孤儿受体GPR149在脱髓鞘疾病中的作用研究及其配体发现

脱髓鞘疾病指的是一类以髓鞘损伤、脱失为主要病理特征的中枢神经系统疾病。脱髓鞘疾病目前的治疗药物以靶向外周免疫系统为主，只能在一定程度延缓疾病进程，不能恢复已有的髓鞘损伤。因此，促髓鞘再生修复靶点的发现与药物研发具有十分广阔的应用前景。在前期研究中，我们发现孤儿受体GPR149在少突胶质细胞细胞前体细胞（OPC）分化的过程中表达量下调；GPR149敲除可提高OPC分化效率与髓鞘形成，并且GPR149敲除小鼠髓鞘的发育比同窝野生型小鼠提前，提示GPR149参与调控髓鞘的发育，有可能在髓鞘再生中发挥重要作用。我们将进一步研究GPR149在髓鞘发育与再生中的作用及其作用机制。我们将利用GPR149细胞系进行化合物筛选，希望发现GPR149小分子配体，明确GPR149偶联的G蛋白及下游效应分子，并探究GPR149拮抗剂在髓鞘再生中的应用价值，为脱髓鞘疾病药物研发提供新的选择。

Demyelinating disease is a kind of central nervous system diseases that results in myelin damage and loss. To date, drugs in clinical target the immune system which can delay the course of disease without curing damaged myelin. Therefore, identification of targets and small molecules that promote remyelination and functional recovery has received much attention. Our preliminary studies demonstrated that GPR149 was downregulated during oligodendrocyte precursor cell (OPC) differentiation. GPR149 knockout significantly promoted OPC differentiation and myelin generation in vitro, as well as mylin development in vivo. These results indicated that GPR149 was involved in myelination, and may play an important role in remyelination. We plan to further study the role and mechanism of GPR149 in myelination and remyelination. We also plan to identify small molecular ligands of GPR149 through compound screening. Hopefully, with new identified GPR149 agonists and antagonists, we would be able to identify downstream G-proteins and effectors of GPR149, understand the role of GPR149 in remyelination and explore the possibility that GPR149 can be used as a new target for remyelination therapy.