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Environment, innate immunity and type 1 diabetes

环境、先天免疫和 1 型糖尿病

基本信息

批准号：
8478090
负责人：
Li Wen
金额：
$ 33.16万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8478090
关键词：
Affect Animals Antigen-Presenting Cells Attenuated Autoimmune Diabetes Autoimmune Diseases Autoimmunity Bacteria Beta Cell Breeding Cell Shape Chronic Clinical Data Dendritic Cells Development Diabetes Mellitus Dietary Factors Disease Environment Environmental Risk Factor Epithelial Cells Experimental Models Exposure to Genetic Germ-Free Housing Human Immune Immune Tolerance Immune response Immune system Inbred NOD Mice Incidence Individual Inflammatory Insulin-Dependent Diabetes Mellitus Intestines Investigation Lead Life Link Mediating Modeling Mouse Strains Mucosal Immunity Mucous Membrane Mus Natural Immunity Nature Non obese Organism Pancreas Pattern Permeability Play Prevention strategy Regulation Regulatory T-Lymphocyte Reporting Research Resistance Role Shapes Signaling Molecule Specific Pathogen Frees Surface Susceptibility Gene System T-Lymphocyte Testing Time Toll-like receptors Toxin Transgenic Organisms Translating Virus Wild Type Mouse adaptive immunity cell type commensal microbes diabetic gastrointestinal epithelium genome wide association study germ free condition high risk insight islet lymph nodes nutritional guideline pathogen programs public health relevance

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) occurs as a result of interplay of genetic and environmental factors. Recent genome-wide scans have given much information about the genes that predispose to disease but much less is known of the environmental interaction that causes susceptible individuals to develop T1D. We have recently generated evidence in the Non Obese Diabetic mouse (NOD) that the innate immune response, mediated through the innate immune adaptor MyD88, may plays a critical role influencing development of disease. We showed that mice deficient in MyD88 did not develop diabetes when bred in a Specific Pathogen free (SPF) environment. There was evidence of increased T regulatory cell activity in the pancreatic lymph nodes of these MyD88-/- mice. However, when the mice were rederived into a germ free facility, they developed the same high incidence of diabetes as wild type mice in the same conditions. Re-introduction of a restricted set of gut commensal bacteria (Altered Schaedler's flora) again reduced diabetes. This indicated that the internal commensal environment was influencing the development of disease. Understanding how commensals interact with the internal mucosa to shape our immune system, both innate and adaptive immunity, is critical to explain how chronic inflammatory diseases, including autoimmune diseases, develop. In this project we will 1) investigate the critical time windows for the exposure to intestinal flora in influencing whether disease develops and the associated immune developmental changes; 2) test the importance of expression of MyD88 in intestinal dendritic cells as the most potent antigen presenting cells and the critical link between innate and adaptive immune responses; 3) investigate the importance of expression of MyD88 in intestinal epithelial cells in responding to and sensing the commensal flora. Our studies will enhance our understanding of how the internal environment may shape the immune response and lead to autoimmunity in a genetically susceptible autoimmune diabetes model. In turn, this may help to direct investigation in people genetically susceptible to diabetes and aid development of new strategies for prevention and treatment of type 1 diabetes.

描述（由申请人提供）：1型糖尿病（T1 D）是遗传和环境因素相互作用的结果。最近的全基因组扫描已经提供了许多关于易患疾病的基因的信息，但对导致易感个体发展为T1 D的环境相互作用知之甚少。我们最近在非肥胖糖尿病小鼠（NOD）中获得的证据表明，通过先天免疫适配器MyD 88介导的先天免疫应答可能对疾病的发展起着关键作用。我们发现，MyD 88缺陷的小鼠在无特定病原体（SPF）环境中繁殖时不会发生糖尿病。在这些MyD 88-/-小鼠的胰腺淋巴结中存在增加的T调节细胞活性的证据。然而，当小鼠被重新衍生到无菌设施中时，它们在相同条件下与野生型小鼠一样患上了糖尿病。重新引入一组有限的肠道细菌（改变的Schaedler植物群）再次减少了糖尿病。这表明，内环境影响疾病的发展。了解肠道如何与内部粘膜相互作用以塑造我们的免疫系统，包括先天性和适应性免疫，对于解释慢性炎症性疾病（包括自身免疫性疾病）如何发展至关重要。本课题将1）研究肠道植物群暴露对疾病发生和相关免疫发育变化的影响的关键时间窗; 2）检测MyD 88在肠道树突状细胞中表达的重要性，MyD 88是最有效的抗原呈递细胞，也是先天性和获得性免疫应答之间的关键联系;（3）探讨MyD 88在肠上皮细胞中的表达在响应和感受肠道植物群中的作用。我们的研究将增强我们对内部环境如何塑造免疫反应并导致遗传易感的自身免疫性糖尿病模型中的自身免疫性的理解。反过来，这可能有助于直接调查遗传上易患糖尿病的人群，并有助于制定预防和治疗1型糖尿病的新策略。