JAML-CAR regulation of adipose tissue homeostasis

JAML-CAR对脂肪组织稳态的调节

• 批准号: 10348218
• 负责人: Dianne B Mckay
• 金额: $ 22.19万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-09 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348218
• 关键词: Address; Adipocytes; Adipose tissue; Age; Anti-Inflammatory Agents; Antigens; Attention; Automobile Driving; Body Weight; CD3 Antigens; COVID-19; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cell physiology; Cells; Chronic; Classification; Clinical Trials; Data; Development; Disease; Eating; Economic Burden; Epidemic; Event; Fasting; Fatty Acids; Genes; Glucose; Health; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Impairment; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Interleukin-17; Lead; Ligands; Link; Lipids; Lymphoid Cell; Lymphoid Tissue; Mediating; Metabolic; Metabolism; Mucous Membrane; Mus; Nomenclature; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Obesity associated disease; Pathway interactions; Patients; Play; Population; Prevention; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Role; Site; Source; Stress; Stromal Cells; T-Lymphocyte; TNF gene; Temperature; Testing; Thermogenesis; Time; Tissues; Update; Wild Type Mouse; ZNF145 gene; adipocyte differentiation; assault; blood glucose regulation; cell type; cytokine; environmental change; glucose uptake; improved; insulin sensitivity; lipid biosynthesis; new therapeutic target; novel therapeutic intervention; obesity development; obesity prevention; obesity treatment; pathogen; receptor; response; systemic inflammatory response; targeted treatment; transcriptome sequencing; uptake; γδ T cells

Obesity and obesity-related diseases are at epidemic levels globally (WHO). Obesity-associated inflammation has recently received much attention due to its devastating consequences for many patients suffering from COVID-19. The low levels of chronic inflammation in obesity have led to the updated classification of obesity as an inflammatory disease that results from disturbed metabolic homeostasis. Crosstalk among immune cells and metabolic regulatory cells, such as adipocytes, in the adipose tissue regulate adipose tissue homeostasis. Cell intrinsic and environmental changes can lead to stress and alterations in cytokine production driving an inflammatory response that builds to metabolic decline and development of obesity. Adipose tissue contains populations of tissue-resident immune cells including γδ T cells that produce significant amounts of IL-17A and TNF-α when activated. IL-17 plays roles in regulation of body weight, adipocyte differentiation and insulin and glucose homeostasis. Mice deficient in the JAML protein that is costimulatory for tissue-resident γδ T cells become significantly obese with age compared to wildtype mice with similar food intake. We hypothesize that JAML-CAR interactions play a critical role in regulation of γδ T cell functions to maintain adipose tissue homeostasis. We plan to investigate the mechanism for development of obesity in these mice by looking at direct control of adipocyte differentiation and homeostasis by γδ T cells during development of obesity.

肥胖症和与肥胖症有关的疾病在全球范围内处于流行水平（世卫组织）。肥胖相关的炎症最近受到了广泛关注，因为它对许多患有COVID-19的患者造成了毁灭性的后果。肥胖症的慢性炎症水平较低，导致肥胖症作为一种炎症性疾病的最新分类，这是由于代谢稳态紊乱引起的。脂肪组织中免疫细胞和代谢调节细胞（如脂肪细胞）之间的相互作用调节脂肪组织的稳态。细胞内在和环境变化可导致应激和细胞因子产生的改变，从而驱动炎症反应，进而导致代谢下降和肥胖的发展。脂肪组织含有组织驻留免疫细胞群，包括γδ T细胞，其在活化时产生显著量的IL-17 A和TNF-α。IL-17在调节体重、脂肪细胞分化以及胰岛素和葡萄糖稳态中起作用。与具有相似食物摄入量的野生型小鼠相比，JAML蛋白缺陷的小鼠随着年龄的增长变得明显肥胖，JAML蛋白对组织驻留γδ T细胞具有共刺激作用。我们假设JAML-CAR相互作用在调节γδ T细胞功能以维持脂肪组织稳态中起关键作用。我们计划通过观察肥胖发生过程中γδ T细胞对脂肪细胞分化和体内平衡的直接控制来研究这些小鼠肥胖发生的机制。