少突胶质细胞分化和髓鞘化过程中QKI转录上调及其同工蛋白QKI-6产生的分子机制和作用研究

弄清少突胶质细胞（OLs）分化和髓鞘化的具体分子机制，有助于建立通过加强髓鞘产生来治疗脱髓鞘疾病的新方法。在前期研究中我们确立了一个新的基于OLs特异性转录抑制因子Nkx2.2和起转录后调控作用的RNA结合蛋白QKI的反馈环路，该环路控制OLs分化和髓鞘化的时间轴。然而启动削弱Nkx2.2对QKI转录的抑制，推动该环路的原始驱动力尚不清楚，且后续QKI如何通过可变剪切产生同工蛋白QKI-6作用于OLs分化和髓鞘产生也不明晰。本项目拟分析在OLs发育过程中，是否是组蛋白去乙酰化消减了转录抑制因子对QKI的转录抑制作用；探究随后QKI可变剪切产生同工蛋白QKI-6的分子机制；利用QKI-6条件性敲除小鼠研究该蛋白对OLs分化和髓鞘化的必要性，并利用小鼠脱髓鞘模型研究上述分子机制是否适用于髓鞘再生。这些研究将使我们进一步完善对QKI调控通路的认识，为髓鞘相关疾病治疗新方法的提出提供理论基础。

To elucidate the mechanisms that control myelinogenesis is a crucial prerequisite for developing novel strategies to enhance myelin repair. Based on the preliminary studies, we identified a novel feedback loop between the Oligodendryctes (OLs)-specific transcription repressor Nkx2.2 and the RNA-binding protein QKI for post-transcriptional regulation, which controls the timing and progression of OLs differentiation. However, how to decline the suppression of Nkx2.2 on QKI transcription to impulse this loop still remains elusive, and following effect of QKI on OLs differentiation and myelination remains nearly completely undefined. In this study, we will determine whether histone deacetylation declines the repression of transcriptional factors on QKI, and up-regulates the transcription of QKI. We will study the underlying mechanisms that trans-acting splicing factor PTB governs alternative splicing of the QKI pre-mRNA to control the isoprotein QKI-6 production. At the same time, we will produce spatiotemporal QKI-6 mutant to test its essentiality for OLs differentiation, myelination. Furthermore, we will demonstrate weather above mechanisms are suitable for remyelination or not. Successful completion of the proposed studies will provide critical insights regarding fundamental mechanisms that control myelination and repair, which ultimately may help to develop novel strategies to enhance myelinogenesis and benefit a variety of myelin disorders.