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

脂肪问题 Tregs：代谢免疫控制的重要参与者

• 批准号: 8677881
• 负责人: DIANE J MATHIS
• 金额: $ 37.54万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-12 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677881
• 关键词: 2,4-thiazolidinedione; Address; Adipocytes; Adipose tissue; Adverse effects; Americas; Anger; Bromodeoxyuridine; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Chronic; Comorbidity; Defect; Diabetes Mellitus; Elements; Enzymes; Family; Family member; Fatty acid glycerol esters; Frequencies; Gene Expression; Gene Expression Profile; Generations; Goals; Health; Human; Immigration; Incidence; Inflammation; Inflammation Mediators; Insulin Resistance; Label; Link; Lymphoid; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular Profiling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; Nuclear; Nuclear Receptors; Obese Mice; Obesity; Organ; Pathway interactions; Pharmaceutical Preparations; Population; Proteins; Regulatory T-Lymphocyte; Reporter; Reporting; Role; Site; T-Cell Receptor; T-Lymphocyte; Thiazolidinediones; Transgenic Mice; Transgenic Organisms; Visceral; adiponectin; arm; cell type; cellular imaging; chemokine; chemokine receptor; cytokine; gain of function; in vivo; indexing; interest; lipid metabolism; loss of function; macrophage; migration; mouse model; new therapeutic target; novel; research study; subcutaneous; transcription factor

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.

描述（由申请人提供）：肥胖及其并发症胰岛素抵抗、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。肥胖与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。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，并且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，Foxp3？调节性 T 细胞 (Treg) 存在于瘦小鼠（和人类）的内脏脂肪组织中，但肥胖小鼠则不然。该群体具有独特的基因表达谱和 T 细胞受体 (TCR) 库。功能丧失和获得的实验证实，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 Tregs 的生成、动态和功能。具体来说，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 转基因小鼠系的构建和表征等方法组合，确定内脏脂肪组织中 Tregs 的起源。然后将讨论候选分子在内脏脂肪 Tregs 迁移中的作用。 2. 确定 PPARg 在脂肪驻留性 Tregs 的出现和功能中的作用。这种核受体超家族成员的活性——在内脏脂肪 Tregs 中被高度特异性地诱导——将通过对来自缺乏 PPARg 的小鼠的细胞进行功能实验和基因表达谱来探索，这些小鼠在 Tregs 中具有高度特异性的诱导作用。扩大的内脏脂肪 Treg 群体，以及用 Foxp3 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 Tregs 显着减少的背后因素，特别是解决它们的迁移是否受阻，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我们对脂肪组织炎症如何在瘦状态下受到调节以及如何随着肥胖的发生而失调的理解，可能揭示新的治疗靶点。鉴于人们越来越认识到一线抗糖尿病噻唑烷二酮 (TZD) 药物的不良副作用，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疾病的新靶点产生了浓厚的兴趣。