Adipose-issue Tregs: Important Players In The Immunological Control Of Metabolis

描述(申请人提供)：肥胖及其共病--胰岛素抵抗、2型糖尿病和心血管疾病--是二十一世纪美国面临的主要健康挑战之一。肥胖和下游心脏代谢紊乱之间的一个关键联系是内脏脂肪组织的慢性低度炎症，最终是全身炎症。值得注意的是，在肥胖的人类和小鼠模型的内脏脂肪中，巨噬细胞可以构成多达一半的细胞，这种细胞类型被认为是肥胖相关炎症的关键驱动因素之一。最近有报道称，有相当数量的Foxp3？调节性T细胞(Treg)存在于瘦小但不肥胖的小鼠(和人类)的内脏脂肪组织中。这个群体有一个独特的基因表达谱和T细胞受体(TCR)谱系。功能丧失和功能获得实验证实，Tregs能够调节脂肪组织炎症和全身代谢指数，促进胰岛素抵抗，从而预防2型糖尿病。该项目的总体目标是阐明内脏脂肪树的产生、动态和功能。具体地说，我们的目标是：1.利用细胞转移、体内光标记细胞成像以及新型报告基因和TCR转基因小鼠品系的构建和鉴定，确定位于内脏脂肪组织中的Tregs的来源。然后将讨论候选分子在内脏脂肪树迁移中的作用。2.确定PPARg在脂肪滞留树的产生和功能中的作用。这个核受体超家族成员的活性--在内脏脂肪Tregs中高度和特异地诱导--将通过功能实验和基因表达谱来探索，这些细胞来自缺乏Tregs中特异性PPARg的小鼠、具有大量和特殊扩大的内脏脂肪Treg群体的小鼠，以及逆转录病毒转导Foxp3 PPARG的体外幼稚T细胞。3.确定肥胖小鼠内脏脂肪组织中Tregs显著减少的原因，特别是它们的迁移是否被阻止，它们在脂肪组织利基中的生存是否受到影响，以及涉及哪些途径和分子。这些研究的结果将极大地丰富我们对脂肪组织炎症在瘦状态下是如何调节的，以及在肥胖发生时如何调节失调的理解，可能会揭示新的治疗靶点。由于人们越来越多地认识到一线抗糖尿病药物(TZD)的不幸副作用，目前人们对发现能够预防或减少胰岛素抵抗和下游心脏代谢性疾病的新靶点非常感兴趣。 与公共卫生相关：该项目专注于一组独特的调节性T细胞的产生、动态和功能，这种调节性T细胞存在于瘦小但不肥胖的小鼠和人类的内脏脂肪组织中，能够控制胰岛素抵抗，从而控制2型糖尿病和心血管疾病。肥胖和下游的心脏代谢紊乱是21世纪的主要健康挑战之一。尤其是增强内脏脂肪Tregs的代表性、它们的活性或它们的某些效应途径或分子提供了一种有趣的替代目前一线的噻唑烷二酮(TZD)药物，其潜在的副作用最近引起了人们的主要关注。

DESCRIPTION (provided by applicant): Obesity - together with its co-morbidities insulin resistance, type-2 diabetes and cardiovascular disease - is one of America's major health challenges in the twenty-first century. One crucial link between obesity and downstream cardio-metabolic disorders is chronic low-grade inflammation of visceral adipose tissue, and ultimately systemically. Strikingly, macrophages can constitute as many as half of the cells residing in the visceral fat of obese humans and mouse models, and this cell-type is recognized to be one of the critical drivers of obesity-associated inflammation. It was recently reported that a substantial population of Foxp3? regulatory T cells (Tregs) resides in the visceral adipose tissue of lean, but not obese, mice (and humans). This population has a distinct gene-expression profile and T cell receptor (TCR) repertoire. Loss- and gain-of-function experiments established that Tregs are capable of regulating adipose-tissue inflammation and systemic metabolic indices, promoting insulin resistance, and thereby protecting from type-2 diabetes. The overall goal of this proposed project is to elucidate the generation, dynamics and function of visceral- fat Tregs. Specifically, we aim to: 1. Determine the origin of Tregs residing in visceral adipose tissue, utilizing a combination of approaches entailing cell transfers, imaging of cells photo-tagged in vivo, and construction and characterization of novel reporter and TCR-transgenic mouse lines. The role of candidate molecules in migration of visceral-fat Tregs will then be addressed. 2. Establish the role of PPARg in the emergence and function of fat-resident Tregs. The activities of this nuclear receptor super-family member -- highly and specifically induced in visceral-fat Tregs -- will be explored through functional experiments and gene-expression profiling on cells from mice lacking PPARg specifically in Tregs, mice with a greatly and specifically expanded visceral-fat Treg population, and ex vivo naive T cells retrovirally transduced with foxp3 pparg. 3. Define elements underlying the impressive reduction in Tregs in visceral adipose tissue of obese mice, addressing, in particular, whether their migration is blocked, whether their survival in the adipose tissue niche is compromised, and what pathways and molecules are implicated. Results from these studies should greatly enrich our understanding of how adipose tissue inflammation is regulated in the lean state and dysregulated with the onset of obesity, likely revealing novel therapeutic targets. Given increasing recognition of the unfortunate side-effects of the front-line diabetes-dampening thiazolidinedione (TZD) drugs, there is currently great interest in the discovery of new targets capable of protecting from or reducing insulin resistance and downstream cardio-metabolic diseases. PUBLIC HEALTH RELEVANCE: This project focuses on the generation, dynamics and function of a unique population of regulatory T cells that resides in the visceral adipose tissue of lean, but not obese, mice and humans, and is capable of controlling insulin resistance and, thereby, type-2 diabetes and cardiovascular disease. Obesity and downstream cardio-metabolic disorders are one of the major health challenges of the 21st century. Specifically enhancing the representation of visceral-fat Tregs, their activity, or certain of their effector pathways or molecules offers an interesting alternative to the current front-line thiazolidinedione (TZD) drugs, whose potential side-effects have elicited major concern of late.