LIGHT and Adipose Tissue Inflammation in Human Obesity

描述（由申请人提供）： 肥胖症与慢性全身性炎症状态有关，慢性全身性炎症状态与许多共病病症的发病机制有关。内脏脂肪组织是肥胖症炎症的重要部位，是肥胖人群不良临床后遗症和死亡率的重要独立危险因素。我们证明，与肥胖人的皮下脂肪组织相比，内脏脂肪组织中LIGHT的表达显著增加，LIGHT是一种研究不足但重要的炎症调节因子。我们的长期目标是阐明肥胖症脂肪组织中炎症和胰岛素抵抗增强的机制，并开发与体重减轻无关的肥胖相关全身炎症和胰岛素抵抗的治疗方法。我们的短期目标是确定LIGHT在人类肥胖症中脂肪组织炎症和胰岛素抵抗中的作用。我们的中心假设是，肥胖人群内脏脂肪组织中T细胞的LIGHT表达增加，诱导组织巨噬细胞的炎症表型，进而导致脂肪细胞的胰岛素抵抗，LIGHT阻断将消除组织巨噬细胞的炎症和致糖尿病特性。我们的具体目标是1.研究肥胖人群脂肪组织中LIGHT和相关介质的表达并鉴定其主要细胞来源2.明确LIGHT在体外调节脂肪组织相关淋巴细胞炎症中的作用; 3.明确LIGHT在体外调节脂肪细胞胰岛素抵抗中的作用。 相关性：这项转化研究提案意义重大，因为它将阐明人类肥胖症中脂肪组织内炎症和胰岛素抵抗的机制，并确定LIGHT相关分子途径的操纵是否会减弱脂肪细胞中的炎症和胰岛素抵抗。这些实验将指导未来的研究，旨在开发基于LIGHT的治疗肥胖相关炎症，胰岛素抵抗，糖尿病和其他独立于减肥的肥胖代谢后遗症。该提案将为Robert O 'Rourke博士提供必要的培训，使其成为一名独立的翻译研究科学家。

DESCRIPTION (provided by applicant): Obesity is associated with a state of chronic systemic inflammation which has been implicated in the pathogenesis of many co-morbid conditions. Visceral adipose tissue is an important site of inflammation in obesity and is a strong independent risk factor for adverse clinical sequelae and mortality in obese humans. We demonstrate marked increased expression of LIGHT, an understudied but important regulator of inflammation, in visceral compared to subcutaneous adipose tissue from obese humans. Our long-term goals are to elucidate mechanisms of heightened inflammation and insulin resistance in adipose tissue in obesity and to develop therapy for obesity-related systemic inflammation and insulin resistance independent of weight loss. Our short-term goals are to define the role of LIGHT in inflammation and insulin resistance in adipose tissue in human obesity. Our central hypothesis is that increased LIGHT expression by T-cells in visceral adipose tissue in obese humans induces an inflammatory phenotype in tissue macrophages which in turn causes insulin resistance in adipocytes, and that LIGHT blockade will abrogate the inflammatory and diabetogenic properties of tissue macrophages. Our specific aims will 1. study the expression of and identify the primary cellular sources of LIGHT and related mediators in adipose tissue in obese humans 2. define the role of LIGHT in regulating inflammation in adipose tissue assocaiteed [sic] lymphocytes in vitro, and 3. define the role of LIGHT in regulating insulin resistance in adipocytes in vitro. Relevance: This translational research proposal is significant because it will elucidate mechanisms of inflammation and insulin resistance within adipose tissue in human obesity and determine if manipulation of LIGHT-related molecular pathways attenuates inflammation and insulin resistance in adipocytes. These experiments will guide future research directed towards developing LIGHT-based therapy for obesity-related inflammation, insulin resistance, diabetes and other metabolic sequelae of obesity independent of weight loss. This proposal will provide Dr. Robert O'Rourke with the training necessary to develop into an independent translational research scientist.