Therapies to Stimulate Remyelination

刺激髓鞘再生的疗法

• 批准号: 8821792
• 负责人: Ernesto Roque Bongarzone
• 金额: $ 20.79万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821792
• 关键词: Animal Model; Animals; Autoimmune Process; Brain; Complement; Data; Demyelinating Diseases; Demyelinations; Disease; Drug Formulations; Family Picornaviridae; Gene Expression; Generations; Gliosis; Goals; Growth; Histological Techniques; Immunologic Techniques; In Vitro; Infection; Knowledge; Laboratories; Mediating; MicroRNAs; Mind; Mission; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Nerve Degeneration; Nerve Tissue; Neuroglia; Neurologic; Neurons; Oligodendroglia; Patients; Pilot Projects; Production; Public Health; Publications; Regulatory Pathway; Research; Role; Severity of illness; Signal Transduction; Small RNA; Syndrome; TMEV; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Viral; Vision; base; design; improved; in vivo; member; mouse model; neuroprotection; pre-clinical; progenitor; public health relevance; relating to nervous system; remyelination; repaired; small molecule; stem

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.

描述（由申请人提供）：尽管在过去的二十年中，我们对少突胶质细胞及其祖细胞的形成及其祖细胞的了解已经大大增长，但特定疗法的提出促进髓磷脂疾病患者（如多发性硬化症（MS））的透露率仍然远非实现。理想的疗法将包括使用 小分子以特异性激活少突胶质细胞祖细胞的产生，并在足够长的时间内使少突胶质细胞再髓呈少突胶质细胞。然后，该疗法应该是可控制的（即治疗师应该能够打开/关闭透明透明的少突胶质细胞的产生，以促进正确的神经修复水平）。考虑到对恢复性的这种概念的概念，该试验应用I的目的是获得概念证明，即可以使用一组microRNA来改善MS鼠标模型中的再生。 microRNA（miR）是小的RNA分子，在转录后水平上对基因表达产生深刻的调节控制。 miR -138，-219和-338以及miR簇17-92的成员似乎可以积极控制少突胶质细胞分化。该应用程序的初步数据表明，其中一些microRNA在Theiler的鼠脑脊髓炎病毒（TMEV）模型中被下调。该应用将挑战以下假设，即通过外源给感染的TMEV感染小鼠中促寡胶质细胞miR的缺乏，通过外源性施用合成miR（互补疗法）将通过增加功能性髓髓性少突胶质细胞来改善透明度。该项目之所以重要，是因为有望提高对MiR如何调节体内的rem髓的理解，尤其是在MS模型中。最终，这种理解有可能为改善MS的现有免疫调节疗法做出贡献。