Drug-mediated enhancement of myelination

药物介导的髓鞘形成增强

• 批准号: 9019775
• 负责人: ROBERT H. MILLER
• 金额: $ 40.51万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9019775
• 关键词: Address; Adult; Animal Disease Models; Antifungal Agents; Area; Autoimmune Process; Autoimmune Responses; Biological Assay; Blood - brain barrier anatomy; Cell Differentiation process; Cells; Chemicals; Chronic; Clinical; Clinical Trials; Complex; Cytochrome P450; Data; Demyelinating Diseases; Demyelinations; Disease; Disease Progression; Electron Microscopy; Etiology; FDA approved; Failure; Frequencies; Generations; Genetic; Grant; Human; Immune system; Immunohistochemistry; Impaired cognition; In Vitro; Inflammatory; Injury; Intervention; Lesion; Libraries; MAPK3 gene; Mediating; Mediator of activation protein; Miconazole; Molecular; Mono-S; Morbidity - disease rate; Multiple Sclerosis; Mus; Myelin; Natural regeneration; Nerve; Nerve Degeneration; Neuraxis; Oligodendroglia; Outcome; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Pluripotent Stem Cells; Prevention; Production; Progressive Disease; Relapse; Rodent; Signal Transduction; Site; Source; Stem cells; System; Testing; Therapeutic; Tissues; Toxin; Translations; axon injury; base; cell type; cellular targeting; central nervous system demyelinating disorder; chemical genetics; disability; high throughput screening; improved; improved functioning; in vitro Model; in vivo; innovation; molecular dynamics; mortality; motor impairment; mouse model; myelination; nervous system disorder; novel; prevent; public health relevance; relating to nervous system; remyelination; repaired; research clinical testing; screening; stem cell population; success; young adult

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a complex, debilitating neural disorder associated with significant morbidity and mortality. Disease etiology is a result o unknown environmental and genetic factors, while disease pathology presents as inflammatory injury to the central nervous system (CNS) causing physical incapacity. This damage is a result of autoimmune-mediated destruction of oligodendrocytes causing demyelination. Prolonged demyelination leads to axonal damage occurring either in focal lesion sites and/or widespread throughout the CNS, depending on presentation of the disease. MS is treated with disease-modifying agents that target the immune system in an attempt to reduce the frequency of relapses and delay disease progression. These drugs have had limited success in improving patient outcomes and lack the unmet need to promote immediate remyelination. Identifying drugs that induce resident oligodendrocyte progenitor cell (OPC) mediated remyelination would provide patients a vital mechanism to halt disease progression and improve function. Using an innovative pluripotent stem cell-based high throughput screening platform we have discovered a class of FDA approved drugs that enhance remyelination in mouse models of MS. In this grant we will use in vivo and in vitro models to study the cellular and molecular effects of this class o drugs on mouse and human OPCs. These studies will provide the basis for potential translation of this drug, or modified derivatives, to clinical testing as a remyelinating therapeutic.

 描述（由申请人提供）：多发性硬化症（MS）是一种复杂的、使人衰弱的神经疾病，与显著的发病率和死亡率相关。疾病病因是未知的环境和遗传因素的结果，而疾病病理表现为中枢神经系统（CNS）的炎性损伤，导致身体机能丧失。这种损伤是自身免疫介导的少突胶质细胞破坏导致脱髓鞘的结果。根据疾病的表现，长期脱髓鞘导致轴突损伤发生在局灶性病变部位和/或广泛分布于整个CNS。MS用靶向免疫系统的疾病修饰剂治疗，试图降低复发频率并延迟疾病进展。这些药物在改善患者预后方面的成功有限，并且缺乏促进立即髓鞘再生的未满足需求。鉴定诱导常驻少突胶质祖细胞（OPC）介导的髓鞘再生的药物将为患者提供阻止疾病进展和改善功能的重要机制。使用创新的多能干细胞为基础的高通量筛选平台，我们已经发现了一类FDA批准的药物，增强髓鞘再生的MS小鼠模型。在这项资助中，我们将使用在体内和体外模型来研究这类药物对小鼠和人类OPCs的细胞和分子效应。这些研究将为这种药物或修饰的衍生物作为髓鞘再生治疗药物进行临床试验提供基础。