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.

肥胖和肥胖相关疾病在全球处于流行水平(世卫组织)。肥胖相关的炎症最近受到了极大的关注，因为它对许多新冠肺炎患者造成了毁灭性的后果。肥胖症的低水平慢性炎症导致了肥胖症作为一种炎症性疾病的最新分类，这种疾病是由代谢稳态失调引起的。脂肪组织中免疫细胞和代谢调节细胞(如脂肪细胞)之间的串扰调节脂肪组织的动态平衡。细胞内在和环境的变化可能会导致压力和细胞因子产生的改变，从而导致炎症反应，从而导致代谢下降和肥胖的发生。脂肪组织包含大量的组织常驻免疫细胞，包括γδT细胞，当被激活时，它们会产生大量的IL-17A和肿瘤坏死因子-α。IL-17在体重调节、脂肪细胞分化、胰岛素和血糖稳态等方面发挥重要作用。与具有类似食物摄入量的野生型小鼠相比，缺乏JAML蛋白的小鼠随着年龄的增长变得明显肥胖。JAML蛋白对组织驻留的γδT细胞具有共刺激作用。我们假设JAML-CAR相互作用在调节γδT细胞功能以维持脂肪组织内稳中起关键作用。我们计划通过观察肥胖发展过程中γδT细胞对脂肪细胞分化和动态平衡的直接控制来研究这些小鼠肥胖发展的机制。