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

项目摘要 在肥胖过程中，巨噬细胞在VAT和其他代谢器官（肝脏、骨骼肌、骨骼肌）中的积累增加， 肌肉）传播慢性炎症，这与全身性胰岛素抵抗有关， 2型糖尿病及其相关的并发症如动脉粥样硬化的发展。而 调节巨噬细胞募集的机制已经得到了很好的研究， 对代谢组织中炎症的持久性和不能解决的理解很少。识别 机制有助于非解决巨噬细胞炎症和关键途径， 干预是本申请的关键目标。新出现的数据表明，神经元的指导线索通常 在发育过程中表达，如netrin-1，在中枢神经系统外具有额外的作用， 诱导和抑制细胞迁移。我们的建议调查的概念，netrin-1表达 通过脂肪组织巨噬细胞和调节免疫细胞的运输，生存和积累肥胖 VAT，从而导致代谢功能障碍和胰岛素抵抗。我们将使用新的小鼠模型， netrin-1及其受体Unc 5 b的组织特异性或条件性缺失/功能获得，以确定这是如何发生的。 引导信号/受体对改变巨噬细胞移入和移出VAT、巨噬细胞存活和巨噬细胞增殖。 炎症极化。此外，使用纳米颗粒技术，我们将测试是否靶向netrin-1和 在已确定的肥胖症中，unc 5 b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积聚的信号和netrin-1的潜力， 其受体作为肥胖症和2型糖尿病以及潜在的其他慢性炎症的治疗靶点， 紊乱

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.