Therapies to Stimulate Remyelination

描述（由申请人提供）：尽管我们关于少突胶质细胞及其祖细胞形成的知识在过去二十年中有了巨大的增长，但促进髓鞘疾病如多发性硬化症（MS）患者髓鞘再生的特异性疗法的制定仍远未实现。理想的治疗方法包括使用 小分子以在足够长的时间段内特异性激活少突胶质细胞祖细胞和髓鞘再生少突胶质细胞的产生，以允许髓鞘修复。这种治疗应该是可控的（即治疗师应该能够打开/关闭髓鞘再生少突胶质细胞的产生，以促进神经修复的正确水平）。考虑到髓鞘再生疗法的这种概念性视野，该试验性应用的目标是获得一组微小RNA可用于改善MS小鼠模型中的髓鞘再生的概念验证。微小RNA（miR）是在转录后水平对基因表达施加深刻调控控制的小RNA分子。miR-138、-219和-338以及miR簇17-92的成员似乎正控制少突胶质细胞分化。本申请的初步数据显示，这些微RNA中的一些在MS的Theiler小鼠脑脊髓炎病毒（TMEV）模型中下调。本申请将挑战以下假设：通过外源性施用合成miR（互补疗法）来恢复TMEV感染的小鼠中的前少突胶质细胞miR的缺乏将通过增加功能性髓鞘生成少突胶质细胞的数量来改善髓鞘再生。该项目意义重大，因为它有望推进对miR如何调节体内髓鞘再生的了解，特别是在MS模型中。最终，这种了解有可能有助于改善MS的现有免疫调节疗法。

DESCRIPTION (provided by applicant): Although our knowledge about the formation of oligodendrocytes and their progenitors has grown enormously during the past two decades, the formulation of specific therapies to promote remyelination in patients with myelin diseases such as multiple sclerosis (MS) is still far from realization. An ideal therapy would include the use of small molecules to specifically activate the production of oligodendrocyte progenitors and remyelinating oligodendrocytes during a period of time sufficiently long to allow myelin repair. This therapy should then be controllable (i.e. therapists should be able to turn on/off the production of remyelinating oligodendrocytes to promote the right level of neural repair). With this conceptual vision of therapies for remyelination in mind, the goal of this pilot application i to obtain proof-of-concept that a set of microRNA can be used to improve remyelination in a mouse model of MS. MicroRNA (miR) are small RNA molecules which exert profound regulatory control of gene expression at the post-transcriptional level. miR-138, -219 and -338 and also members of the miR cluster 17-92 appear to positively control oligodendrocyte differentiation. Preliminary data for this application show that some of these microRNA are downregulated in the Theiler's murine encephalomyelitis virus (TMEV) model of MS. This application will challenge the hypothesis that reverting the deficiency of pro-oligodendrocyte miR in TMEV-infected mice by exogenous administration of synthetic miR (complementation therapy) will improve remyelination by increasing numbers of functional myelinating oligodendrocytes. The project is significant because it is expected to advance the understanding of how miR regulate remyelination in vivo, particularly in a model of MS. Ultimately, such understanding has the potential to contribute to improve existing immunomodulatory therapies for MS.