Promotion of beta cell proliferation by epigenetically reprogrammed macrophages

所有类型的糖尿病都会出现β细胞质量和功能的缺陷。持续的胰岛炎症要么破坏β细胞，要么损害其功能，从而阻碍了改进β细胞替代疗法的努力。我们的长期目标是开发新的方法，既能扩大贝塔细胞，同时又能保护贝塔细胞免受炎性侮辱。我们集中研究了胰腺巨噬细胞，以了解它们在调节胰岛炎症和β细胞生物学中的作用。在这项提案中，我们将探索一种新的机制来扩大β细胞。我们的初步研究发现，在1型糖尿病动物模型中，针对BET蛋白溴域的表观遗传调节可促进体内β细胞的增殖。我们的数据有力地表明，胰岛巨噬细胞在这一过程中发挥了关键作用。这些巨噬细胞表现出PPAR-γ途径的激活升高，同时也具有免疫抑制作用。基于这些发现，我们认为，在免疫抑制的胰岛环境中，BET蛋白溴域的调节对胰岛巨噬细胞进行重新编程，以促进β细胞的增殖。我们将使用1型糖尿病的动物模型以及人类胰岛培养来严格评估这一在体外和体内扩大β细胞的新策略。这项建议的总体目标是深入了解这一新的表观遗传修饰策略，在“保护性”的胰岛微环境中扩大功能β细胞。我们将在三个具体目标的框架内实现我们的目标。目的1将专门探讨PPAR-伽马途径在巨噬细胞中的激活对这些细胞促进β细胞增殖的作用。在目标2中，我们将确定哪些因素参与巨噬细胞介导的β细胞增殖，重点是PDGF信号转导。在目标3中，我们将确定巨噬细胞介导的免疫抑制是否是在自身免疫条件下促进β细胞功能恢复的机制。这些目标的成功实现将极大地促进我们对巨噬细胞在β细胞生物学中的新角色的理解。这项研究将为扩大糖尿病治疗的功能β细胞铺平新的道路。

Deficit of beta cell mass and function occurs in all types of diabetes. The efforts to improve beta cell replacement therapy are compromised by persistent islet inflammation that either destructs beta cells or impairs their function. Our long-term goal is to develop novel approaches that can expand beta cells, while simultaneously protect beta cells from inflammatory insults. We have concentrated on pancreatic macrophages to understand their role in regulating islet inflammation and beta cell biology. In this proposal, we will explore a new mechanism to expand beta cells. Our preliminary studies have found that an epigenetic modulation targeting BET protein bromodomain enhances beta cell proliferation in vivo in animal models of type 1 diabetes. Our data strongly suggest that islet macrophages play a critical role in this process. These macrophages exhibit an elevated activation of PPAR-gamma pathway and also are immunosuppressive. Based on these findings, we propose that modulation of BET protein bromodomain reprograms islet macrophages to promote beta cell proliferation in an immunosuppressive islet environment. We will use animal models of type 1 diabetes, as well as human islet cultures to rigorously assess this novel strategy to expand beta cells in vitro and in vivo. The overall objective of this proposal is to gain an in-depth mechanistic view of this novel epigenetic modification strategy in expanding functional beta cells in a “protective” islet microenvironment. We will address our goal in the framework of three specific aims. Aim 1 will specifically focus on exploring the role of PPAR-gamma pathway activation in macrophages for these cells to promote beta cell proliferation. In Aim 2, we will determine what factors are involved in macrophage-mediated beta cell proliferation, with a focus on PDGF signaling. In Aim 3, we will determine whether macrophage-mediated immunosuppression is a mechanism to promote beta cell functional recovery under autoimmune conditions. Successful completion of these aims will significantly advance our understanding of the novel roles of macrophages in beta cell biology. This study will pave a new way to expand functional beta cells for diabetes treatment.