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.

在过去的三十年中，肥胖症的增长显着，并行增加 胰岛素抵抗，2型糖尿病，心血管疾病和某些癌症。肥胖之间的关键联系 它的下游合并症是通过促炎性分泌促进的慢性低度炎症性 内脏脂肪组织（VAT）中的“愤怒”脂肪细胞和巨噬细胞的介体。抗炎细胞 并且能够在这些过程中进行重新制定的分子仍然了解得很糟糕。 2009年，我们报告了 FOXP3+ CD4+调节性T细胞（Tregs）的种群高度富含附子增值税（EVAT），但不是 随着年龄的增长，在瘦小小鼠的淋巴或其他非淋巴器官中。这些细胞具有独特的基因 表达谱，T细胞受体（TCR）曲目和介体依赖性的轮廓。 evat treg是 在肥胖的几种耐胰岛素耐药蛋白模型以及损失和损失中，明显地降低了 功能实验已经确认它们调节局部和全身注射和代谢。一个 人类大脑中存在类似的treg人群。 evat tregs充当treg的范式 专门适应特定组织环境中生存和运作的种群。 在最后一个资金周期中，我们在照亮增值税的生物学方面取得了长足的进步：解剖 随着年龄和饮食的转录组调制；从 淋巴管tregs;发现分子多样化的模式，包括构建组织 Treg转录因子网络；并证明对TCR特异性的依赖性FOXP3和IL-33。 在这些发现的基础上，这个拟议项目的总体目标是阐明新发现的 控制EVAT TREG的产生，稳态或功能的细胞和分子元素。我们 将实现三个特定目标，每个目标旨在解决从获得的结果中提出的假设 在最后一个资金周期中。 1）检查脾pparγlotreg室的前体电位。 2）确定引起，促进或指导EVATPPARγHI的脾PPARγLO前体的因素 Tregs。 3）确定evat treg的体内平衡和功能是否受到A的影响 昼夜节律。 这些研究应产生有关涉及的细胞和分子途径的重要新信息 调节肥胖的毁灭性下游后果。新型热目标的识别 考虑到这些疾病的不关心增加，这些途径尤其重要 某些药物选择的不可接受的副作用。