Dissecting the interplay of MHC/HLA loci, the microbiota and autoimmune diabetes

剖析 MHC/HLA 位点、微生物群和自身免疫性糖尿病的相互作用

• 批准号: 8805092
• 负责人: Michael A Silverman
• 金额: $ 17.96万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-06 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805092
• 关键词: Address; Affect; Alleles; Antibiotics; Antigen-Presenting Cells; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Bacteria; CD4 Positive T Lymphocytes; Cells; Collaborations; Data; Data Set; Development; Development Plans; Diabetes Mellitus; Diabetic mother; Disease; Environment; European; Exposure to; Feces; Female; Flow Cytometry; Gene Expression; Genetic; Genomic DNA; Germ-Free; Gnotobiotic; Goals; HLA Antigens; Histocompatibility Antigens Class II; Human; Immune; Immune system; Immunologist; Inbred NOD Mice; Infectious Disease Immunology; Institutes; Insulin-Dependent Diabetes Mellitus; Intestines; Italy; Laboratories; Lamina Propria; Large Intestine; Lead; Light; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Mediating; Mentors; Mentorship; Microbe; Molecular; Molecular Profiling; Monitor; Mothers; Mouse Strains; Mus; Non obese; PTPRC gene; Patients; Physicians; Population; Preventive; Principal Investigator; Proteins; Recombinant DNA; Research; Research Personnel; Research Project Grants; Resources; Risk; Sampling; Sardinia; Scientist; Small Intestines; Sorting - Cell Movement; Susceptibility Gene; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Training; Transgenic Organisms; Vertical Disease Transmission; base; career; career development; commensal microbes; diabetic; disorder prevention; genetic association; genetic linkage; gut microbiota; human disease; loss of function; medical schools; microbial; microbial colonization; microbial community; non-diabetic; novel; protective effect; public health relevance; pup; research and development; research study; risk variant; screening

DESCRIPTION (provided by applicant): This proposal describes a 5-year mentored research project that has the goal of exploring the relationship between disease-protective major histocompatibility complex (MHC)/human leukocyte antigen (HLA) genetic loci, gut commensal microbiota and autoimmune diabetes (T1D). This project will build upon the principal investigator's preliminary data and strong background in immunology and infectious diseases. The comprehensive career development plan combines a strong mentorship team with additional didactic and practical training in gnotobiotic, microbiologic and large data set analyti techniques, which will facilitate the PI's transition into a successful independent investigator. The proposed research will take place in the stimulating research environment of Harvard Medical School within the laboratory of Drs. Diane Mathis and Christophe Benoist. The mentor, Dr. Mathis, is a world-renowned immunologist who has successfully mentored many physician-scientists during her 30-year career. The research and career development of the primary investigator will benefit from the extensive scientific and mentorship resources available to him. The MHC and HLA loci possess the strongest genetic association with T1D, in mice and humans respectively. Some loci such as the MHC class II E molecule offer dominant protection from T1D, but the mechanisms for this protection remains poorly understood. Commensal microbiota also influences the development of the immune system and affects the risk for developing T1D. The goal of this proposal is to explore interactions between gut microbiota, the MHC/HLA loci and the development of T1D in the non-obese diabetic (NOD) strain of mice and its closely related but non-diabetic transgenic line, expressing the protective MHCII E molecule (E�.NOD). Our preliminary data indicate that antibiotic disruption of the gut microbiota induces insulitis in E�.NOD mice. We have also demonstrated maternal transfer of protection from insulitis and T1D from E�.NOD mothers to NOD pups, suggesting transfer of protective microbiota from mother to pup. Therefore, we hypothesize that the diabetes-protective effect of the E molecule reflects an impact on the gut microbiota, which has a secondary influence on the immune system. To explore this hypothesis, we will directly test whether E�.NOD mice possess different microbes than NOD mice, and whether transfer of these microbes protects NOD mice from T1D. We will further identify these protective microbes and identify immune system components in E�.NOD mice that correlate with protection from T1D. To test whether the HLA alleles behave similarly we will explore the microbiota and gut immune system of NOD mice expressing human disease protective or risk-associated HLA alleles in place of their MHC genes. Ultimately, these experiments will shed light on the relationship between MHC and HLA loci, commensal microbiota and autoimmune diabetes. Moreover, identification of immunomodulatory bacteria and their associated immune system targets offers the potential for novel therapies for T1D, and perhaps other autoimmune diseases.

描述（由申请人提供）：该提案描述了一个为期5年的指导研究项目，其目标是探索疾病保护性主要组织相容性复合体（MHC）/人类白细胞抗原（HLA）遗传基因座、肠道菌群和自身免疫性糖尿病（T1 D）之间的关系。该项目将建立在首席研究员的初步数据和免疫学和传染病的强大背景。全面的职业发展计划结合了强大的导师团队，以及在gnotobiotic，微生物和大型数据集分析技术方面的额外教学和实践培训，这将有助于PI过渡到成功的独立研究者。拟议的研究将在哈佛医学院的Diane马西斯和Christophe Benoist博士实验室内进行。导师马西斯博士是一位世界知名的免疫学家，在她30年的职业生涯中，她成功地指导了许多医学科学家。主要研究者的研究和职业发展将受益于他可获得的广泛的科学和指导资源。 MHC和HLA基因座分别在小鼠和人类中与T1 D具有最强的遗传关联。一些基因座，如MHC II类E分子提供显性保护T1 D，但这种保护的机制仍然知之甚少。共生菌群也影响免疫系统的发育，并影响发展T1 D的风险。该提案的目标是探索肠道微生物群，MHC/HLA基因座和非肥胖糖尿病（NOD）小鼠品系及其密切相关但非糖尿病转基因系中T1 D的发展之间的相互作用，表达保护性MHCII E分子（E.NOD）。我们的初步数据表明，抗生素对肠道微生物群的破坏会诱导E.NOD小鼠的胰岛炎。我们还证明了从E.NOD母亲到NOD幼崽的胰岛炎和T1 D的母体转移，这表明保护性微生物群从母亲转移到幼崽。因此，我们假设E分子的糖尿病保护作用反映了对肠道微生物群的影响，这对免疫系统有次要影响。为了探索这一假设，我们将直接测试E.NOD小鼠是否拥有与NOD小鼠不同的微生物，以及这些微生物的转移是否能保护NOD小鼠免受T1 D的侵害。我们将进一步鉴定这些保护性微生物，并鉴定E.NOD小鼠中与T1 D保护相关的免疫系统成分。为了测试HLA等位基因是否表现相似，我们将探索NOD小鼠的微生物群和肠道免疫系统，这些小鼠表达人类疾病保护性或风险相关的HLA等位基因来代替它们的MHC基因。最终，这些实验将揭示MHC和HLA基因座，肠道微生物群和自身免疫性糖尿病之间的关系。此外，免疫调节细菌及其相关免疫系统靶标的鉴定为T1 D以及可能的其他自身免疫性疾病的新疗法提供了潜力。