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.

项目摘要/摘要 候选人：我是Gretchen E. Diehl博士实验室的博士后研究助理 纪念斯隆 - 凯特林癌症中心的免疫学计划。我获得了我在肠道工作的博士学位 在马丁·克里格尔（Martin Kriegel）博士的监督下，微生物群和全身性红斑狼疮。我目前的研究 应用我在博士后和研究生院学习的技术来评估肠道微生物在 微生物群特异性T细胞的胸腺开发以及这些T细胞如何调节易感性的疾病 主持人。为了阐明这一过程，我使用了基于四聚体的方法来识别和跟踪抗原特异性T细胞 胸腺在分布和区分周围之前的膨胀。我打算研究如何 自身免疫性的过程发生了变化。我提出的研究和指导计划将为我提供所需的 过渡到具有长期职业目标的独立研究人员的基础，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的发病机理。实现这一目标 目标，与我的指导团队一起，我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）提高我的沟通能力，4）扩大我的科学网络。 研究：狼疮的发育与患者和小鼠模型的肠道营养不良有关。 狼疮中的营养不良的特征是病原体过度生长，与免疫反应失调有关 加剧发病机理。在我的研究生工作中，我发现包括乳杆菌在内的病原体增加 小鼠狼疮模型和SLE患者子集的Reuteri。我展示了Reuteri的易位，全身易位， 导致炎症途径增加和促炎的T细胞加剧了全身性 炎症和狼疮发病机理恶化。在我的博士后工作中，我正在研究如何差异化 在发育过程中调节微生物群特异性T细胞及其在炎症过程中的影响。尽管 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细胞的外围膨胀，在 年轻的小鼠我们出人意料地发现微生物群特异性T细胞首先在胸腺中膨胀，这是一个不以前的部位 已知可以允许抗原特异性T细胞扩展。我的目的是协同我的知识 研究生和博士后训练，以确定胸腺特异性T细胞的胸腺发育是否得到扩增 在狼疮中，易感宿主并评估其在狼疮加剧中的作用。我将以1的形式开发此建议） 确定胸腺微生物特异性T细胞如何调节狼疮的发病机理，并定义狼疮如何 Pathobionts调节病原体特异性T细胞的扩展。 环境：实验室是纪念斯隆凯特癌的免疫学计划的一部分 中心，最先进的研究所。此外，我的指导委员会和合作者将 为提出的研究和职业发展提供所需的科学和非科学支持。