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

基本信息

批准号：
10665758
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
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10665758
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 Growth Immune response Immune system Immunologic Deficiency Syndromes Immunology Individual Inflammation Inflammatory Intestinal permeability Intestines Knowledge Laboratories Lactobacillus reuteri Learning 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 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 career career development design dysbiosis effector T cell graduate school 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 synergism systemic inflammatory response

项目摘要

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.

项目概要/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。我在肠道工作中获得了博士学位在 Martin Kriegel 博士的监督下研究微生物群和系统性红斑狼疮。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主机。为了阐明这个过程，我使用了基于四聚体的方法来识别和跟踪抗原特异性 T 细胞在胸腺中扩张，然后在周围分布和分化。我打算研究一下如何自身免疫过程发生改变。我提出的研究和指导计划将为我提供所需的为转变为具有长期职业目标的独立研究人员奠定基础，以了解如何微生物群特异性 T 细胞反应的出现并决定了它们如何加剧狼疮发病机制。为了实现这一目标为了实现这一目标，我与我的指导团队一起制定了职业计划，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菌群失调有关。狼疮的生态失调的特点是病原体过度生长，并与免疫反应失调有关从而加剧发病。在我的研究生工作中，我发现包括乳酸菌在内的病原体有所增加小鼠狼疮模型和 SLE 患者亚群中的罗伊氏菌。我展示了罗伊氏乳杆菌的系统易位，导致炎症途径和促炎性 T 细胞增加，从而加剧全身性炎症炎症和狼疮发病机制恶化。在我的博士后工作中，我正在研究分化如何微生物群特异性 T 细胞在发育过程中受到调节及其对炎症过程的影响。尽管我们和其他人发现成年小鼠中具有效应功能的微生物群特异性 T 细胞的外周扩张在年轻小鼠中，我们令人惊讶地发现微生物群特异性 T 细胞首先在胸腺中扩增，这是一个以前从未出现过的部位已知允许抗原特异性 T 细胞扩增。我的目标是整合我在大学期间获得的知识研究生和博士后培训以确定罗伊氏乳杆菌特异性 T 细胞的胸腺发育是否得到放大狼疮易感宿主并评估其在狼疮恶化中的作用。我将通过 1) 制定此提案确定胸腺微生物群特异性 T 细胞如何调节狼疮发病机制以及 2) 定义狼疮如何 Pathobionts 调节 Pathobiont 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。