Adipose-tissue Tregs: important players in immunological control of metabolism

脂肪组织 Tregs：代谢免疫控制的重要参与者

• 批准号: 10398115
• 负责人: DIANE J MATHIS
• 金额: $ 42.38万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398115
• 关键词: ATAC-seq; Address; Adipocytes; Adipose tissue; Adoptive Transfer; Age; Anger; Anti-Inflammatory Agents; Antibodies; Architecture; Biology; Cardiovascular Diseases; Cells; Chromatin; Chronic; Data; Dependence; Diet; Disease; Elements; Environment; FOXP3 gene; Flow Cytometry; Funding; Gene Expression; Generations; Genes; Goals; Health; Heterogeneity; Homeostasis; Human; Immunologics; Inflammation; Inflammation Mediators; Inflammatory; Insulin Receptor; Insulin Resistance; Knockout Mice; Link; Lymphoid; Malignant Neoplasms; Mediator of activation protein; Metabolic; Metabolism; Mining; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Omentum; Organ; Pathway interactions; Periodicity; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Population; Process; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Site; System; T-Cell Activation Pathway; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-cell receptor repertoire; Thinness; Tissues; Transgenic Mice; Visceral; chemokine; cholesterol biosynthesis; circadian pacemaker; comorbidity; conditional knockout; cytokine; design; experimental study; gain of function; indexing; insulin sensitizing drugs; lymphoid organ; macrophage; member; migration; mouse model; new therapeutic target; progenitor; side effect; single-cell RNA sequencing; systemic inflammatory response; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

Over the last three decades, there has been a striking rise in obesity, together with parallel increases in insulin resistance, type-2 diabetes, cardiovascular disease and certain cancers. A critical link between obesity and its downstream comorbidities is chronic low-grade inflammation promoted by secretion of pro-inflammatory mediators by “angry” adipocytes and macrophages in visceral adipose tissue (VAT). Anti-inflammatory cells and molecules capable of reining in these processes remain poorly understood. In 2009, we reported a population of Foxp3+CD4+ regulatory T cells (Tregs) that is highly enriched in epididymal VAT (eVAT), but not in lymphoid or other nonlymphoid organs, of lean mice as they age. These cells have a distinct gene- expression profile, T cell receptor (TCR) repertoire and profile of mediator dependencies. eVAT Tregs are strikingly and specifically reduced in several insulin-resistant mouse models of obesity, and loss- and gain-of- function experiments have confirmed that they regulate local and systemic inflammation and metabolism. An analogous Treg population is present in human omentum. eVAT Tregs serve as a paradigm for Treg populations specifically adapted to survive and function within particular tissue environments. Over the last funding cycle, we made substantial strides in illuminating the biology of VAT Tregs: dissecting transcriptome modulation with age and diet; discovering a two-step, two-site scenario of diversification from lymphoid-organ Tregs; uncovering modes of molecular diversification, including the construction of a tissue- Treg transcription-factor network; and demonstrating dependencies on TCR specificity, Foxp3 and IL-33. Building on these findings, the overall goal of this proposed project is to elucidate newly uncovered cellular and molecular elements controlling the generation, homeostasis or function of eVAT Tregs. We will undertake three Specific Aims, each designed to address a hypothesis that emerged from results obtained during the last funding cycle. 1) To examine the precursor potential of the splenic PPARγlo Treg compartment. 2) To identify factors that elicit, promote or guide the splenic PPARγlo precursors of eVAT PPARγhi Tregs. 3) To determine whether and how the homeostasis and function of eVAT Tregs are influenced by a circadian clock. These studies should yield important new information on cellular and molecular pathways involved in regulating the devastating downstream consequences of obesity. Identification of novel therapeutic targets within these pathways is especially important given the disconcerting increases in these disorders and the unacceptable side-effects of certain drug options.

在过去的三十年里，肥胖率急剧上升，同时肥胖率也随之增加。 胰岛素抵抗、2 型糖尿病、心血管疾病和某些癌症之间的重要联系。 其下游合并症是促炎细胞分泌促进的慢性低度炎症 内脏脂肪组织（VAT）中的“愤怒”脂肪细胞和巨噬细胞作为介质。 2009 年，我们报道了一种能够控制这些过程的分子。 Foxp3+CD4+ 调节性 T 细胞 (Treg) 群体在附睾 VAT (eVAT) 中高度富集，但并非如此 在瘦小鼠的淋巴或其他非淋巴器官中，随着年龄的增长，这些细胞具有独特的基因- 表达谱、T 细胞受体 (TCR) 库和 eVAT Tregs 依赖性谱。 在几种肥胖的胰岛素抵抗小鼠模型中，显着且具体地减少了 功能实验已证实它们调节局部和全身炎症和代谢。 类似的 Treg 群体存在于人类网膜中，作为 Treg 的范例。 专门适应在特定组织环境中生存和发挥作用的群体。 在上一个融资周期中，我们在阐明 VAT Tregs 生物学方面取得了重大进展：剖析 转录组随年龄和饮食的调节；发现多样化的两步、两位点场景 淋巴器官Tregs；揭示分子多样化的模式，包括构建组织- Treg 转录因子网络；并展示了对 TCR 特异性、Foxp3 和 IL-33 的依赖性。 基于这些发现，该拟议项目的总体目标是阐明新发现的 控制 eVAT Tregs 的生成、稳态或功能的细胞和分子元件。 将实现三个具体目标，每个目标旨在解决从所获得的结果中得出的假设 在最后一个融资周期内。 1) 检查脾 PPARγlo Treg 室的前体电位。 2) 确定诱发、促进或引导 eVAT PPARγhi 的脾 PPARγlo 前体的因素 特雷格斯。 3) 确定 eVAT Tregs 的稳态和功能是否以及如何受到某种因素的影响 生物钟。 这些研究应该会产生有关参与的细胞和分子途径的重要新信息。 调节肥胖的破坏性下游后果。确定新的治疗靶点。 考虑到这些疾病的令人不安的增加以及 某些药物选择的不可接受的副作用。