Regulation of lupus pathogenesis through modulation of thymic development of pathobiont-specific T cells

通过调节病原体特异性 T 细胞的胸腺发育来调节狼疮发病机制

• 批准号: 10525740
• 负责人: Daniel Fernando Zegarra Ruiz
• 金额: $ 9.19万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525740
• 关键词: Adult; Antigens; Attention; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacteria; Bacterial Translocation; Cell Differentiation process; Cells; Chronic; Communication; Data; Development; Disease; Disease Progression; Disease model; Doctor of Philosophy; Ensure; Exhibits; Foundations; Generations; Goals; Immune response; Immune system; Immunology; Individual; Inflammation; Inflammatory; Intestinal permeability; Intestines; Knowledge; Laboratories; Lactobacillus reuteri; Link; Liver; Lupus; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Modeling; Mus; Organ; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral; Postdoctoral Fellow; Predisposition; Process; Production; Regulation; Research; Research Institute; Research Personnel; Research Support; Role; Schools; Site; Spleen; Supervision; Systemic Lupus Erythematosus; T cell response; T-Cell Development; T-Lymphocyte; Technical Expertise; Techniques; Testing; Therapeutic; Thymus Gland; Tissues; Training; Weaning; Wild Type Mouse; Work; adaptive immune response; antigen-specific T cells; base; career; career development; design; dysbiosis; effector T cell; gut inflammation; gut microbes; gut microbiota; host-microbe interactions; improved; innate immune pathways; lupus prone mice; mesenteric lymph node; microbial colonization; microbiota; mouse model; pathobiont; post-doctoral training; programs; prophylactic; research and development; response; skills; systemic inflammatory response

PROJECT SUMMARY/ABSTRACT CANDIDATE: I am a postdoctoral research associate in the laboratory of Dr. Gretchen E. Diehl in the Immunology Program at Memorial Sloan-Kettering Cancer Center. I obtained my PhD working in gut microbiota and systemic lupus erythematosus under the supervision of Dr. Martin Kriegel. My current research applies the techniques I learned in my postdoc and graduate school to assess the role of gut microbes in the thymic development of microbiota-specific T cells and how these T cells can modulate disease in susceptible hosts. To elucidate this process, I used a tetramer-based approach to identify and track antigen-specific T cells expansion in the thymus before they distribute and differentiate in the periphery. I plan to study how this process is altered in autoimmunity. My proposed research and mentoring plan will provide me the required foundation to transition into an independent researcher with a long-term career goal to understand how microbiota-specific T cell responses arise and define how they exacerbate lupus pathogenesis. To achieve this goal, together with my mentoring team, I have developed a career plan that will 1) increase my technical skills, 2) refine my scientific scope, 3) improve my communication skills, and 4) expand my scientific network. RESEARCH: Lupus development is associated with intestinal dysbiosis in patients and mouse models. Dysbiosis in lupus is characterized by pathobiont overgrowth and is linked to dysregulated immune responses that exacerbate pathogenesis. In my graduate work, I found increased pathobionts including Lactobacillus reuteri in mouse lupus models and subsets of SLE patients. I showed L. reuteri translocated systemically, leading to increased inflammatory pathways and proinflammatory T cells which exacerbated systemic inflammation and worsened lupus pathogenesis. In my postdoctoral work, I am investigating how differentiation of microbiota-specific T cells is regulated during development and its effects in inflammatory processes. While we and others find peripheral expansion of microbiota-specific T cells with effector function in adult mice, in young mice we surprisingly found microbiota-specific T cells first expanded in the thymus, a site not previously known to allow for antigen-specific T cell expansion. I aim to synergize the knowledge generated during my graduate and postdoctoral training to determine if thymic development of L. reuteri-specific T cells is amplified in lupus susceptible hosts and to assess their role in lupus exacerbation. I will develop this proposal by 1) Determining how thymic microbiota-specific T cells modulate lupus pathogenesis and 2) Defining how lupus pathobionts modulate pathobiont-specific T cells expansion. ENVIRONMENT: The laboratory is part of the Immunology program at Memorial Sloan-Kettering Cancer Center, a state-of-the-art research institute. Furthermore, my mentoring committee and collaborators will provide the required scientific and non-scientific support for the research and career development proposed.

项目总结/文摘