Detection of disease-relevant CD8+ T cells in Multiple Sclerosis

多发性硬化症中疾病相关 CD8 T 细胞的检测

• 批准号: 10415878
• 负责人: Joseph John Sabatino
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415878
• 关键词: Adaptive Immune System; Advanced Technology Center; Affect; Alleles; Animal Model; Antigen Targeting; Antigens; B-Lymphocytes; Blood; Blood Cells; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell surface; Cells; Cerebrospinal Fluid; Clinical; Clonal Expansion; Data; Demyelinating Diseases; Demyelinations; Detection; Disease; Environment; Epitopes; Equipment; Faculty; Frequencies; Funding; Future; Goals; HLA-A gene; HLA-A2 Antigen; HLA-A3 Antigen; HLA-DRB1; Human; Immune; Immune system; Immunology; Inflammatory; Injury; Institution; K-Series Research Career Programs; Lead; Mediating; Mediator of activation protein; Memory; Mentors; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Neuraxis; Neurologic; Neurology; Neurosciences; Pathogenesis; Pathogenicity; Patients; Peptide/MHC Complex; Persons; Phenotype; Population; Positioning Attribute; Predisposition; Probability; Process; Production; Regulation; Research; Research Personnel; Research Proposals; Role; Scientist; Specificity; Spinal Cord; Stains; T cell receptor repertoire sequencing; T-Lymphocyte; T-Lymphocyte Epitopes; T-cell receptor repertoire; Testing; Training; Transgenic Mice; Tumor Immunity; Viral; Work; career; cytokine; cytotoxic; exhaustion; experience; improved; insight; multiple sclerosis patient; nervous system disorder; next generation sequencing; novel; novel therapeutic intervention; peripheral blood; professor; research facility; success; young adult

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is an inflammatory demyelinating neurologic disorder thought to be caused by immune-mediated injury against the central nervous system (CNS). The adaptive immune system, in particular, is considered to be a central mediator of MS immunopathogenesis. B cells and CD4+ T cells have historically received greater focus in MS research. CD8+ T cells are best known for their cytotoxic function in viral and tumor immunity, yet compelling evidence suggests an important, but still largely unknown role in MS. I am seeking a K08 Mentored Clinical Scientist Research Career Development Award in order to gain the experience and expertise needed to advance our understanding of T cells in MS. The goal of this K08 application is to delineate which CD8+ T cells are likely important in MS. Two parallel, complementary aims are proposed to achieve this goal. In Specific Aim 1, novel myelin CD8+ T cell epitopes will be identified and characterized in order to test the hypothesis that myelin-reactive CD8+ T cells are more abundant and pro- inflammatory in MS patients compared to control subjects. In Specific Aim 2, CD8+ T cells isolated from the blood and cerebrospinal fluid (CSF) will undergo high throughput next generation sequencing. This aim will test the hypothesis that the CD8+ T cell repertoire in MS patients is less diverse compared to control subjects and CD4+ T cells owing to intrathecal CD8+ T cell clonal expansion. The two aims will be bridged by sequencing the TCR repertoire of myelin-reactive CD8+ T cells from the blood in order to search for myelin-specific clonotypes in the CSF of MS patients. Elucidation of which CD8+ T cell populations are relevant to MS will pave the way toward determining their role in the disease. My long-term goal is to significantly advance our understanding of MS pathogenesis and hopefully provide guidance for novel therapeutic strategies. As I transition to Assistant Professor, I have assembled an outstanding team of mentors and advisors to guide me towards becoming an independent investigator. The research environment at UCSF is unparalleled and offers access to world-class faculty and researchers in the fields of Neurology and Immunology as well as cutting-edge equipment and research facilities, including at the Sandler Neurosciences Building and Center for Advanced Technology where my work will be completed. With the support of my mentors, institution, and the K08 Career Development Award, I am confident I will be well positioned to transition to an independent research career with R01 or equivalent funding by the end of my five-year training plan.

项目概要/摘要 多发性硬化症 (MS) 是一种炎症性脱髓鞘性神经系统疾病，被认为是由 针对中枢神经系统（CNS）的免疫介导损伤。适应性免疫系统，特别是， 被认为是 MS 免疫发病机制的核心介质。 B 细胞和 CD4+ T 细胞历史上曾 在 MS 研究中受到更多关注。 CD8+ T 细胞以其在病毒和肿瘤中的细胞毒功能而闻名 免疫，但令人信服的证据表明，它在多发性硬化症中具有重要但仍很大程度上未知的作用。 我正在寻求 K08 指导临床科学家研究职业发展奖，以获得 增进我们对 MS 中 T 细胞的理解所需的经验和专业知识。这次K08的目标 该应用的目的是确定哪些 CD8+ T 细胞在 MS 中可能很重要。两个平行、互补的目标是 提议实现这一目标。在具体目标 1 中，将鉴定新的髓磷脂 CD8+ T 细胞表位并 特征是为了检验髓磷脂反应性 CD8+ T 细胞更加丰富且亲-的假设。 与对照受试者相比，多发性硬化症患者的炎症。在具体目标 2 中，从 血液和脑脊液（CSF）将接受高通量下一代测序。这个目标将考验 假设与对照受试者相比，多发性硬化症患者的 CD8+ T 细胞库多样性较低， 由于鞘内 CD8+ T 细胞克隆扩增而产生 CD4+ T 细胞。这两个目标将通过排序来实现 血液中髓磷脂反应性 CD8+ T 细胞的 TCR 库，以寻找髓磷脂特异性克隆型 多发性硬化症患者的脑脊液中。阐明哪些 CD8+ T 细胞群与 MS 相关将为我们铺平道路 以确定它们在疾病中的作用。我的长期目标是显着增进我们对 MS 发病机制并有望为新的治疗策略提供指导。 当我过渡到助理教授时，我组建了一支优秀的导师和顾问团队 指导我成为一名独立调查员。 UCSF 的研究环境无与伦比 并提供接触神经学和免疫学领域世界一流的教师和研究人员以及 尖端设备和研究设施，包括桑德勒神经科学大楼和中心 我的工作将在先进技术中完成。在我的导师、机构和社会的支持下 K08职业发展奖，我相信我将有能力过渡到独立研究 在我的五年培训计划结束时，我将获得 R01 或同等资金的职业生涯。