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MicroRNAs as critical regulators of remyelination in Multiple Sclerosis

MicroRNA 作为多发性硬化症髓鞘再生的关键调节因子

基本信息

批准号：
9272452
负责人：
Ranjan Dutta
金额：
$ 34.67万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272452
关键词：
Address Affect Anti-Inflammatory Agents Anti-inflammatory Binding Bioinformatics Brain Cell Maturation Cell Survival Cells Central Nervous System Diseases Chronic Cuprizone Data Demyelinating Diseases Demyelinations Development Dicer Enzyme Disease Experimental Autoimmune Encephalomyelitis Future Gene Expression Gene Targeting Genes Human In Situ Hybridization In Vitro Inflammatory Lead Lesion Measures Messenger RNA MicroRNAs Molecular Target Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Neurodegenerative Disorders Oligodendroglia Pattern Phase Process Progressive Disease Proteins Protocols documentation Regulator Genes Relapse Repression Research Role Signal Transduction Source Specificity Stem cells Testing Therapeutic Translations combinatorial comparative density design gene synthesis gray matter improved in vivo inhibitor/antagonist mind control mouse model multiple sclerosis patient multiple sclerosis treatment myelination novel novel therapeutic intervention oligodendrocyte progenitor overexpression prevent remyelination repaired success therapeutic target white matter

项目摘要

Scientific Summary: 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.

科学总结：本项目的目的是确定多发性硬化症（MS）髓鞘再生的关键调节因子大脑长期以来，已经确定少突胶质祖细胞（OPCs）在MS病变中聚集，但在MS病变中，未转化为成熟的少突胶质细胞（OL）的原因尚未解决。因此，其中的关键的问题是我们能否识别出阻止这些细胞成熟的因素，髓鞘再生近年来，microRNAs（miRNAs）已被鉴定为基因调控的关键因子，表情我们对MS白色病变进行了全面分析，并鉴定了9种miRNA，靶向与OPCs成熟为成熟OL相关的12个基因。本提案中的目标1将因此验证了这些miRNA和MS大脑中的靶基因，特别是在灰质中。目标2将建立在这些发现提供了这些miRNAs诱导OPCs髓鞘形成能力的体外证据。下一个需要回答的问题是“miRNAs的丢失是否会通过阻止髓鞘再生而导致髓鞘再生减少？ OPCs在体内成熟为髓鞘化OLs的进展？我们建议用以下方法来回答这个问题：在成熟OL和OPC中缺失miRNA加工酶Dicer的小鼠。miRNAs在促进体内髓鞘再生将在目标3中测试。MS治疗的未来在于识别额外的治疗靶点和开发组合策略。通过描述髓磷脂修复失败在多发性硬化症的大脑中，这项提案中概述的研究应该确定新的靶点，大脑女士