Promotion of beta cell proliferation by epigenetically reprogrammed macrophages

所有类型的糖尿病都存在β细胞质量和功能缺陷。改善β细胞替代疗法的努力受到持续性胰岛炎症的损害，这种炎症破坏β细胞或损害其功能。我们的长期目标是开发能够扩增β细胞的新方法，同时保护β细胞免受炎症损伤。我们集中研究胰腺巨噬细胞，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。我们的初步研究已经发现，靶向BET蛋白溴结构域的表观遗传调节在1型糖尿病动物模型中增强体内β细胞增殖。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升高的PPAR-gamma途径活化，并且也具有免疫抑制性。基于这些发现，我们提出BET蛋白布罗莫结构域的调节重新编程胰岛巨噬细胞以促进免疫抑制胰岛环境中的β细胞增殖。我们将使用1型糖尿病的动物模型以及人类胰岛培养物来严格评估这种在体外和体内扩增β细胞的新策略。该提案的总体目标是获得这种新型表观遗传修饰策略在“保护性”胰岛微环境中扩增功能性β细胞的深入机制观点。我们将在三个具体目标的框架内实现我们的目标。目的1将特别关注于探索巨噬细胞中的PPAR-gamma通路活化对这些细胞促进β细胞增殖的作用。在目标2中，我们将确定哪些因子参与巨噬细胞介导的β细胞增殖，重点是PDGF信号传导。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。这些目标的成功完成将大大推进我们对巨噬细胞在β细胞生物学中的新作用的理解。这项研究将为扩大功能性β细胞用于糖尿病治疗铺平新的道路。

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.