中枢髓鞘丢失或生成异常见于多种神经及精神疾病之中，保护或修复髓鞘成为此类疾病治疗的新途径。糖皮质激素GC对CNS的生理结构和功能具有重要塑造作用，也参与了诸多病理过程。深入揭示GC在少突胶质细胞OL生成和髓鞘形成与再生中的作用及机制，无疑有助于髓鞘相关疾病新治疗策略的开发。本组发现，双侧肾上腺摘除小鼠对铜腙诱导的毒性非免疫性脱髓鞘损伤高度敏感，而其再髓鞘化能力则显著降低。该结果强烈提示内源性GC可能以某种不依赖于其寻常抗炎和免疫抑制效应的全新分子机制作用于OL，对后者的生成与存活，以及髓鞘形成和再生起到直接的重要作用。本项目将利用本组新近报道的新生OL标记物ENPP6，在多种体内外实验模型，尤其是OL前体细胞中特异敲除GC受体的转基因小鼠，以转录组测序分析mRNA、LncRNA等寻找下游关键作用基因，结合分子生化和形态学方法，求证上述猜想并探明分子机制，有望为GC的神经作用研究打开新境界。

Myelin is a critical structure for the normal function of the central nervous system (CNS). Central myelin is made by the oligodendrocytes (OLs) through wrapping of the axons with their membranes. It is susceptible to various insults and can result in myelin loss, e.g. demyelination or myelin malformation, which can be seen in a wide variety of neurological and psychiatric disorders such as multiple sclerosis (MS) and depression in adults, or hypoxic ischemic encephalopathy (HIC) and autism in children. Thus, protecting or repairing the myelin structure has emerged as an important therapeutic approach for these myelin related diseases. Glucocorticoid (GC) is known to intensively sculpture the structure and function of the CNS/brain and at the same time, highly involved in various pathological conditions. An insight in to the effect and mechanism of GC on OL production and myelin formation as well as remyelination will obviously helpful for the pursuing of new strategies to the treatment of OL and myelin related disorders. This group has focused on OL and myelin related research for years and also carried out several works dealing with the GC’s function in the CNS. Most recently, we found that bilateral adrenalectomized (ADX) mice, which are deprived of endogenous GC, showed a hypersensitivity to cuprizone induced demyelination (a widely used non-immune toxin-induced demyelination model) and also a significantly decreased ability of remyelination comparing to the sham operated mice. Moreover, both phenotypes can be rescued by intraperitoneal administration of corticosterone, the endogenous GC in rodents. Given the ever-reported (and also firmed in our own hands) expression of glucocorticoid receptor (GR) in both OL and OL precursor cell (OPC), this result strongly suggests that GC may act directly on OPC and OL to regulate the production and survival of OL, the forming and maintenance of myelin structure, as well as remyelination, through novel mechanisms independent of its generally known anti-inflammation and immune suppression effects. In the current proposal, we aim to take advantage of our most recently defined newly forming OL marker Enpp6 to further test this hypothesis by using various in vivo and in vitro models. And in particular, we will use GRloxP/loxP and Pdgfra-Cre ERT2 (Pdgfra: platelet derived growth factor receptor alpha, which is specifically expressed by OPC in the CNS and has been widely used as a biomarker for OPC) transgenic mice to time controllably knock out GR gene specifically in OPC during embryonic stage or in adult. We will then introduce transcriptome sequencing to figure out the key molecules/genes including protein, LncRNA or microRNA that are responsible for the GC’s effects on OPC and reveal the underlying mechanisms. This research project shall shed new light on the classical scientific question of how GC functions in the CNS, and provide new avenues for refining the use of GC therapy in various clinical neuropsychiatric conditions.