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

项目摘要/摘要 候选人：我是Gretchen E.Diehl博士实验室的博士后研究员 纪念斯隆-凯特琳癌症中心的免疫学项目。我拿到了博士学位，在TUT工作 微生物区系和系统性红斑狼疮在马丁·克里格尔博士的监督下。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 胸腺微生物区系特异性T细胞的发育以及这些T细胞如何调节易感人群的疾病 主持人。为了阐明这一过程，我使用了一种基于四聚体的方法来识别和跟踪抗原特异性T细胞 它们在胸腺周围分布和分化之前在胸腺中扩张。我计划研究这是如何 在自身免疫过程中会发生改变。我提议的研究和指导计划将为我提供所需的 基金会转型为独立研究人员，具有长期的职业目标，以了解如何 微生物区系特异性T细胞反应的出现并定义了它们如何加剧狼疮的发病。要做到这一点 Goal和我的指导团队一起制定了一份职业计划，这将1)提高我的技术技能， 2)细化我的科学范围，3)提高我的沟通能力，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物失调有关。 狼疮的生物失调以病理性过度生长为特征，并与免疫反应调节失调有关。 这加剧了发病机制。在我的研究生工作中，我发现包括乳杆菌在内的致病菌增加了 小鼠狼疮模型和SLE患者亚群中的reuri。我显示了L.reuri全身性移位， 导致炎症途径和促炎T细胞增加，从而加剧系统性 炎症加重了狼疮的发病机制。在我的博士后工作中，我正在研究如何区分 微生物区系特异性T细胞的数量在发育过程中受到调节，在炎症过程中发挥作用。而当 我们和其他人在成年小鼠身上发现了具有效应功能的微生物区系特异性T细胞的外周扩张， 年轻的小鼠，我们惊讶地发现微生物区系特异性T细胞最先在胸腺扩张，这是以前没有的地方 已知允许抗原特异的T细胞增殖。我的目标是将在我的工作中产生的知识 研究生和博士后培训以确定路支杆菌特异性T细胞的胸腺发育是否被扩增 并评估它们在狼疮恶化中的作用。我将在1)之前开发此提案 确定胸腺微生物区系特异性T细胞如何调节狼疮发病机制和2)确定狼疮如何 病毒肽调节病毒肽特异性T细胞的增殖。 环境：该实验室是斯隆-凯特琳癌症纪念中心免疫学项目的一部分 中心，一家最先进的研究机构。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。

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.