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: 10178129
• 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/10178129
• 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; 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; 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.

项目摘要/摘要 多发性硬化症(MS)是一种炎症性脱髓鞘神经系统疾病，被认为是由 免疫介导的对中枢神经系统(CNS)的损伤。尤其是适应性免疫系统， 被认为是多发性硬化症免疫发病的中枢调节因子。B细胞和CD4+T细胞历史上 在MS研究中获得了更多的关注。CD8+T细胞因其在病毒和肿瘤中的细胞毒作用而广为人知 豁免权，但令人信服的证据表明，一个重要的，但在很大程度上仍不为人所知的作用。 我正在寻求K08临床科学家导师研究职业发展奖，以获得 促进我们对多发性硬化症患者T细胞的理解所需的经验和专业知识 应用是描绘哪些CD8+T细胞在MS中可能是重要的两个平行的、互补的目标是 提出要实现这一目标。在特定目标1中，将识别新的髓鞘CD8+T细胞表位并 特征是为了验证髓鞘反应性CD8+T细胞更丰富和更有利于 多发性硬化症患者与对照组的炎症反应比较。在特定目的2中，从人外周血中分离出CD8+T细胞 血液和脑脊液(CSF)将进行高通量的下一代测序。这一目标将考验 MS患者CD8+T细胞谱系与对照组相比差异较小的假设 鞘内CD8+T细胞克隆性增殖所致的CD4+T细胞。这两个目标将通过对 从血液中提取髓鞘反应性CD8+T细胞的TCR谱系，以寻找髓鞘特异性克隆型 在MS患者的脑脊液中。阐明哪些CD8+T细胞群与多发性硬化症相关将为 以确定它们在疾病中的作用。我的长期目标是显著提高我们对 MS的发病机制，有望为新的治疗策略提供指导。 在我过渡到助理教授的过程中，我组建了一支优秀的导师和顾问团队，以 引导我成为一名独立的调查员。加州大学旧金山分校的研究环境无与伦比。 并提供神经学和免疫学领域的世界级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 先进的技术，在那里我的工作将完成。在我的导师、机构和 K08职业发展奖，我相信我会很好地过渡到独立研究 在我的五年培训计划结束时，获得R01或同等资金的职业生涯。