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

项目摘要 在肥胖期间，巨噬细胞在VAT和其他代谢器官(肝脏、骨骼)中积累的增加 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的并存疾病，如动脉粥样硬化。而当 调节巨噬细胞募集的机制已经被很好地研究了，这些信号引导巨噬细胞 新陈代谢组织中的炎症持续和未能消退的情况还知之甚少。识别 非消解性巨噬细胞炎症的机制及其关键途径 干预是这一应用程序的一个关键目标。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，如netrin-1，在中枢神经系统之外还有额外的作用 细胞迁移的诱导和抑制。我们的提案调查了Netrin-1表达的概念 通过脂肪组织巨噬细胞调节肥胖者免疫细胞的运输、存活和积聚 增值税，从而导致代谢功能障碍和胰岛素抵抗。我们将使用新的鼠标模型 组织特异性或有条件地删除/获得netrin-1及其受体Unc5b的功能，以确定这是如何 引导信号/受体对改变巨噬细胞进入和离开增值税，巨噬细胞存活和 炎症性分化。此外，利用纳米颗粒技术，我们将测试靶向netrin-1和 肥胖患者中的Unc5b可以逆转代谢性炎症和功能障碍。这些研究将提供 深入了解肥胖期间促进巨噬细胞聚集的信号以及Netrin-1和Netrin-1的潜力 其受体作为肥胖和2型糖尿病以及潜在的其他慢性炎症性疾病的治疗靶点 精神错乱。

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.