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.

Public Health Relevance

This research application is relevant to the public health because the identification of microRNA-based therapies for remyelination brings the opportunity to improve treatment of multiple sclerosis and other demyelinating diseases. Therefore, this proposal is relevant to the NIH's mission of furthering knowledge that will contribute to reduce neurological burden.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
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University of Illinois at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
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Moyano, Ana Lis; Steplowski, Jeffrey; Wang, Haibo et al. (2018) microRNA-219 Reduces Viral Load and Pathologic Changes in Theiler's Virus-Induced Demyelinating Disease. Mol Ther 26:730-743
Wang, Haibo; Moyano, Ana Lis; Ma, Zhangyan et al. (2017) miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS. Dev Cell 40:566-582.e5
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