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Therapies to Stimulate Remyelination

刺激髓鞘再生的疗法

基本信息

批准号：
8935960
负责人：
Ernesto Roque Bongarzone
金额：
$ 21.8万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8935960
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 Health 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 relating to nervous system remyelination repaired small molecule stem therapeutic miRNA

项目摘要

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(申请人提供)：尽管我们对少突胶质细胞及其前体细胞的形成的了解在过去20年中有了巨大的增长，但促进多发性硬化症(MS)等髓鞘疾病患者重新髓鞘形成的特定疗法的制定仍远未实现。理想的治疗方法应该包括使用小分子特异性地激活少突胶质前体细胞的产生，并在足够长的时间内重新分化少突胶质细胞，以允许髓鞘修复。这种疗法应该是可控的(即治疗师应该能够打开/关闭再生髓鞘少突胶质细胞的产生，以促进适当水平的神经修复)。考虑到这种再髓鞘形成疗法的概念性愿景，这一试点应用程序的目标是获得概念证明，即一组microRNA可用于改善MS小鼠模型中的再髓鞘形成。microRNA(MiR)是在转录后水平对基因表达施加深刻调控的小RNA分子。MiR-138、-219和-338以及miR簇17-92的成员似乎对少突胶质细胞的分化有积极的控制作用。这一应用的初步数据显示，其中一些microRNA在多发性硬化症的泰勒小鼠脑脊髓炎病毒(TMEV)模型中下调。这一应用将挑战这样一种假设，即通过外源性给予合成miR(补充疗法)来逆转TMEV感染小鼠的前少突胶质细胞miR缺陷，将通过增加功能性髓鞘少突胶质细胞的数量来促进再髓鞘形成。该项目意义重大，因为它有望促进对miR如何调节体内再髓鞘形成的理解，特别是在MS的模型中。归根结底，这种理解有可能有助于改进现有的MS免疫调节疗法。