Autoimmunity to Axoglial Apparatus Proteins in Multiple Sclerosis

多发性硬化症中轴神经胶质装置蛋白的自身免疫

• 批准号: 9806719
• 负责人: Kristina Rae Patterson
• 金额: $ 19.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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/9806719
• 关键词: Age; Aggressive course; Antibodies; Antigen Targeting; Antigens; Area; Atrophic; Autoantibodies; Autoantigens; Autoimmune encephalitis; Autoimmunity; Avidity; Axon; Benchmarking; Biological Assay; Biometry; Brain imaging; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell Proliferation; Cells; Cellular Immunity; Cellular Immunology; Cerebrospinal Fluid; Child; Chronic Inflammatory Demyelinating Polyradiculoneuropathy; Clinical; Collaborations; Databases; Demyelinating Diseases; Deterioration; Development; Environment; Ethics; Flow Cytometry; Frequencies; Future; Goals; Grant; Heterogeneity; Humoral Immunities; Immune; Immune Targeting; Immunity; Immunodominant Epitopes; Inflammation; Inflammatory; Injury; K-Series Research Career Programs; Knowledge; Lesion; MHC Class II Genes; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Mentors; Methodology; Mimosa; Molecular; Molecular Immunology; Monitor; Multiple Sclerosis; Myelin; Myelin Sheath; Outcome; Pathogenesis; Pathology; Patients; Peptide Library; Peptides; Phenotype; Play; Prevalence; Proteins; Proteomics; Recombinants; Regulation; Reporting; Research; Research Personnel; Role; Scientist; Serum; Severity of illness; Structure; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Tissues; Training; Translational Research; Work; antigen-specific T cells; autoreactivity; axon injury; base; career; career development; cerebral atrophy; contactin; cytokine; disability; experience; human subject; injured; memory CD4 T lymphocyte; multiple sclerosis patient; nervous system disorder; neurofascin; neuroimaging; novel; pediatric multiple sclerosis; personalized strategies; programs; relating to nervous system; research and development; response; skills; tool

PROJECT SUMMARY This K08 career development award will facilitate the development of the PI into a clinician-scientist with an independent research program focused on humoral and cellular immunity of MS and other neurological disorders. The PI and her coworkers have recently reported on the prevalence and mechanisms antibodies to axoglial antigens in neurological diseases, e.g. CIDP and autoimmune encephalitis (Patterson et al. 2018, Burnor et al., 2018). This work demonstrates functional and structural consequences of autoimmunity to the axoglial apparatus in the pathogenesis of neurological diseases. The scientific program in this grant expands on this prior work, focusing axoglial autoimmunity in MS, an exciting new avenue of research with the potential to explain the dual pathology of both myelin and underlying axons in MS, as well as the substantial heterogeneity in the clinical course and outcomes that exists across patients. The modulating more study are to: (1) test matched frequencies as MRI trajectories central hypothesis of this proposal is that autoimmunity to the axoglial apparatus plays a role in MS pathogenesis and that patients with autoimmunity to the axoglial apparatus will experience severe axonal loss and consequently higher r ate s of brain atrophy . whether MS patients are more likely to have axoglial autoantibodies compared to age- healthy controls and controls with other inflammatory neurological diseases, (2) enumerate the and proinf lammatory potential of axoglial- reactive T cells in MS patients versus controls, and (3) a proof of principle, axoglial autoimmunity will be measured in subsets of MS patients defined based on measures of differing rates of atrophy to test the hypothesis that axoglial autoimmunity correlates with of brain atrophy. The objectives of the proposed These studies will lead to not only a better understanding of the pathogenesis and heterogeneity that exists in the spectrum of MS but also develop specific for tools to better monitor relevant antigen- responses and potentially to better prognosticate and possibly revisit more individualized strategies antigen-specific therapies. The PI will be guided by three mentors with distinct areas of expertise that are necessary to complete this project. Dr. Bar-Or is a world regulation expert in molecular and cellular immunology studying the principles of immune and immune neural interactions in MS;Dr. Scherer is an expert on the molecular organization of myelinated axons; and Dr. Lancaster is a leading expert in the field CNS autoimmunity, and particularly of antibody-mediated neurological diseases with extensive experience in the discovery of novel autoantigens, including axoglial apparatus molecules. A training plan to assist the PI in developing new research skills is an integral part of this application. In addition to completing the proposed research, the applicant will engage in a rigorous program of didactic courses and mentoring by experts in cellular and molecular immunology, brain imaging, and biostatistics. She will gain expertise in identification of immunodominant epitopes using overlapping peptide libraries, immunospot assays, cell proliferation assays, multiparametric flow cytometry, and statistical methodologies relevant to translational research as well as gain a working knowledge of development of recombinant MHC receptors and advanced MRI analytic techniques (MIMoSA and SuBLIME). Since this project involves both human subjects, specific training in the ethical concerns involved is integrated into the training plan. The applicant's progress and attainment of specific benchmarks in research and career development will be regularly reviewed by her mentors who have extensive experience in training junior investigators and facilitating their transition to independent research careers. Completion of the proposed study will be facilitated by an institutional environment that prioritizes collaboration and provides exemplary research and career support. Through the proposed study, the applicant will make significant contributions to the understanding of axoglial autoimmunity in neurological diseases and novel tools necessary for future projects examining T-cell mediated axoglial immunity in not only MS but also other neurological diseases such as autoimmune encephalitis and CIDP.

项目摘要 该K 08职业发展奖将促进PI发展成为临床科学家， 一项独立的研究计划，专注于MS和其他神经系统疾病的体液和细胞免疫 紊乱PI和她的同事最近报道了 神经系统疾病中的轴胶质抗原，例如CIDP和自身免疫性脑炎（Patterson et al.2018， Burnor等人，2018年）。这项工作证明了自身免疫对免疫系统的功能和结构影响。 神经系统疾病发病机制中的轴舌装置。这项资助的科学项目 在这项先前的工作，重点轴胶质自身免疫性MS，一个令人兴奋的新途径的研究与潜力 为了解释MS中髓鞘和底层轴突的双重病理学，以及MS中大量的 患者之间存在的临床过程和结局的异质性。 的 调制 更 研究目的是：（1）测试 匹配 频率 作为 MRI 轨迹 这一建议的中心假设是，对轴突神经胶质装置的自身免疫在 MS发病机制和对轴舌体有自身免疫的患者将经历 严重的轴突损失和因此更高的脑萎缩率。 与年龄相比，MS患者是否更有可能患有轴胶质自身抗体， 健康对照组和其他炎性神经系统疾病对照组，（2）列举 MS患者与对照组中轴突胶质反应性T细胞的促炎潜力，以及（3） 作为原理证明，将在基于以下定义的MS患者亚组中测量轴神经胶质自身免疫性： 测量不同的萎缩率，以检验轴突胶质自身免疫与 脑萎缩的症状 建议的目标 这些研究不仅有助于更好地了解发病机制， 以及MS谱中存在的异质性， 具体 为 更好地监测相关抗原的工具- 应对措施，并有可能更好地阐明和重新审视更个性化的战略 抗原特异性疗法。 PI将由三名导师指导，他们具有完成此项目所需的不同专业领域 项目巴尔-奥尔博士是一个世界 调控 分子和细胞免疫学专家，研究免疫原理 和免疫神经相互作用;谢勒博士是一个专家的分子组织， 兰开斯特博士是中枢神经系统自身免疫领域的领先专家，特别是 抗体介导的神经系统疾病，在发现新的自身抗原方面具有丰富的经验， 包括轴突胶质器分子。 培训计划，以帮助PI在发展新的研究技能是本申请的一个组成部分。在 除了完成拟议的研究，申请人将从事严格的教学计划， 细胞和分子免疫学、脑成像和生物统计学专家的课程和指导。她 将获得使用重叠肽库鉴定免疫显性表位的专业知识， 免疫斑点试验、细胞增殖试验、多参数流式细胞术和统计学方法 与翻译研究相关，并获得重组MHC开发的工作知识 受体和先进的MRI分析技术（MIMoSA和SubLIME）。由于该项目涉及两个 对于人类受试者，将有关伦理问题的具体培训纳入培训计划。的 申请人在研究和职业发展方面的进展和达到的具体基准将被 她的导师在培训初级调查员方面具有丰富的经验， 促进他们向独立研究职业的过渡。将协助完成拟议的研究 通过优先考虑合作并提供示范性研究和职业生涯的机构环境 支持.通过拟议的研究，申请人将对了解 神经系统疾病中的轴神经胶质自身免疫和未来检查T细胞的项目所需的新工具 介导的轴胶质免疫不仅在MS，而且在其他神经系统疾病，如自身免疫性疾病， 脑炎和CIDP。