Development of drug screening platforms for central nervous system regeneration

许多神经疾病的特征是神经纤维周围的绝缘层受损，称为髓鞘，导致神经损伤/丧失以及认知、运动和感觉障碍。尽管髓鞘可以再生，但这一过程在疾病中经常失败(例如，在脑瘫或进行性多发性硬化症中)，目前还没有批准加强这一过程的治疗方法。确定药物靶点以开发新的治疗方法是具有挑战性的，因为支持髓鞘成功再生的机制尚未被很好地了解。因此，识别促再生治疗的最快途径是筛选已被批准用于其他适应症的药物。然而，如果不使用大量的实验动物，目前还不存在在受伤的哺乳动物大脑中有效筛选药物的平台。该博士项目将开发一个筛选平台，该平台将允许在受伤的哺乳动物大脑中首次进行专门针对适合再利用的再生药物的无偏见药物筛选。该项目将包括将已建立的脑损伤脑外植体模型与自动实时成像和分析相结合，以进行髓鞘再生的药物筛选。这涉及到转基因动物的使用、细胞培养、活体成像、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。这种方法还将作为自动化器官外植体筛选的概念验证研究，并确定一种最终可能导致髓鞘再生的临床试验的药物。这个实验室设在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来支持疾病中的这一过程。该实验室由PI、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项目和爱丁堡MS研究中心，并将参加具有共同研究兴趣的小组的实验室会议、本地会议和国际会议。

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.