Insulin Signaling in Tissue Resident Macrophages

7.项目摘要/摘要 胰岛素是一种关键的代谢激素和生长因子，因其在血糖稳态中的作用而闻名。因为 在代谢性疾病中，对胰岛素的反应经常被失调，相关的信号通路在 代谢组织(脂肪细胞、骨骼肌细胞和肝细胞)的实质细胞 具有广泛的特征。相比之下，其他类型细胞中的胰岛素信号，如组织驻留 巨噬细胞，就不那么清楚了。然而，鉴于驻留巨噬细胞在组织功能中的关键作用 以及在代谢性疾病的发病机制中，了解胰岛素是如何 影响他们的行为和功能。在这个项目中，我们计划探索胰岛素，一种可靠的 食物的摄取，向巨噬细胞发出信号，并根据不同的需要影响它们的极化 喂饱的或禁食的状态。初步实验表明，巨噬细胞中的胰岛素信号与此不同 在新陈代谢组织中。最引人注目的是，在体外，明显缺乏下游信号。 用生理浓度的胰岛素刺激巨噬细胞，尽管 受体。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 In信号结构可能使巨噬细胞对胰岛素信号敏感，我们已经观察到了这一点。 胰岛素信号在巨噬细胞中的作用已经在不同的疾病过程中进行了研究。 然而，对于胰岛素信号的影响，一个清晰的逻辑仍然难以捉摸。此外，许多研究都是 因使用超生理学浓度的胰岛素而混淆，这可能会导致与 其他受体，如胰岛素样生长因子1受体，也由巨噬细胞表达，或其他 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 对白介素4的替代激活反应。为了进一步确定胰岛素信号在 巨噬细胞与组织功能的关系，在第二个目标中，我计划评估胰岛素可能如何影响 M2极化与伤口愈合。

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.