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.

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