Macrophage Trafficking, Inflammation & Metabolism in Adipose Tissue in High Fat Feeding: Role of Guidance Cue Molecules

巨噬细胞贩运、炎症

基本信息

批准号：
9209591
负责人：
KATHRYN J MOORE
金额：
$ 49.16万
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/9209591
关键词：
Adipose tissue Advanced Glycosylation End Products Apoptosis Arterial Fatty Streak Atherosclerosis Biological Assay Bone Marrow Bone Marrow Transplantation CCL19 gene Cell Migration Inhibition function Cells Central obesity Chronic Comorbidity Cues Data Development Diabetes Mellitus Disease Emigrations Failure Fatty acid glycerol esters Functional disorder Gene Targeting Genetic Transcription Glean Glucose Glycolysis Hematopoietic High Fat Diet Human Hyperglycemia Hypoxia Hypoxia Inducible Factor ITGAM gene ITGAX gene Immune Impairment Inflammation Inflammatory Insulin Resistance Interleukin-1 beta Intervention Kinetics Knockout Mice Ligands Link Liver Locomotion Mediating Messenger RNA Metabolic Metabolism Mus Myelopoiesis NTN1 gene Neuraxis Neuroimmune Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obese Mice Obesity Organ Pathway interactions Pentosephosphate Pathway Process Recruitment Activity Regulation Reporting Resistance development Resolution Role Signal Pathway Signal Transduction Site Skeletal Muscle Source Technology Testing Thinness Tissue Model Tissue Transplantation Tissues Visceral Work aerobic glycolysis base chemokine cytokine feeding gain of function in vitro Assay in vivo inhibitor/antagonist insight macrophage metabolic profile metabolomics migration monocyte mouse model nanomedicine nanoparticle neuronal guidance novel receptor receptor for advanced glycation endproducts screening therapeutic target trafficking transcription factor transcriptome sequencing

项目摘要

Project 2: Summary During obesity, the increased accumulation of macrophages in VAT and other metabolic organs (liver, skeletal muscle) propagates chronic inflammation, which is associated with systemic insulin resistance, the development of type 2 diabetes, and its associated co-morbidities such as atherosclerosis. While the mechanisms regulating macrophage recruitment have been well studied, the signals directing macrophage persistence and failure to resolve inflammation in metabolic tissues are poorly understood. Identifying the mechanisms contributing to non-resolving macrophage inflammation and crucial pathways amenable for intervention is a key objective of this application. Emerging data suggest that neuronal guidance cues typically expressed during development, such as netrin-1, have additional roles outside the central nervous system in the induction and inhibition of cell migration. Our proposal investigates the concept that netrin-1 is expressed by adipose tissue macrophages and regulates immune cell trafficking, survival and accumulation in obese VAT, thereby leading to metabolic dysfunction and insulin resistance. We will use novel mouse models of tissue-specific or conditional deletion/gain-of-function of netrin-1 and its receptor Unc5b to determine how this guidance cue/receptor pair alters macrophage migration into and out of VAT, macrophage survival and inflammatory polarization. In addition, using nanoparticle technology, we will test how targeting netrin-1 and Unc5b alters metabolic inflammation and dysfunction. Furthermore, we will work with other projects to determine the role of factors that accumulate in hyperglycemia and insulin resistance in the induction of netrin- 1 in macrophages from obese VAT and atherosclerotic plaques in order to glean common and tissue-specific mechanisms promoting macrophage dysfunction. These studies will provide insight into the signals that promote macrophage accumulation during obesity and the potential of netrin-1 and its receptor as therapeutic targets in obesity and type 2 diabetes, and potentially other chronic inflammatory disorders.

项目2：总结肥胖期间，VAT 和其他代谢器官（肝脏、骨骼）中巨噬细胞的积累增加肌肉）传播慢性炎症，这与全身胰岛素抵抗有关， 2 型糖尿病的发展及其相关并发症，如动脉粥样硬化。虽然调节巨噬细胞募集的机制已得到充分研究，指导巨噬细胞的信号对于代谢组织中炎症的持续存在和无法解决，人们知之甚少。识别导致无法解决巨噬细胞炎症的机制和适合的关键途径干预是该应用程序的一个主要目标。新出现的数据表明，神经元引导信号通常在发育过程中表达的蛋白，例如 netrin-1，在中枢神经系统之外具有其他作用细胞迁移的诱导和抑制。我们的提案研究了 netrin-1 表达的概念由脂肪组织巨噬细胞调节肥胖者的免疫细胞运输、存活和积累 VAT，从而导致代谢功能障碍和胰岛素抵抗。我们将使用新颖的小鼠模型组织特异性或条件性删除/获得 netrin-1 及其受体 Unc5b 的功能，以确定如何引导信号/受体对改变巨噬细胞进出 VAT 的迁移、巨噬细胞的存活和炎症极化。此外，利用纳米颗粒技术，我们将测试如何靶向 netrin-1 和 Unc5b 改变代谢炎症和功能障碍。此外，我们将与其他项目合作确定高血糖和胰岛素抵抗中积累的因素在诱导 netrin- 中的作用 1 来自肥胖 VAT 和动脉粥样硬化斑块的巨噬细胞，以便收集常见的和组织特异性的促进巨噬细胞功能障碍的机制。这些研究将深入了解以下信号：促进肥胖期间巨噬细胞的积累以及 Netrin-1 及其受体的治疗潜力目标是肥胖和 2 型糖尿病，以及潜在的其他慢性炎症性疾病。