Major Histocompatibility Complex Shapes Early Life Microbial Events to prevent Autoimmunity

主要组织相容性复合体塑造生命早期微生物事件以预防自身免疫

• 批准号: 10154318
• 负责人: Jamal Green
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10154318
• 关键词: Affect; Age; Alleles; Animal Model; Antibiotic Therapy; Antibodies; Antibody Response; Antigens; Aptitude; Autoimmune Diseases; Autoimmunity; Bacteria; Binding; CD4 Positive T Lymphocytes; Cell Compartmentation; Childhood; Communities; Data; Development; Diabetes Mellitus; Disease; Disease model; Environmental Risk Factor; Event; Experimental Designs; Fellowship; Flow Cytometry; Genetic; Genetic Models; Germ-Free; Gnotobiotic; Goals; Haplotypes; Human; Immune; Immune system; Immunoglobulin A; Immunology; Immunophenotyping; Inbred NOD Mice; Incidence; Insulin-Dependent Diabetes Mellitus; Intestines; Investigation; Laboratories; Lead; Life; MHC Class II Genes; Major Histocompatibility Complex; Measures; Medical; Mentorship; Metagenomics; Microbe; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Non obese; Pathway interactions; Patients; Pennsylvania; Peripheral; Physicians; Population; Preventive measure; Preventive therapy; Publishing; Regulatory T-Lymphocyte; Resources; Risk; Scientist; Shapes; Structure; System; Systems Development; T-Lymphocyte; Technical Expertise; Techniques; Training Programs; Transgenic Organisms; Universities; Weaning; base; career development; clinically relevant; commensal bacteria; diabetes mellitus therapy; diabetic; experimental analysis; experimental study; genetic association; germ free condition; gut colonization; gut microbiome; gut microbiota; high risk; immunoregulation; improved; innovation; insight; insulitis; metagenomic sequencing; microbial; microbial colonization; microbiome; microbiota; microorganism antigen; microorganism interaction; mortality; mouse model; novel; prevent; programs; response; restoration; skills

Project Summary: Type 1 diabetes (T1D) is a debilitating autoimmune disease that affects millions. Unfortunately, the incidence of T1D is rising. The strongest genetic factor in T1D is the MHC class II locus. Some MHC haplotypes are associated with higher risk to T1D, while others provide dominant protection. Yet, the mechanism remains unknown. Recent studies suggest that environmental factors, such as the microbiome, also contribute to the increasing incidence of T1D. While both genetic and environmental factors contribute to the risk of developing T1D, little is known of how MHC II genetic factors interact with microbial factors. The non-obese diabetic (NOD) murine model recapitulates many features of T1D in humans including the dominant protection associated with the MHC class II locus. NOD mice spontaneously develop T1D, but autoimmunity can be prevented by transgenic expression of the MHCII E allele (Eα16/NOD mice). Recent published studies and new preliminary data from our laboratory suggests that microbiota are critical for this protection. The goal of this proposal is to identify immunomodulatory bacteria and immune system pathways that can be used to develop preventative T1D therapies for genetically at-risk patients To rigorously study the early-life microbiota, we developed a novel consortium of 9 culturable bacteria (which we call PedsCom) that represent over 90% of the bacteria in pre-weaning diabetes-protected Eα16/NOD mice. To investigate immunomodulatory mechanisms of specific bacteria, we are applying gnotobiotic techniques using the PedsCom consortium and genetic models of disease utilizing Eα16/NOD mice. The experiments outlined in this proposal will elucidate the mechanisms by which MHC II molecules interact with intestinal microbes to prevent T1D. In Aim 1, I will investigate if MHC II E expression impacts early-life events to shape microbial colonization by comparing colonization dynamics and humoral responses to commensal bacteria in the NOD and Eα16/NOD mice colonized by the PedsCom consortia. In Aim 2, I will determine if the PedsCom consortia of early-life microbes are sufficient to prevent T1D and whether peripheral regulatory T cells prevent T1D in Eα16/NOD mice by studying PedsCom, specific pathogen free (SPF), and germ-free colonized mice. During this fellowship, these investigations will expand my technical skills, improve my aptitude for experimental design and analysis, and enhance my ability to communicate findings to the scientific community. I will complete this fellowship at the University of Pennsylvania, which offers programs, courses, and structured mentorships that will aid my career development. In addition, I will take advantage of opportunities offered by the Immunology Graduate Group and the Medical Scientist Training Program to enhance my abilities as an educator and a clinician. With the resources available to me, I will explore the fundamental and clinically relevant questions in this proposal to gain the skills necessary to become a successful physician scientist.

项目摘要： 1型糖尿病（T1D）是一种影响数百万的自身免疫性疾病。不幸的是， T1D的发病率正在上升。 T1D中的强遗传因子是MHC II类基因座。一些MHC单倍型 与T1D的风险更高有关，而其他人则提供了主导保护。然而，机制仍然存在 未知。最近的研究表明，环境因素（例如微生物组）也有助于 T1D的发生率增加。遗传和环境因素均有助于发展的风险 T1D，鲜为人知的MHC II遗传因子如何与微生物因子相互作用。非肥胖糖尿病（点头） 鼠模型概括了人类中T1D的许多特征，包括与 MHC II类基因座。 NOD小鼠赞助开发T1D，但可以通过转基因预防自身免疫性 MHCII E等位基因（Eα16/NOD小鼠）的表达。最近发表的研究和新的初步数据 我们的实验室表明，微生物群对于这种保护至关重要。该提议的目的是确定 可用于开发预防性T1D的免疫调节细菌和免疫系统途径 一般风险患者的疗法 为了严格研究早期生命的菌群，我们开发了一个由9种可培养细菌组成的新型财团 （我们称之为PEDSCOM），代表受预性糖尿病保护Eα16/NOD的细菌的90％以上 老鼠。为了研究特定细菌的免疫调节机制，我们正在应用gnotobiotic技术 使用疾病利用Eα16/NOD小鼠的PEDSCOM联盟和遗传模型。实验 该提案中概述将阐明MHC II分子与肠相互作用的机制 微生物预防T1D。在AIM 1中，我将调查MHC II E表达是否会影响早期生命事件的形状 微生物定殖通过比较对共生细菌的定殖动力学和体液反应 由Pedscom联盟定殖的点头和Eα16/NOD小鼠。在AIM 2中，我将确定PEDSCOM是否 早期微生物的财团足以预防T1D，以及外围调节性T细胞是否防止 通过研究PEDSCOM，特定病原体（SPF）和无细菌定植小鼠，Eα16/NOD小鼠中的T1D。 在此奖学金期间，这些调查将扩大我的技术技能，提高我的才能 实验设计和分析，并增强了我向科学界传达发现的能力。 我将在宾夕法尼亚大学完成这项奖学金，该奖学金提供课程，课程和结构化 将有助于我的职业发展的遗产。此外，我将利用提供的机会 免疫学研究生组和医学科学家培训计划，以增强我的能力 教育工作者和临床。有了我的资源，我将探索基本和临床相关的 该提案中的问题是获得成功的物理科学家所需的技能。