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Defining the role of B cells in modulating CNS inflammation in multiple sclerosis

定义 B 细胞在调节多发性硬化症中枢神经系统炎症中的作用

基本信息

批准号：
10407572
负责人：
Julie J Ahn
金额：
$ 2.28万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407572
关键词：
Ablation Address Affect Animal Model Animals Apoptosis Ataxia Autoimmune Diseases of the Nervous System Autopsy Axon B cell therapy B-Lymphocytes Brain CASP9 gene CD19 gene Caspase Cell Line Cell physiology Cells Central Nervous System Diseases Chronic Complex Cytokine Signaling Data Demyelinating Diseases Demyelinations Development Disease Disease Progression Enzyme-Linked Immunosorbent Assay Experimental Autoimmune Encephalomyelitis Factor Analysis Fellowship Flow Cytometry Foundations Genes Genetic Transcription Goals Health Sciences Human Immune Immune system Immunocompromised Host Immunohistochemistry Immunology Immunomodulators Infiltration Inflammation Inflammatory Inflammatory Response Injury Innate Immune System Knowledge Lead Lesion MAP Kinase Gene MAPK Signaling Pathway Pathway Manuscripts Mediating Mentors Microglia Molecular Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Neuraxis Neurodegenerative Disorders Neurosciences Oral Pain Pathogenesis Pathogenicity Pathway interactions Patients Peripheral Persons Phosphorylation Plasma Population Production Property Relapse Research Role Scientist Severities Severity of illness Signal Pathway Signaling Protein Spinal Cord Symptoms Tamoxifen Technical Expertise Techniques Testing Training Transgenic Animals Transgenic Organisms Transmission Electron Microscopy Universities Washington axon injury brain tissue burden of illness career central nervous system demyelinating disorder cytokine differential expression experimental study functional disability immunopathology inflammatory marker insight medical schools mouse model multiple sclerosis patient multiple sclerosis treatment neuroimmunology neuroinflammation new therapeutic target novel novel therapeutics peripheral blood prevent protein expression remyelination repaired response responsible research conduct targeted treatment tool transcriptome sequencing transcriptomics

项目摘要

Summary The debilitating central nervous system (CNS) disease multiple sclerosis (MS), is characterized by an influx of peripheral immune cells that coincides with axonal demyelination and damage, resulting in pain and impaired coordination. The role of B cells in MS pathogenesis has emerged as studies showed that B cell directed therapies substantially reduce the formation of new inflammatory demyelinating lesions. Further, the majority of lesions from patients with established MS harbor B cells as well as reactive microglia. While these findings corroborate a pathogenic role for B cells, it is unclear which B cell function contributes to demyelination within the inflamed CNS. In addition, systemic B cell elimination can severely immunocompromise patients, establishing the need to develop more targeted therapies. Emerging evidence suggests that B cells of MS patients are potent regulators of pro-inflammatory cytokines, and these abnormal B cells can regulate the CNS innate immune system when they enter the CNS. Studies in this application will selectively and locally ablate B cells in the CNS using a novel caspase 9-mediated apoptosis transgenic tool in the well-studied experimental autoimmune encephalomyelitis (EAE) animal model of MS. Preliminary data indicate that targeting CNS B cells after the onset of symptoms in EAE reduces microglial reactivity and is accompanied by decreased myelin damage and functional impairment. Inflammatory signaling pathways in microglia from CNS B cell depleted EAE animals will be evaluated using advanced phospho-flow cytometry techniques. Demyelination and remyelination in the brain and spinal cord will be further studied in this powerful, novel animal model to test if CNS B cell ablation prevents further myelin injury and promotes myelin repair. The role of MS B cells in neuroinflammation will be determined by stimulating human microglia with MS patient-derived B cell secreted factors and analyzing transcriptional and translational inflammatory activity of microglial cells. B cell induced microglial activation will be confirmed in human MS brain lesions. Together, the proposed studies will provide novel insights into the complex immunopathology of MS that involves the interaction of CNS B cells and microglia. Completion of these studies will lead to novel immunomodulatory therapeutic avenues that reduce the disease burden of multiple sclerosis without immunocompromising the patient. The proposed training plan is sponsored by Dr. Robert H. Miller at the George Washington University School of Medicine and Health Sciences. The overall goal is to build a strong foundation for the PI, Julie J Ahn, to prepare her for a successful career as an independent scientist in the fields of neuroimmunology and neuroinflammation. The fellowship training plan includes the following goals: 1) enhance scientific knowledge and technical skills that integrate neuroscience and immunology, 2) present research findings through oral presentations and manuscripts, 3) mentor and lead young scientists, and 4) conduct research responsibly.

总结使人衰弱的中枢神经系统（CNS）疾病多发性硬化症（MS）的特征在于，与轴突脱髓鞘和损伤同时发生的外周免疫细胞，导致疼痛和受损协同B细胞在MS发病机制中的作用已经出现，因为研究表明B细胞定向的MS发病机制是由细胞因子介导的。治疗显著减少了新的炎性脱髓鞘损伤的形成。此外，大多数已确诊的MS患者的病变含有B细胞以及反应性小胶质细胞。虽然这些发现虽然这证实了B细胞的致病作用，但尚不清楚哪种B细胞功能导致了脑内脱髓鞘。发炎的中枢神经系统此外，全身性B细胞消除可严重损害患者的免疫功能，这就需要开发更有针对性的治疗方法。新出现的证据表明MS的B细胞患者是促炎细胞因子的有效调节者，这些异常的B细胞可以调节CNS 当它们进入中枢神经系统时，本应用中的研究将选择性和局部消融B 在一项充分研究的实验中，使用一种新的半胱天冬酶9介导的凋亡转基因工具，初步数据表明，靶向CNS B细胞在EAE症状发作后，小胶质细胞反应性降低，并伴有髓鞘减少损伤和功能障碍。中枢神经系统B细胞缺失的小胶质细胞炎症信号通路将使用高级磷酸流式细胞术技术评价EAE动物。脱髓鞘和将在这个强大的新型动物模型中进一步研究大脑和脊髓的髓鞘再生，以测试 CNS B细胞消融防止进一步的髓鞘损伤并促进髓鞘修复。MS B细胞在通过用分泌的MS患者来源的B细胞刺激人小胶质细胞来确定神经炎症因子和分析小胶质细胞的转录和翻译炎症活性。B细胞诱导将在人MS脑损伤中证实小胶质细胞活化。这些研究将提供新的见解复杂的免疫病理学的MS，涉及相互作用的中枢神经系统B细胞和小胶质细胞这些研究的完成将导致新的免疫调节治疗途径，多发性硬化症的疾病负担而不损害患者的免疫力。建议的培训计划是由罗伯特H。米勒在乔治华盛顿大学医学院医学和健康科学。总体目标是为PI Julie J Ahn奠定坚实的基础，为她作为神经免疫学领域的独立科学家的成功职业生涯做好准备，神经炎症研究金培训计划包括以下目标：1）增进科学知识和技术技能，整合神经科学和免疫学，2）通过口头展示研究成果演讲和手稿，3）指导和领导年轻科学家，4）负责任地进行研究。