗是否能改善肥胖患者的血管功能障碍，以及这些改变是否与脂肪组织的炎症水平有关。该项目提出了一种高度新颖的研究方法，并利用独特的多学科合作伙伴关系，在日益增长的主要公共卫生关注领域研究肥胖相关血管疾病的机制。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未来超重和肥胖患者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.