Insulin Signaling in Tissue Resident Macrophages

7.项目总结/摘要 胰岛素是一种关键的代谢激素和生长因子，以其在葡萄糖稳态中的作用而闻名。因为 在代谢疾病中，对胰岛素的反应经常失调， 代谢组织的实质细胞（脂肪细胞、骨骼肌细胞和肝细胞）已经被 广泛的特点。相比之下，胰岛素信号在其他细胞类型，如组织驻留细胞， 巨噬细胞，就不那么清楚了。然而，考虑到常驻巨噬细胞在组织功能中的关键作用， 和生理学，以及在代谢疾病的发病机制，重要的是要了解如何胰岛素 影响其行为和功能。在这个项目中，我们计划探索胰岛素，一个可靠的指标， 食物摄入，信号巨噬细胞，并影响他们的极化，根据不同的需要，在 进食或禁食状态。初步实验表明巨噬细胞中的胰岛素信号与 在代谢组织中。最引人注目的是，在体外， 用生理浓度的胰岛素刺激巨噬细胞， 受体的在第一个目标中，我们计划研究这种观察的机制基础，以及如何改变 在信号传导结构中，可以使巨噬细胞对胰岛素信号传导敏感，这是我们已经观察到的。 胰岛素信号在巨噬细胞中的作用已经在各种疾病过程的背景下进行了研究。 然而，胰岛素信号作用的清晰逻辑仍然难以捉摸。此外，许多研究 由于使用超生理浓度的胰岛素而混淆，这可能导致与 其它受体，如也由巨噬细胞表达的胰岛素样生长因子1受体，或其它 非特异性表面受体一些初步数据表明胰岛素可能对巨噬细胞有影响， 对白细胞介素4的交替激活。为了进一步确定胰岛素信号转导在 巨噬细胞与组织功能的关系，在第二个目标中，我计划评估胰岛素如何影响 M2极化和伤口愈合。

7. Project Summary / Abstract Insulin is a key metabolic hormone and growth factor best known for its role in glucose homeostasis. Because responses to insulin are frequently dysregulated in metabolic disease, the relevant signaling pathways in parenchymal cells of metabolic tissues (adipocytes, skeletal myocytes, and hepatocytes) have been extensively characterized. In contrast, insulin signaling in other cell types, such as tissue resident macrophages, is much less clear. However, given the pivotal role of resident macrophages in tissue function and physiology, as well as in the pathogenesis of metabolic disease, it is important to understand how insulin affects their behavior and function. In this project we plan to explore how insulin, a reliable indicator of food intake, signals to macrophages and affects their polarization according to different needs in the fed or fasted state. Preliminary experiments suggest insulin signaling in macrophages is different from that in metabolic tissues. Most strikingly, there is an apparent lack of downstream signaling upon in vitro stimulation of macrophages with physiological concentrations of insulin, despite robust expression of the receptor. In the first aim, we plan to study the mechanistic basis of this observation, and how changes in signaling architectures may sensitize macrophages to insulin signaling, which we have observed. The role of insulin signaling in macrophages has been studied in the context of various disease processes. However, a clear logic to the effects of insulin signaling remains elusive. Furthermore, many studies are confounded by the use of supraphysiological concentrations of insulin, which may cause cross reactivity with other receptors such as the insulin-like growth factor 1 receptor, also expressed by macrophages, or other nonspecific surface receptors. Some preliminary data suggest insulin may have an effect on macrophage alternative activation in response to interleukin 4. To further define the role of insulin signaling in macrophages in relation to tissue function, in the second aim I plan to assess how insulin may affect M2 polarization and wound healing.