可变剪接调控分子Tra2β介导衰老阶段中枢髓鞘再生障碍的作用及机制研究

大脑极易受到衰老的影响而发生退行性改变，其中髓鞘化神经纤维所受的影响较皮层灰质的更为严重。研究表明衰老是影响髓鞘再生效率最重要的因素之一，但衰老阶段由OPCs自身分化缺陷导致髓鞘再生障碍的发生机制尚未阐明。本课题预实验发现：①可变剪接调控分子Tra2β在中枢白质中的表达水平随着衰老逐渐下降，且主要在少突胶质谱系细胞中下调；②Tra2β可以明显地促进OPCs的体外、体内分化及髓鞘化；③诱导性条件性敲除Tra2β则会显著抑制LPC病灶中OPCs分化及再髓鞘化。拟将采用LPC脱髓鞘模型、条件性基因敲除小鼠、分子生物学等技术进一步检测Tra2β的下调是否介导了衰老对中枢髓鞘再生的抑制作用；其次，评估Tra2β过表达能否挽救衰老阶段中枢髓鞘再生障碍；最后，揭示Tra2β发挥作用的下游靶分子。这些研究为衰老阶段中枢髓鞘再生障碍提供了新的分子机制，并为脱髓鞘相关神经精神类疾病的治疗提供新思路和新靶点。

Brain is susceptible to degeneration associated with aging. In the brain, myelinated nerve fibers are more severely affected than cortical gray matter by aging. Studies had manifested that aging acted as one of the most significant factors affecting the efficiency of myelin regeneration. However, the underlying mechanism by which aging affects OPCs differentiation and remyelination is not fully understood yet. Our preliminary data have shown that：①The expression of Transformer 2 beta (Tra2β) was dramatically decreased in white matter during aging. The decline of Tra2β expression was mainly located in oligodendrocyte lineage cells. ②Tra2β was found to promote the differentiation and myelination of OPCs in vitro and in vivo. ③Significantly, the induced conditional deletion of Tra2β in OPCs remarkably inhibited OPCs differentiation and remyelination in LPC mice. Next, we aim to further clarify the effect of Tra2β down-regulation in mediating the inhibitory effect of aging on remyelination based on LPC induced demyelination models, conditional knockout mice, cellular and molecular biological technologies. Secondly, we will examine whether Tra2β overexpression could rescue the remyelination failure of aged CNS. Lastly, we will explore the molecular mechanism of Tra2β in regulating OPCs differentiation and remyelination in aged CNS. These studies will help elucidate the molecular mechanism of aging in affecting myelin regeneration, and provide a novel strategy and drug target for the therapy of demyelinating diseases.