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/摘要 候选人：我是Gretchen E博士实验室的博士后研究助理。迪尔在 Memorial Sloan-Kettering癌症中心的免疫学项目。我获得了我的博士学位， 微生物群和系统性红斑狼疮的监督下，马丁Kriegel博士。我目前的研究 应用我在博士后和研究生院学到的技术来评估肠道微生物在 微生物群特异性T细胞的胸腺发育以及这些T细胞如何调节易感人群的疾病 hosts.为了阐明这一过程，我使用了基于四聚体的方法来识别和追踪抗原特异性T细胞 在它们分布和分化到周围之前，它们在胸腺中扩张。我打算研究一下 在自身免疫中过程发生改变。我提出的研究和指导计划将为我提供所需的 基金会过渡到一个独立的研究人员与长期的职业目标，以了解如何 微生物群特异性T细胞反应出现并定义它们如何加剧狼疮发病机制。实现这一 为了实现这一目标，我和我的指导团队一起制定了一个职业计划，该计划将1）提高我的技术技能， 2)完善我的科学范围，3）提高我的沟通技巧，4）扩大我的科学网络。 研究：狼疮的发展与患者和小鼠模型的肠道生态失调有关。 狼疮中的生态失调的特征是病原体过度生长，并与免疫反应失调有关 加重了发病机制。在我的研究生工作中，我发现包括乳酸杆菌在内的致病菌增加了， reuteri在小鼠狼疮模型和SLE患者亚群中的应用。我给L看了。reuteri系统性易位， 导致炎症途径和促炎T细胞增加，从而加剧全身性疾病 炎症和恶化的狼疮发病机制。在我的博士后工作中，我正在研究分化如何 微生物组特异性T细胞在发育过程中受到调节，并在炎症过程中发挥作用。而 我们和其他人发现，在成年小鼠中，具有效应功能的微生物群特异性T细胞的外周扩增， 我们惊奇地发现，微生物特异性T细胞首先在胸腺中扩增，这是一个以前没有的部位。 已知允许抗原特异性T细胞扩增。我的目标是协同在我的过程中产生的知识， 研究生和博士后培训，以确定是否胸腺发育的L。罗伊特氏特异性T细胞被扩增 在狼疮易感宿主中，并评估它们在狼疮恶化中的作用。我将通过以下方式发展这一建议：1） 确定胸腺微生物群特异性T细胞如何调节狼疮发病机制和2）定义狼疮如何 致病菌调节致病菌特异性T细胞扩增。 环境：该实验室是纪念斯隆-凯特琳癌症中心免疫学项目的一部分 中心，一个最先进的研究机构。此外，我的指导委员会和合作者将 为拟议的研究和职业发展提供所需的科学和非科学支持。