Regulation of adipose tissue microvascular function by IL19

IL19对脂肪组织微血管功能的调节

基本信息

批准号：
10686973
负责人：
MICHAEL V AUTIERI
金额：
$ 55.48万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686973
关键词：
Ablation Acute Disease Adhesions Adhesives Adipocytes Adipose tissue Angiogenesis Pathway Ants Atherosclerosis Attenuated Biochemical Blood Glucose Blood Vessels Blood flow Cardiometabolic Disease Cardiovascular Diseases Cell Adhesion Molecules Cells Central obesity Chronic Disease Data Development Disease Disease Resistance Dyslipidemias Endothelial Cells Endothelium Epidemic Fasting Fatty acid glycerol esters Fibrosis Flow Cytometry Functional disorder Gene Expression Genetic Goals Health Heart Diseases Homeostasis Hypertension Hypoxia Impairment Incidence Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Insulin Resistance Interleukins Kidney Diseases Knock-out Laboratories Leucocytic infiltrate Leukocytes Lymphocyte Macrophage Metabolic Diseases Microcirculation Modeling Molecular Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Organism Overweight Pathway interactions Peripheral Persons Phenotype Physiological Population Publishing Regulation Reperfusion Injury Research Research Personnel Risk Risk Factors Role Techniques Technology Testing Therapeutic Transgenic Mice Vascular Endothelium Vascularization Visceral Visceral fat Weight Gain Work adipokines angiogenesis cardiometabolic risk cardiometabolism cytokine density diet-induced obesity experience feeding human tissue immune cell infiltrate improved insulin sensitivity insulin signaling interleukin-19 intravital microscopy knock-down monocyte mouse model neutrophil new therapeutic target novel novel therapeutic intervention obese person overexpression preservation prevent response subcutaneous trafficking

项目摘要

PROJECT SUMMARY / ABSTRACT The expanding visceral fat depots (VAT) of overweight and obese individuals experience dysfunction of the microcirculation with hypoxia and abnormal infiltration of leukocytes. Infiltrating immune cells and hypoxic adipocytes cause a systemic low-grade inflammation that is considered now causative of cardiovascular disease and metabolic disorders. Thus, the incidence of cardiometabolic disorders (hypertension, kidney disease, and insulin resistance) are becoming epidemic in the ever-growing overweight population of the USA. The precise mechanisms by which weight gain alters microvascular responses in VAT remain poorly understood. Furthermore, it has not been determined whether impaired microvascular responses of VAT are the initiating cause of cardiometabolic dysfunction and disease. We have identified a novel adipokine, IL-19, expressed in the adipose tissue of humans and mice. IL-19 is a newly discovered Th2-interleukin which has been recently studied for its protective vascular effects in the setting of large vessels disease, such as atherosclerosis and ischemia reperfusion injury. Preliminary data obtained in the Co-PI's laboratories strongly suggest that IL-19 regulate the homeostasis of adipose tissue microcirculation in diet-induced obesity. Accordingly, the overarching hypothesis of this dual-investigator application is that IL-19 is a unique interleukin that maintains cardiometabolic homeostasis by controlling angiogenesis and inflammatory responses in VAT depots. The long-term goals of this project are: 1) to understand the mechanisms through which IL-19 regulates vascularity and inflammation in VAT; and 2) to mechanistically correlate these microvascular actions of IL-19 to whole-body insulin signaling. Toward these goals, we will utilize knockout and transgenic mouse technology along with physiological, cellular, molecular, and biochemical techniques. We anticipate that the results of this work will advance our understanding of the integrated mechanisms that initiate and maintain VAT dysfunction and related cardiometabolic disorders in the overweight/obese organism.

项目概要/摘要超重和肥胖个体的内脏脂肪库（VAT）不断扩大，导致内脏脂肪库功能障碍。微循环缺氧，白细胞浸润异常。浸润免疫细胞和缺氧脂肪细胞引起全身性低度炎症，目前被认为是心血管疾病的原因和代谢紊乱。因此，心脏代谢疾病（高血压、肾脏疾病和胰岛素抵抗）在美国不断增长的超重人群中正变得流行。精确的体重增加改变增值税微血管反应的机制仍知之甚少。此外，尚未确定 VAT 微血管反应受损是否是引发心脏代谢功能障碍和疾病的原因。我们已经鉴定出一种新型脂肪因子 IL-19，其表达于人类和小鼠的脂肪组织。 IL-19是一种新发现的Th2-白细胞介素，最近被研究了其在大血管疾病（例如动脉粥样硬化和）中的保护性血管作用缺血再灌注损伤。 Co-PI 实验室获得的初步数据强烈表明 IL-19 调节饮食引起的肥胖中脂肪组织微循环的稳态。据此，该双重研究者应用的总体假设是 IL-19 是一种独特的白细胞介素通过控制血管生成和炎症来维持心脏代谢稳态增值税仓库的回复。该项目的长期目标是：1）了解机制 IL-19 通过其调节 VAT 中的血管分布和炎症； 2）机械地将这些关联起来 IL-19 对全身胰岛素信号传导的微血管作用。为了实现这些目标，我们将利用淘汰赛和转基因小鼠技术以及生理、细胞、分子和生化技术。我们预计这项工作的结果将增进我们对综合机制的理解超重/肥胖者引发并维持 VAT 功能障碍和相关心脏代谢紊乱生物。