Promotion of beta cell proliferation by epigenetically reprogrammed macrophages

表观遗传重编程巨噬细胞促进 β 细胞增殖

基本信息

批准号：
10226833
负责人：
Maike Sander
金额：
$ 37.82万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226833
关键词：
Address Adult Affect Animal Model Antiinflammatory Effect Autoimmune Autoimmune Diseases Automobile Driving Beta Cell Bromodomain Cell Proliferation Cell physiology Cells Cellular biology Child Coculture Techniques Data Diabetes Mellitus Disease Environment Epigenetic Process Exhibits Glucose Goals Human Immunosuppression Impairment In Vitro Inbred NOD Mice Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Mediating Modeling Modification Molecular NF-kappa B Natural regeneration Outcome PDGFRB gene PPAR gamma Pancreas Pathway interactions Pharmacology Platelet-Derived Growth Factor Play Prevalence Prevention Process Production Proliferating Proteins Public Health Recovery of Function Regulation Reporting Role Severities Signal Transduction Techniques Testing Time base beta cell replacement betacell therapy cell replacement therapy diabetes mellitus therapy experimental study genetic manipulation improved in vivo inhibitor/antagonist insight insulin secretion islet loss of function macrophage novel novel strategies novel therapeutic intervention restoration success tissue regeneration transcription factor

项目摘要

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.

所有类型的糖尿病都会出现β细胞质量和功能缺陷，改善β细胞替代疗法的努力会受到持续性胰岛炎症的影响，这种炎症会破坏β细胞或损害其功能。扩大β细胞，同时保护β细胞免受炎症损伤。在本提案中，我们将探索一种扩大β细胞的新机制。已经发现针对 BET 蛋白溴结构域的表观遗传调节可增强 1 型糖尿病动物模型中 β 细胞的增殖，我们的数据强烈表明，胰岛巨噬细胞在此过程中发挥着关键作用。基于这些发现，我们提出，BET 蛋白溴结构域的调节可以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。 1 型糖尿病以及人类胰岛培养物，以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深入了解这种新的表观遗传修饰策略在扩增中的作用。 “保护性”胰岛微环境中的功能性 β 细胞将在三个具体目标的框架内实现我们的目标，目标 1 将特别关注探索巨噬细胞中 PPAR-γ 通路激活对促进 β 细胞增殖的作用。瞄准2，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。这些目标的完成将显着增进我们对巨噬细胞在β细胞生物学中的新作用的理解，这项研究将为扩展功能性β细胞用于糖尿病治疗铺平道路。