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

转移：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: 9413309
• 负责人: Michael A Silverman
• 金额: $ 17.8万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 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/9413309
• 关键词: Address; Affect; Alleles; Antibiotics; Antigen-Presenting Cells; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Bacteria; Biological Response Modifiers; CD4 Positive T Lymphocytes; Cells; Collaborations; Communicable Diseases; Data; Data Set; Development; Development Plans; Diabetes Mellitus; Diabetic mother; Disease; Environment; European; Exposure to; Feces; Female; Flow Cytometry; Gene Expression Profiling; Genetic; Genetic Predisposition to Disease; Genomic DNA; Germ-Free; Gnotobiotic; Goals; HLA Antigens; Human; Immune; Immune system; Immunologist; Immunology; Inbred NOD Mice; 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; Microbiology; Molecular; 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; Susceptibility Gene; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Training; Transgenic Organisms; Vertical Disease Transmission; base; career; career development; commensal microbes; diabetic; disorder prevention; experimental study; genetic association; genetic linkage; gut microbiota; human disease; immunoregulation; loss of function; medical schools; metaproteomics; microbial; microbial colonization; microbial community; microbiota; non-diabetic; novel; novel therapeutics; protective effect; public health relevance; pup; research and development; 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)：本提案描述了一项为期5年的指导性研究项目，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)遗传位点、肠道共生微生物区系与自身免疫性糖尿病(T1D)之间的关系。这个项目将建立在首席研究员在免疫学和传染病方面的初步数据和强大背景的基础上。全面的职业发展计划将强大的指导团队与额外的指导性和实践性培训结合在一起，培训内容包括生物质、微生物和大数据集分析技术，这将有助于PI转变为一名成功的独立调查员。这项拟议的研究将在哈佛医学院Diane Mathis博士和Christophe Benoist博士的实验室内刺激的研究环境中进行。这位导师马西斯博士是一位世界知名的免疫学家，在她30年的职业生涯中成功地指导了许多内科科学家。首席调查员的研究和职业发展将受益于向他提供的广泛的科学和指导资源。 在小鼠和人类中，MHC和HLA基因座分别与T1D有最强的遗传关联。一些基因座，如MHC II类E分子，提供了对T1D的显性保护，但这种保护的机制仍然知之甚少。共生微生物区系也影响免疫系统的发育，并影响发生T1D的风险。本研究的目的是探讨非肥胖糖尿病(NOD)小鼠及其表达保护性MHCIIE分子(E�.NOD)的转基因小鼠的肠道微生物区系、MHC/HLA位点数与T1D发病的相互作用。我们的初步数据表明，肠道微生物区系的抗生素破坏会导致E�.NOD小鼠发生岛炎。我们还展示了从E�.NOD母亲向NOD幼崽转移对胰岛素炎和T1D的保护，建议将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区系的影响，而肠道微生物区系对免疫系统有二次影响。为了探索这一假说，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保护NOD小鼠免受T1D的影响。我们将进一步识别这些保护性微生物，并在E�.NOD小鼠中识别与T1D保护相关的免疫系统组件。为了测试人类白细胞抗原等位基因的行为是否相似，我们将探索NOD小鼠的微生物区系和肠道免疫系统，这些小鼠表达人类疾病保护性或风险相关的HLA等位基因，而不是它们的MHC基因。最终，这些实验将阐明MHC和人类白细胞抗原基因座、共生微生物区系和自身免疫性糖尿病之间的关系。此外，识别免疫调节细菌及其相关的免疫系统靶点为治疗T1D，也许还有其他自身免疫性疾病提供了新的治疗方法。