Macrophage Trafficking, Inflammation & Metabolism in Adipose Tissue in High Fat Feeding: Role of AGE/RAGE/DIAPH1

巨噬细胞贩运、炎症

• 批准号: 9925270
• 负责人: ANN MARIE SCHMIDT
• 金额: $ 43.84万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9925270
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Agents; Affect; Animal Model; Anti-Inflammatory Agents; Atherosclerosis; Binding; Biological Assay; Bone Marrow; Candidate Disease Gene; Cardiovascular system; Cells; Coculture Techniques; Conditioned Culture Media; Cytoplasmic Tail; Data; Diabetes Mellitus; Endothelium; Energy Metabolism; Expression Profiling; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genus Hippocampus; Glucose; Goals; High Fat Diet; Human; Hypertrophy; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Laboratories; Lead; Ligands; Link; Lipids; Lipolysis; LoxP-flanked allele; Mediating; Messenger RNA; Metabolic; Metabolic dysfunction; Metabolism; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Oleates; Palmitates; Pathogenesis; Property; Proteins; Publishing; RNA analysis; Regulation; Role; Signal Transduction; Sympathetic Nervous System; Testing; Therapeutic; Thermogenesis; Time; Tissue Transplantation; Tissues; Transcript; Visceral; Wild Type Mouse; Work; adiponectin; cardiovascular disorder risk; cell type; combat; diabetic; effective therapy; energy balance; experimental study; feeding; gene discovery; human subject; in vivo; insulin sensitivity; macrophage; metabolomics; monocyte; mortality; mouse Cre recombinase; novel; novel therapeutic intervention; programs; receptor; receptor expression; receptor for advanced glycation endproducts; receptor function; recruit; response; small molecule; subcutaneous; trafficking; transcriptome sequencing; transcriptomics

The problems of obesity and insulin resistance have been linked to type 2 diabetes. Diabetes is on the rise and fully effective treatments are lacking. In the spectrum from obesity and insulin resistance, to diabetes, profound metabolic dysfunction is linked to increased risk for cardiovascular disease. In this Program Project, our goal is to uncover fundamental mechanisms by which macrophage inflammation impacts metabolic dysfunction in diabetic atherosclerosis and obesity. Published and preliminary data reveal that in high fat feeding and obesity in human subjects and in mice, ligands of the receptor for AGE (RAGE) are increased in adipose tissue and other key metabolic tissues, even in the absence of diabetes. Our data reveal that genetic deletion of Ager (gene encoding RAGE) results in significant protection against high fat feeding induced obesity and insulin resistance. Importantly, the accumulation and inflammatory polarization of adipose tissue macrophages are greatly reduced by deletion of Ager. Project 3 will address the hypothesis that RAGE/DIAPH1 regulates obesity, adiposity and metabolic dysfunction in high fat feeding, both via cell autonomous mechanisms, and via macrophage cross-talk with the adipocyte. Our Project will explore four key properties of macrophage inflammation to discover RAGE-dependent mechanisms in high fat feeding: monocyte recruitment; macrophage retention and egress; polarization; and metabolic regulation. Project 3 will work closely with Projects 1 and 2 to address the common vs. distinct mechanisms of macrophage inflammation in diabetic atherosclerosis and in obesity. Project 3 will work closely with Project 1 to test novel small molecule antagonists of RAGE/DIAPH1 interaction in atherosclerosis and in high fat feeding, and will work closely with Project 2 to discern common vs. distinct mechanisms by which RAGE/DIAPH1 contribute to regulation of NETRIN1/UNC5B and metabolic dysfunction in macrophages in high fat feeding. Project 3 will utilize all three Cores of the Program over all five years.

肥胖和胰岛素抵抗的问题与2型糖尿病有关。糖尿病正在上升， 缺乏有效的治疗方法。从肥胖、胰岛素抵抗到糖尿病， 代谢功能障碍与心血管疾病风险增加有关。在这个项目中，我们的目标是 揭示巨噬细胞炎症影响代谢功能障碍的基本机制， 糖尿病动脉粥样硬化和肥胖。已发表的和初步的数据表明，在高脂肪喂养和肥胖， 在人类受试者和小鼠中，AGE（AGE）受体的配体在脂肪组织中增加， 其他关键的代谢组织，即使没有糖尿病。我们的数据显示， (gene编码β-内酰胺酶）对高脂喂养诱导的肥胖和胰岛素产生显著的保护作用 阻力重要的是，脂肪组织巨噬细胞的积累和炎症极化是 通过删除Ager而大大减少。项目3将解决的假设，ESTA/DIAPH 1调节 肥胖症、肥胖症和高脂喂养中的代谢功能障碍，这两者都是通过细胞自主机制， 巨噬细胞与脂肪细胞的交互作用。我们的项目将探讨巨噬细胞的四个关键特性 炎症，以发现高脂喂养中RAGE依赖性机制：单核细胞募集; 巨噬细胞滞留和排出;极化;和代谢调节。项目3将与 项目1和项目2旨在解决糖尿病患者巨噬细胞炎症的常见机制与不同机制 动脉粥样硬化和肥胖。项目3将与项目1密切合作，测试新的小分子 在动脉粥样硬化和高脂饮食中，拮抗剂的β-淀粉样蛋白/DIAPH 1相互作用，并将密切合作， 项目2，以辨别共同与独特的机制，通过这些机制，ESTA/DIAPH 1有助于调节 NETRIN 1/UNC 5 B与高脂喂养中巨噬细胞的代谢功能障碍项目3将利用所有三个 该计划的核心在所有五年。