Regulation of Adipose Tissue Inflammation By Antigen Presenting Cells

抗原呈递细胞对脂肪组织炎症的调节

基本信息

批准号：
10579916
负责人：
Carey N Lumeng
金额：
$ 49.93万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-11 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579916
关键词：
Address Adipose tissue Adopted Antibodies Antigen-Presenting Cells CTLA4 gene Cell Communication Cell Ontogeny Cell Shape Cell physiology Cells Chronic Communication Data Dendritic Cells Diabetes Mellitus Disease Ensure Environment Funding Genes Genetic Genetic Models Glucocorticoids Goals Grant Health Human Hyperactivity IL2RA gene Immune Immune response Immune system Immunosuppression Impairment Inflammation Inflammatory Insulin Resistance Interferon Type II Interleukin-2 Intervention Leukocytes Link Macrophage Mediating Metabolic Metabolic Diseases Metabolism Modeling Morbidity - disease rate Mus Myelogenous Myeloid Cells Natural Immunity Nature Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pathway interactions Persons Predisposition Production Proliferating Proteins Publishing Regulation Research Resolution Role Sampling Sepsis Severity of illness Shapes Signal Pathway Signal Transduction Stimulus T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte T-cell diversity Testing Thinness Time Virus Diseases Work adaptive immunity cytokine diabetic dietary effector T cell exhaust exhaustion herpesvirus entry mediator immunoregulation improved in vivo inflammatory milieu novel pharmacologic preservation programmed cell death protein 1 receptor respiratory respiratory virus restraint single-cell RNA sequencing vaccine response

项目摘要

Adipose tissue contains a network of leukocytes that respond to obesity by generating proinflammatory signals that contribute to metabolic disease. At the same time, there is strong evidence that many healthy immune responses are impaired in obesity and contribute to an increased severity of illness to many diseases that include respiratory viruses. We currently do not have a clear understanding of the mechanisms behind this dichotomy. Addressing this gap can reveal mechanisms by which a hyperactive immune system can be restrained to improve insulin resistance and can also identify mechanisms by which normal immune responses can be preserved to improve health in people with obesity. This proposal seeks to understand immune responses in adipose tissue by focusing on the mechanisms by which the innate and adaptive components of the adipose tissue immune system interact in mice and humans. Our central hypothesis is that the chronic pro-inflammatory environment generated by obesity triggers T cell and myeloid exhaustion. We further posit that the diversity of adipose tissue macrophages (ATM) and dendritic cells (ATDC) shape adipose tissue T cell responses that impair healthy resolution of adipose tissue inflammation. The premise for this hypothesis is based on the published work generated in the last grant cycle, as well as preliminary data demonstrating a impaired T cell activation capacity in obese adipose tissue from mice and humans associated with decrease diversity of T cells in obese humans and enrichment for novel subtypes of ATDC. Our approach will identify the mechanisms by which adipose tissue T cells become exhausted with dietary obesity by testing the hypothesis that the induction of T cell exhaustion profiles requires differential APC signals and the induction of BTLA receptors in T cells. We will also evaluate the hypothesis that endogenous glucocorticoids alter the ability of ATMs and ATDC to activate T cells in a way that promotes exhaustion. Completing these aims further advance the understanding of the cell-cell communication networks that are generated in adipose tissue and how they contribute to metabolic disease.

脂肪组织包含一个白细胞网络，该网络通过产生促进代谢疾病的促炎信号来应对肥胖。同时，有充分的证据表明，肥胖症中许多健康的免疫反应受到损害，并导致包括呼吸道病毒在内的许多疾病的严重程度增加。目前，我们对这种二分法背后的机制尚不清楚。解决这一差距可以揭示可限制过度活跃免疫系统以提高胰岛素抵抗的机制，还可以识别可以保留正常免疫反应以改善肥胖患者健康的机制。该提案试图通过关注脂肪组织免疫系统在小鼠和人类中相互作用的先天和适应性成分的机制来理解脂肪组织中的免疫反应。我们的中心假设是肥胖产生的慢性促炎环境会触发T细胞和髓样疲惫。我们进一步认为，脂肪组织巨噬细胞（ATM）和树突状细胞（ATDC）的多样性塑造了脂肪组织T细胞反应，从而损害了脂肪组织炎症的健康分辨率。该假设的前提是基于上一个赠款周期中产生的已发表的工作，以及初步数据，表明来自小鼠的肥胖脂肪组织中T细胞激活能力受损，与肥胖人类中T细胞的多样性相关的人类和人类降低了ATDC的新型亚型的T细胞的多样性。我们的方法将通过测试诱导T细胞衰竭轮廓需要差异APC信号以及T细胞中BTLA受体的诱导的假设来确定脂肪组织T细胞耗尽饮食肥胖的机制。我们还将评估以下假设：内源性糖皮质激素会改变ATM和ATDC以促进疲劳的方式激活T细胞的能力。完成这些目标进一步促进了对脂肪组织中产生的细胞电池通信网络以及它们如何对代谢疾病的贡献的理解。