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

巨噬细胞贩运、炎症

基本信息

批准号：
9209593
负责人：
ANN MARIE SCHMIDT
金额：
$ 42.83万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
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/9209593
关键词：
Address Adipocytes Adipose tissue Adrenergic Agents Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Binding Biological Assay Bone Marrow Candidate Disease Gene Cardiovascular system Cells Coculture Techniques Conditioned Culture Media Cytoplasmic Tail Data Diabetes Mellitus Energy Metabolism Epidemic Fat-Restricted Diet Fatty Acids Fatty acid glycerol esters Functional disorder Gene Expression Genes Genetic Genetic Transcription Genus Hippocampus Glucose Goals High Fat Diet Human Hypertrophy ITGAX gene In Vitro Inflammation Inflammatory Insulin Resistance Laboratories Lead Ligands Link Lipids Lipolysis LoxP-flanked allele Mediating Messenger RNA Metabolic Metabolism Molecular Profiling Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oleates Palmitates Pathogenesis Property Proteins Publishing RNA analysis Recruitment Activity 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 response small molecule subcutaneous trafficking transcriptome sequencing transcriptomics

项目摘要

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.

肥胖和胰岛素抵抗问题与2型糖尿病有关。糖尿病的发病率正在上升