MicroRNAs as critical regulators of remyelination in Multiple Sclerosis

科学摘要： 这个项目的目的是确定多发性硬化症(MS)重新髓鞘形成的关键调节因素。 大脑。少突胶质细胞前体细胞(OPC)存在于多发性硬化症的皮损中，这一点早已得到证实。 由于尚未解决的原因，未转化为成熟的少突胶质细胞(OL)。因此，其中一个 要问的关键问题是，我们能否识别阻止这些细胞能够成熟和 再生髓鞘？近年来，microRNAs(MiRNAs)被认为是基因的关键调控因子。 表情。我们对多发性硬化症白质病变进行了全面的分析，发现了9个miRNAs 靶向12个与OPC成熟成成熟OL相关的基因。当前提案中的目标1将 因此，验证这些miRNAs和MS大脑中的靶基因，特别是灰质中的基因。AIM 2将在此基础上发展 这些发现并为这些miRNAs诱导OPC髓鞘形成的能力提供了体外证据。 下一个需要回答的问题是：miRNAs的丢失是否会通过阻止 OPC在体内成熟为髓鞘OL的研究进展？我们建议使用以下方法来回答这个问题 在成熟的OPC和OPC中丢失miRNA处理酶Disher的小鼠。MiRNAs在生物信息学中的作用 在体内促进髓鞘再生将在目标3中进行测试。多发性硬化症治疗的未来在于确定 更多的治疗靶点和开发组合策略。通过描述失败的髓鞘修复 在多发性硬化症大脑中，这项提议中概述的研究应该确定新的靶点，这些靶点将加强对 布莱恩女士。

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.