RAGE/mDia1, Macrophage Trafficking and Inflammation in High Fat Feeding

RAGE/mDia1、高脂肪喂养中的巨噬细胞运输和炎症

基本信息

批准号：
9906204
负责人：
Ravichandran Ramasamy
金额：
$ 51.99万
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：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906204
关键词：
Address Adipocytes Adipose tissue Anti-Inflammatory Agents Biological Assay Bone Marrow Cardiovascular system Cell model Cells Coculture Techniques Complications of Diabetes Mellitus Conditioned Culture Media Cytoplasmic Tail Data Deletion Mutation Development Diabetes Mellitus Energy Metabolism Fat-Restricted Diet Fatty acid glycerol esters Functional disorder Gene Chips Gene Expression Genes Genetic Genetic Transcription Goals High Fat Diet Human Hypertrophy ITGAM gene ITGAX gene In Vitro Inflammation Inflammation Mediators Inflammatory Insulin Resistance Knockout Mice Laboratories Ligands Link Liver Locomotion LoxP-flanked allele Luciferases Mediating Messenger RNA Metabolic Metabolic dysfunction Metabolism Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Organ Overnutrition Pathway interactions Plasma Play Pre-Clinical Model Property Regulation Reporter Role Serum Response Factor Signal Pathway Signal Transduction Skeletal Muscle Testing Therapeutic Intervention Thinness Tissues Transcript Visceral Wild Type Mouse Work adiponectin base cardiovascular disorder risk cell type chromatin immunoprecipitation effective therapy experimental study feeding human subject macrophage monocyte mortality mouse Cre recombinase mutation assay new therapeutic target novel novel therapeutics programs promoter public health relevance receptor receptor binding receptor for advanced glycation endproducts receptor function reconstitution recruit small molecule trafficking transcription factor transcriptome translational study

项目摘要

DESCRIPTION (provided by applicant): The problems of obesity and insulin resistance have been linked to type 2 diabetes. Diabetes is on the rise; fully effective treatments are lacking. In the spectrum from obesity, insulin resistance, to diabetes, profound metabolic dysfunction is linked to increased risk for cardiovascular disease. Our goal is to uncover fundamental mechanisms by which macrophage inflammation impacts metabolic dysfunction in high fat feeding and obesity. Our preliminary data reveal that in high fat feeding in mice, ligands of the receptor for AGE (RAGE) are increased in key metabolic tissues even before the development of frank diabetes. Our data reveal that genetic deletion of RAGE results in significant protection against high fat feeding induced obesity and insulin resistance. Importantly, the accumulation, inflammatory polarization, and metabolic properties of adipose tissue macrophages are greatly reduced by deletion of RAGE. We will address the hypothesis that macrophage RAGE regulates obesity, adiposity and metabolic dysfunction in high fat feeding, both inherently and via 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 stasis; polarization; and metabolic regulation. Finally, we explore how the binding of the RAGE cytoplasmic domain to the formin, mDia1, which is required for RAGE signaling, contributes to macrophage dysfunction in high fat feeding. Translational studies relevant to human subjects will include examination of human adipose tissue macrophages in obesity and, in preclinical models, the testing of novel small molecule antagonists of RAGE signal transduction.

描述（由适用提供）：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。缺乏完全有效的治疗方法。在从肥胖，胰岛素抵抗到糖尿病的频谱，深刻的代谢功能障碍与心血管疾病的风险增加有关。我们的目标是揭示巨噬细胞炎症会影响高脂进食和肥胖症代谢功能障碍的基本机制。我们的初步数据表明，在小鼠的高脂肪喂养中，即使在弗兰克糖尿病的发展之前，关键代谢组织中的受体（愤怒）的配体也会增加。我们的数据表明，愤怒的遗传缺失可为高脂肪进食引起的肥胖症和胰岛素抵抗提供明显的保护。重要的是，通过rage的缺失，脂肪组织巨噬细胞的积累，炎症极化和代谢特性大大降低了。我们将解决以下假设：巨噬细胞的愤怒可以调节高脂进食的高脂肪喂养中的肥胖，肥胖和代谢功能障碍，无论是固有的还是通过与脂肪细胞交叉对话。我们的项目将探索巨噬细胞注入的四个关键特性，以发现高脂进食中的愤怒依赖机制：单核细胞募集；巨噬细胞保留和停滞；极化;和代谢调节。最后，我们探讨了愤怒的细胞质结构域与rage信号所必需的formin MDIA1的结合如何导致高脂肪进食的巨噬细胞功能障碍。与人类受试者相关的翻译研究将包括检查肥胖症中人类脂肪组织巨噬细胞的检查，以及在临床前模型中，对新型的rage信号转导的新型小分子拮抗剂的测试。