The Role of B cells in the Origin and Progression of Multiple Sclerosis

B 细胞在多发性硬化症的起源和进展中的作用

• 批准号: 10401443
• 负责人: STEPHEN L HAUSER
• 金额: $ 112.92万
• 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: 2019-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401443
• 关键词: Acute; Affect; Antibodies; Axon; B-Lymphocytes; CNS autoimmune disease; Cellular biology; Cerebrospinal Fluid; Chronic; Clinical; Data; Disease; Disease Progression; Elements; Fingerprint; Genetic Determinism; Goals; Human; Individual; Inflammation; Magnetic Resonance Imaging; Mediating; Molecular; Multiple Sclerosis; Myelin; Neurologic Dysfunctions; Neurons; Oligodendroglia; Onset of illness; Pathogenicity; Pathology; Patient-Focused Outcomes; Patients; Phage Display; Pharmaceutical Preparations; Play; Population; Progressive Disease; Protein Array; Proteins; Recombinant Antibody; Research; Role; Serial Magnetic Resonance Imaging; Serum; Spinal Cord; Techniques; Technology; Therapeutic; United States; Viral; antibody libraries; biobank; brain magnetic resonance imaging; chronic autoimmune disease; cohort; falls; genetic information; improved; microbial; novel; peripheral blood; receptor; screening; synthetic protein; tool; transcriptomics

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system affecting nearly one million individuals in the United States. The disease is characterized by acute and chronic inflammation, myelin loss; oligodendrocyte, neuronal and axonal pathology; and progressive neurological dysfunction. A number of breakthrough translational discoveries, and especially the highly beneficial effects of B cell depleting drugs, have set the stage for a growing, yet still imperfect, therapeutic pipeline. Research will fall short of its potential to improve patient outcomes until the trigger(s) of disease onset and modifiers of progression are identified. Central to this project is the hypothesis that B cells presenting in the cerebrospinal fluid (CSF) and peripheral blood during early MS play key roles in triggering MS and in mediating ongoing progressive disease activity. We propose to interrogate unique patient cohorts, including an incident cohort, with novel enabling technologies to identify triggers of MS and modifiers of the clinical course. Well characterized clinical populations, high-field serial magnetic resonance imaging (MRI), genetic information organized as functional operational networks, and a focus on B cell biology are the central elements of this initiative. A primary goal will be to characterize the molecular diversity of B cells and their receptors at various stages of disease to identify pathogenic populations and their antigenic targets. A multi-layered experimental strategy includes single cell B cell transcriptomics, together with comprehensive phage-displayed synthetic human, viral and microbial peptidomes for the screening of antibody fingerprints against external drivers in the serum, CSF, and recombinant antibody libraries. The integrative analysis will contextualize the data using clinical, MRI and genetic determinants, striving to apply rigorous statistical principles, including independent replication.

多发性硬化症 (MS) 是一种中枢神经系统慢性自身免疫性疾病，影响近乎一个人 美国有 100 万人。该疾病的特点是急性和慢性炎症、髓磷脂 损失;少突胶质细胞、神经元和轴突病理学；和进行性神经功能障碍。一些 突破性的转化发现，尤其是 B 细胞耗竭药物的高度有益作用，已经 为不断发展但仍不完善的治疗渠道奠定了基础。研究将达不到其潜力 改善患者的治疗效果，直到确定疾病发作的触发因素和进展的调节因素。 该项目的核心是假设 B 细胞存在于脑脊液 (CSF) 和外周血中 早期多发性硬化症期间的血液在引发多发性硬化症和介导持续进行性疾病活动方面发挥着关键作用。我们 提议利用新颖的支持技术来询问独特的患者群体，包括事件群体 识别多发性硬化症的触发因素和临床过程的修饰因素。临床人群特征明确，高场 串行磁共振成像 (MRI)、组织为功能操作网络的遗传信息，以及 对 B 细胞生物学的关注是该计划的核心要素。主要目标是描述 B 细胞及其受体在疾病各个阶段的分子多样性，以识别致病群体 及其抗原靶标。 多层实验策略包括单细胞 B 细胞转录组学以及综合 噬菌体展示的合成人类、病毒和微生物肽组，用于筛选抗体指纹 对抗血清、脑脊液和重组抗体库中的外部驱动因素。综合分析将 使用临床、MRI 和遗传决定因素将数据置于背景中，努力应用严格的统计 原则，包括独立复制。