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: 9925282
• 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/9925282
• 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; 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.

项目总结 这个K08职业发展奖将促进PI发展成为一名具有 专注于多发性硬化症和其他神经系统的体液和细胞免疫的独立研究计划 精神错乱。PI和她的同事们最近报告了抗体的流行率和机制 神经疾病中的轴突抗原，例如CIDP和自身免疫性脑炎(Patterson等人)。2018年, Burnor等人，2018年)。这项工作展示了自身免疫对细胞的功能和结构影响。 轴突在神经系统疾病发病机制中的作用。这项拨款中的科学计划扩大了 在此之前的工作中，专注于多发性硬化症的轴突自身免疫，这是一个令人兴奋的新研究途径，具有潜在的 为了解释MS中髓鞘和潜在轴突的双重病理以及实质上的 临床病程和结果的异质性存在于患者之间。 这个 调制 更多 学习是为了：(1)测试 相匹配 频率 AS 磁共振成像 轨迹 这一提议的中心假设是，对轴突的自身免疫在 MS的发病机制以及对轴突具有自身免疫力的患者将经历 严重的轴突丢失，从而使S脑萎缩的比例更高。 与年龄相比，多发性硬化症患者是否更有可能患有轴突自身抗体- 健康对照和患有其他炎症性神经疾病的对照，(2)列举 MS患者与对照组相比轴突反应性T细胞的炎症潜能，以及(3) 作为原则的证明，轴突自身免疫将在MS患者的亚群中进行测量，其定义基于 测量不同的萎缩率以检验轴突自身免疫与 脑部萎缩的症状。 建议的目标 这些研究不仅将使我们更好地了解其发病机制 以及MS光谱中存在的异质性，但也会发展 专一 为 更好地监测相关抗原的工具- 回应，潜在地更好地预测并可能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，他们拥有完成这项工作所需的不同领域的专业知识 项目。巴尔博士--或者说是一个世界 调节 研究免疫原理的分子和细胞免疫学专家 以及多发性硬化症的免疫神经相互作用；Scherer博士是多发性硬化症的分子组织方面的专家 兰开斯特博士是中枢神经系统自身免疫领域的领先专家，尤其是 抗体介导的神经系统疾病在发现新的自身抗原方面有丰富的经验， 包括轴突分子。 一个培训计划，以协助私人投资发展新的研究技能是这项申请不可或缺的一部分。在……里面 除了完成拟议的研究外，申请人还将参加严格的教学计划 由细胞和分子免疫学、脑成像和生物统计学专家提供的课程和指导。她 将获得使用重叠多肽文库识别免疫优势表位的专业知识， 免疫斑点分析、细胞增殖分析、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开发的实用知识 受体和先进的MRI分析技术(含羞草和Suplime)。因为这个项目既涉及到 在涉及人类主体的具体培训中，所涉及的伦理关切被纳入培训计划。这个 申请人在研究和职业发展方面的进展和达到特定基准的情况将是 定期由她的导师进行审查，这些导师在培训初级调查员和 促进他们向独立研究职业的过渡。建议的研究将会加快完成。 通过优先协作并提供模范研究和职业的机构环境 支持。通过拟议的研究，申请者将对理解 神经系统疾病中的轴突自身免疫和未来T细胞检测项目所需的新工具 介导性轴突免疫不仅与MS有关，还与自身免疫等其他神经系统疾病有关 脑炎和CIDP。