Macrophage ERK Signaling and Its Application in Modulating Skeletal Muscle Insulin Resistance

项目摘要/摘要 胰岛素抵抗是2型糖尿病的先兆和致病因素，现在人们认为 慢性炎症是肥胖引起的胰岛素抵抗的根源。最近的研究表明， 小鼠和人的骨骼肌在高脂肪喂养时巨噬细胞数量增加 肥胖。然而，巨噬细胞聚集和胰岛素抵抗的分子机制， 骨骼肌还不为人所知。一种可能的联系是Toll样受体4(TLR4)，一种膜受体，它可以 通过激活细胞外等炎症介质，在先天免疫系统中发挥重要作用 信号调节蛋白1和2(ERK1和ERK2)。TLR4信号激活后的正向调节因子， 尤其是内体转运系统，仍然不清楚，这些可能是发展的关键。 胰岛素抵抗。假设ERK1和ERK2正向调节TLR4介导的炎症 抑制ERK信号转导将保护胰岛素抵抗。在追求的过程中 在总体项目目标方面，将解决以下具体目标。目标1：表征ERK1的作用 和ERK2在调节TLR4内吞作用和信号转导中的作用。使用siRNA，ERK1和ERK2亚型将是 在骨髓来源的巨噬细胞中敲除以确定调节TLR4的分子机制 内吞作用。目的2：探讨抑制巨噬细胞ERK信号转导在保护巨噬细胞中的作用 抗胰岛素抵抗，调节骨骼肌巨噬细胞的浸润。胰岛素夹 将进行研究，以检查巨噬细胞中ERK1和ERK2的缺失是否会导致改善 胰岛素敏感性及其对高脂饮食诱导的骨骼肌炎症和胰岛素的保护作用 小鼠模型中的抵抗力。巨噬细胞ERK1和ERK1表型的研究进展 ERK2有助于解开和理解ERK1和ERK2亚型的具体功能。

PROJECT SUMMARY/ABSTRACT Insulin resistance precedes and contributes to the development of type 2 diabetes, and it is now believed that chronic inflammation is the source of obesity-induced insulin resistance. Recent studies demonstrate that mouse and human skeletal muscle have an increased macrophage population upon high fat feeding and obesity. However, the molecular mechanisms linking macrophage accumulation in, and insulin resistance of, the skeletal muscle are not known. One possible link is Toll-like receptor 4 (TLR4), a membrane receptor that plays an important role in the innate immune system by activating inflammatory mediators such as extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). The positive regulators of TLR4 signaling after activation, especially the endosomal transport system, remain unclear, and these may be critical in the development of insulin resistance. The hypothesis is that ERK1 and ERK2 positively regulate TLR4-mediated inflammatory responses and that inhibition of ERK signaling will protect against insulin resistance. In the process of pursuing the overall project goal, the following specific aims will be addressed. Aim 1: To characterize the role of ERK1 and ERK2 in regulating TLR4 endocytosis and signaling. Using siRNA, ERK1 and ERK2 isoforms will be knocked down in bone marrow derived macrophages to determine the molecular mechanisms regulating TLR4 endocytosis. Aim 2: To assess the contributions of inhibiting ERK signaling in macrophages to the protection against insulin resistance, and to the regulation of skeletal muscle macrophage infiltration. Insulin clamp studies will be performed to examine whether ERK1 and ERK2 deficiencies in macrophages result in improved insulin sensitivity and protection against high fat diet-induced skeletal muscle inflammation and insulin resistance in a mouse model. The proposed studies in characterizing the phenotype of macrophage ERK1 and ERK2 will contribute to the unraveling and understanding of the specific functions of ERK1 and ERK2 isoforms.