Development of drug screening platforms for central nervous system regeneration

中枢神经系统再生药物筛选平台的开发

• 批准号: 2266079
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2266079
• 关键词: Development; drug; screening; platforms; central

Numerous neurological disorders are characterized by damage to the insulation surrounding nerve fibres, termed myelin, leading to nerve damage/ loss and cognitive, motor, and sensory deficits. Although myelin can be regenerated, this process often fails in disease (for example in cerebral palsy or progressive MS), and no therapies are currently approved to enhance this process. Identifying drug targets to develop new therapies is challenging, as the mechanisms underpinning successful regeneration of myelin are not well understood.Thus, the most rapid route to identifying pro-regenerative therapies is to screen drugs that have been approved for other indications. However, no platform currently exists for efficient screening of drugs in the injured mammalian brain without the use of a large number of experimental animals.This PhD project will develop a screening platform that will allow for the first unbiased drug screen in injured mammalian brain specifically for regenerative drugs suitable for repurposing. The project will involve combining established brain explant models of brain injury with automated live-imaging and analyses to carry out a drug screen for myelin regeneration. This involves the use of transgenic animals, cell culture, live imaging, confocal microscopy, setting up imaging analyses pipelines, 3D printing, experimental design and statistical analyses. This approach will also serve as a proof-of-concept study for automated organ explant screening, and identify a drug that may eventually lead to a clinical trial for myelin regeneration. The focus of this lab, based at The Queen's Medical Research Institute in the MRC Centre for Reproductive Health, is to understand the cellular and molecular mechanisms regulating myelin regeneration and to identify new therapeutic strategies to support this process in disease. The lab is composed of the PI, a PhD student, 2 postdocs, and a research assistant. The student will be integrated into the Edinburgh Neuroscience program and the Edinburgh Centre for MS Research, and will participate in lab meetings from groups with shared research interests, local conferences/meetings, and international conferences.

许多神经系统疾病的特征在于神经纤维周围的绝缘层（称为髓磷脂）受损，导致神经损伤/丧失以及认知、运动和感觉缺陷。虽然髓鞘可以再生，但这一过程在疾病中往往失败（例如脑瘫或进行性MS），目前没有批准的治疗方法可以增强这一过程。确定药物靶点以开发新疗法是具有挑战性的，因为支持髓鞘成功再生的机制还不清楚。因此，确定促再生疗法的最快速途径是筛选已被批准用于其他适应症的药物。然而，目前还没有一个平台可以在不使用大量实验动物的情况下有效地筛选受损哺乳动物大脑中的药物。本博士项目将开发一个筛选平台，该平台将允许在受损哺乳动物大脑中进行第一次无偏见的药物筛选，专门用于再生药物。该项目将涉及将已建立的脑损伤脑外植体模型与自动化实时成像和分析相结合，以进行髓鞘再生的药物筛选。这涉及转基因动物的使用、细胞培养、实时成像、共聚焦显微镜、建立成像分析管道、3D打印、实验设计和统计分析。这种方法也将作为自动器官移植筛选的概念验证研究，并确定最终可能导致髓鞘再生临床试验的药物。该实验室位于MRC生殖健康中心的女王医学研究所，其重点是了解调节髓鞘再生的细胞和分子机制，并确定新的治疗策略以支持疾病中的这一过程。实验室由主要研究者、一名博士生、两名博士后和一名研究助理组成。学生将被纳入爱丁堡神经科学计划和爱丁堡MS研究中心，并将参加具有共同研究兴趣的小组，当地会议/会议和国际会议的实验室会议。