Function and Regulation of Islet-associated Macrophages in Obesity and Diabetes

项目摘要 申请者的职业目标是开发一个多学科研究计划，重点是定义如何 炎症有助于代谢性疾病的发展。过去十年的新兴数据 肥胖诱导的代谢性炎症是2型糖尿病发病的关键驱动力 糖尿病(T2 DM)。在脂肪组织、肝脏和肌肉中，人们普遍认为肥胖导致 活化的促炎巨噬细胞和其他白细胞的渐进性渗透 导致胰岛素抵抗和代谢功能障碍。目前，人们对是否和 胰岛相关巨噬细胞在胰岛炎症、糖耐量异常和β细胞中的作用 2型糖尿病患者的功能障碍。此外，胰岛相关巨噬细胞的表型、功能和调节 在代谢性炎症和T2 DM的发展过程中，还没有完全定义，在 我们对这种严重代谢性疾病的发病机制的理解。这一点的中心假设是 应用是肥胖诱导的代谢应激导致促炎巨噬细胞的积聚 在胰岛内，加剧了T2 DM患者的β细胞功能障碍。来检验这一假说并开始揭示 胰岛相关巨噬细胞在T2 DM进展中的作用，提出了三个具体的目标。目标1 将确定胰岛相关巨噬细胞的免疫表型和炎症特征 糖耐量异常和2型糖尿病小鼠模型的进展。目标2将定义测试版之间的相互作用 细胞内质网应激与胰岛相关巨噬细胞的募集和激活。目标3 将研究促炎巨噬细胞对肥胖和肥胖患者β细胞分泌功能的影响 T2 DM。研究计划中概述的各种实验方法将允许申请者扩大 他的糖尿病专业知识，通过开发新的熟练程度和补充技能集来评估Beta 小鼠模型、分离的胰岛和常用的β细胞系中的细胞功能。申请者将受益 在赫尔曼·B·威尔斯儿科研究中心基础糖尿病研究组接受培训 在印第安纳大学医学院，那里有五个实验室，致力于 了解导致各种形式糖尿病发生的分子机制。这 新的胰岛生物学培训将补充申请人以前的生理学、新陈代谢和 肥胖引起的炎症。一个由资深调查人员组成的多样化团队将监督申请人的职业生涯 在获奖期间，通过在智力上为他的研究培训做出贡献，提供 指导，并提供职业建议。

Project Summary The applicant's career goal is to develop a multidisciplinary research program focused on defining how inflammation contributes to the development of metabolic disease. Emerging data from the past decade has revealed that obesity-induced metabolic inflammation is a key driving force in the pathogenesis of Type 2 diabetes mellitus (T2DM). In the adipose tissue, liver, and muscle, it is well recognized that obesity leads to progressive infiltration of activated pro-inflammatory macrophages and other leukocytes that act in concert to induce insulin resistance and metabolic dysfunction. At present, relatively little is known about whether and how islet-associated macrophages contribute to islet inflammation, glucose intolerance, and beta cell dysfunction in T2DM. Furthermore, the phenotype, function, and regulation of islet-associated macrophages during the progression of metabolic inflammation and T2DM have yet to be fully defined, leaving critical gaps in our understanding of the pathogenesis of this serious metabolic disease. The central hypothesis of this application is that obesity-induced metabolic stress causes the accumulation of pro-inflammatory macrophages within the islet that exacerbate beta cell dysfunction in T2DM. To test this hypothesis and to begin to uncover the role of islet-associated macrophages in the progression of T2DM, three Specific Aims are proposed. Aim 1 will determine the immunophenotype and inflammatory profile of islet-associated macrophages during the progression of glucose intolerance and T2DM in mouse models. Aim 2 will define the interplay between beta cell endoplasmic reticulum (ER) stress and recruitment and activation of islet-associated macrophages. Aim 3 will investigate the effects of pro-inflammatory macrophages on beta cell secretory function in obesity and T2DM. The diverse experimental approaches outlined in the research plan will allow the applicant to broaden his diabetes expertise by developing new proficiencies and complementary skill sets in the assessment of beta cell function in mouse models, isolated islets, and commonly used beta cell lines. The applicant will benefit from training in the Basic Diabetes Research Group within the Herman B Wells Center for Pediatric Research at the Indiana University School of Medicine, which houses five laboratories that are committed to understanding the molecular mechanisms that lead to the development of all forms of diabetes mellitus. This new training in islet biology will complement the applicant's previous training in physiology, metabolism, and obesity-induced inflammation. A diverse team of established investigators will oversee the applicant's career development during the award period by contributing intellectually to his research training, providing mentorship, and offering career advice.