The purpose of this project is to identify the critical regulators of remyelination in multiple sclerosis (MS) brains. It has been long established that oligodendrocyte progenitor cells (OPCs) populate MS lesions but do not transform into mature oligodendrocytes (OL) for reasons that remain unresolved. Therefore, one of the critical questions to ask is can we identify factors that prevent these cells from being able to mature and remyelinate? In recent years, microRNAs (miRNAs) have been identified as critical regulators of gene expression. We performed a comprehensive analysis of MS white matter lesions and identified 9 miRNAs that target 12 genes associated with the maturation of OPCs into mature OLs.
Aim 1 in the current proposal will therefore validate these miRNAs and target genes in MS brains, specifically in grey matter.
Aim 2 will build on these findings and provide in vitro evidence of the capacity of these miRNAs to induce myelination in OPCs. The next question to be answered is does loss of miRNAs lead to decreased remyelination by halting the progression of OPCs maturing into myelinating OLs in vivo? We propose to answer this question by using mice with loss of the miRNA processing enzyme Dicer in mature OLs and in OPCs. The role of miRNAs in promoting remyelination in vivo will be tested in Aim 3. The future of MS therapeutics lies in the identification of additional therapeutic targets and in developing combinatorial strategies. By characterizing failed myelin repair in MS brains, the studies outlined in this proposal should identify novel targets that will enhance repair of the MS brain.

Public Health Relevance

Multiple Sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system. While current anti-inflammatory therapies are effective during the initial relapsing phase of the disease, limited success is achieved during the progressive disease course. Promoting remyelination is considered to be the best option for the treatment of progressive MS. This project is designed to further enhance our understanding of the factors that influence remyelination in MS. Our data have identified several critical regulators that could account for failed myelin repair in MS brains. The current study will further investigate these regulators and could lead to the development of novel therapeutic approaches to repair the damage caused by demyelination and to improve the lives of patients with MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS096148-03
Application #
9431252
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2016-05-15
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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