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

描述（由申请人提供）：肥胖症-连同其共病胰岛素抵抗、2型糖尿病和心血管疾病-是美国在二十一世纪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，最终是全身性的。引人注目的是，巨噬细胞可以构成肥胖人类和小鼠模型内脏脂肪中多达一半的细胞，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。最近有报道说，大量的Foxp 3？调节性T细胞（T细胞）存在于瘦而非肥胖小鼠（和人）的内脏脂肪组织中。该群体具有独特的基因表达谱和T细胞受体（TCR）库。功能丧失和获得实验证实，TGFAP能够调节脂肪组织炎症和全身代谢指标，促进胰岛素抵抗，从而预防2型糖尿病。本研究的主要目的是阐明内脏脂肪组织的产生、动力学和功能。具体而言，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转基因小鼠系的构建和表征等方法的组合，确定内脏脂肪组织中TCR 4的来源。候选分子的作用，内脏脂肪THEORY迁移将被解决。2.确定PPARg在脂肪驻留THBG的出现和功能中的作用。这种核受体超家族成员的活动-在内脏脂肪TcR中高度特异性诱导-将通过功能实验和基因表达谱对来自TcR中特异性缺乏PPARg的小鼠的细胞进行探索，小鼠具有极大和特异性扩增的内脏脂肪Treg群体，以及用foxp 3 pparg逆转录病毒转导的离体幼稚T细胞。3.定义肥胖小鼠内脏脂肪组织中令人印象深刻的TbR减少的潜在因素，特别是解决它们的迁移是否被阻断，它们在脂肪组织生态位中的生存是否受到损害，以及涉及哪些途径和分子。这些研究的结果应该极大地丰富了我们对脂肪组织炎症在瘦状态下如何调节以及随着肥胖的发生而失调的理解，可能揭示了新的治疗靶点。由于越来越多的人认识到一线糖尿病抑制噻唑烷二酮（TZD）药物的不幸副作用，目前人们对发现能够保护或减少胰岛素抵抗和下游心脏代谢疾病的新靶点非常感兴趣。 公共卫生相关性：该项目的重点是一个独特的调节性T细胞群的产生，动力学和功能，该细胞群存在于瘦但不肥胖的小鼠和人类的内脏脂肪组织中，并且能够控制胰岛素抵抗，从而控制2型糖尿病和心血管疾病。肥胖和下游心脏代谢紊乱是21世纪世纪的主要健康挑战之一。特别是提高内脏脂肪TdR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个有趣的替代目前的一线噻唑烷二酮（TZD）药物，其潜在的副作用引起了主要关注的后期。

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.