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Macrophage Trafficking, Inflammation & Metabolism in Obesity: Role of Guidance Cue Molecules

Macrophage Trafficking, Inflammation & Metabolism in Obesity: Role of Guidance Cue Molecules
巨噬细胞贩运、炎症
批准号:
9196307
负责人:
KATHRYN J MOORE
金额:
$32.07万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-19 至 2017-04-30

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中文摘要
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英文摘要
Project 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 whether targeting netrin-1 and Unc5b in established obesity can reverse metabolic inflammation and 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.
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Pathology and Biochemistry Core
Netrin-1 in Metabolic and Inflammatory Crosstalk in Cardiometabolic Disease
Non-coding RNA regulation of cholesterol homeostasis and atherosclerosis
Non-coding RNA regulation of cholesterol homeostasis and atherosclerosis
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