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

描述(由申请者提供)：申请者的职业目标是开发一个多学科的研究计划，重点是确定炎症如何促进代谢性疾病的发展。过去十年的新数据显示，肥胖引起的代谢性炎症是2型糖尿病(T2 DM)发病的关键驱动力。在脂肪组织、肝脏和肌肉中，众所周知，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，这些细胞协同作用导致胰岛素抵抗和代谢功能障碍。目前，关于胰岛相关巨噬细胞是否以及如何在T2 DM的胰岛炎症、糖耐量减低和β细胞功能障碍中起作用的研究相对较少。此外，胰岛相关巨噬细胞在代谢性炎症和T2 DM进展过程中的表型、功能和调节尚未完全确定，这给我们对这一严重代谢性疾病的发病机制留下了严重的空白。这一应用的中心假设是肥胖诱导的代谢应激导致促炎症巨噬细胞在胰岛内聚集，从而加剧T2 DM患者的β细胞功能障碍。为了验证这一假设，并开始揭示胰岛相关巨噬细胞在T2 DM进展中的作用，提出了三个特定的目标。目的1研究糖耐量低减和2型糖尿病小鼠模型中胰岛相关巨噬细胞的免疫表型和炎症特征。目的2将确定β细胞内质网(ER)应激与胰岛相关巨噬细胞的募集和激活之间的相互作用。目的探讨促炎巨噬细胞对肥胖和2型糖尿病患者胰岛β细胞分泌功能的影响。研究计划中概述的多样化实验方法将允许申请者通过开发新的熟练程度和补充技能集来扩大他的糖尿病专业知识，以评估小鼠模型、分离的胰岛和常用的β细胞系的β细胞功能。申请者将受益于印第安纳大学医学院赫尔曼·B·威尔斯儿科研究中心基础糖尿病研究小组的培训，该中心有五个实验室，致力于了解导致所有形式糖尿病发展的分子机制。这项新的胰岛生物学培训将补充申请人以前在生理学、新陈代谢和肥胖引起的炎症方面的培训。一个由不同的资深调查人员组成的团队将在颁奖期间监督申请人的职业发展，为他的研究培训做出智力贡献，提供指导，并提供职业建议。

DESCRIPTION (provided by applicant): 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.