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

肥胖和糖尿病中胰岛相关巨噬细胞的功能和调节

基本信息

批准号：
8617401
负责人：
David L Morris
金额：
$ 10.9万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-05 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8617401
关键词：
Adipose tissue Apoptosis Autoimmune Process Award Beta Cell Biology Cell Line Cell physiology Cells Chemotaxis Chronic Coculture Techniques Commit Complement Data Defect Development Diabetes Mellitus Exhibits Flow Cytometry Foundations Functional disorder Future Gene Expression Profiling Glucose Glucose Intolerance Goals Housing Human Imaging Techniques Immune Immunophenotyping Indiana Infiltration Inflammation Inflammatory Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Interdisciplinary Study Islets of Langerhans Laboratories Lead Left Leukocytes Liver Macrophage Activation Mediating Mentorship Metabolic Metabolic Diseases Metabolic stress Metabolism Modeling Molecular Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pathogenesis Patients Pediatric Research Phenotype Physiology Population Regulation Research Research Personnel Research Training Risk Rodent Model Role Secretory Cell Staining method Stains System Testing Therapeutic Tissues Training Universities Work career career development cytokine design driving force endoplasmic reticulum stress impaired glucose tolerance improved innovation insulin secretion islet macrophage medical schools monocyte mouse model programs public health relevance research study response skills

项目摘要

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.

项目总结