Role of GPNMB Signaling in Remyelination by Oligodendrocyte Progenitor Cells

摘要 少突胶质细胞的丢失会引起脱髓鞘，最终导致轴突退化和衰弱。 多发性硬化症等疾病的临床结果。虽然重新髓鞘化能防止神经退化，但 目前还没有被批准的促进髓鞘再生的疗法。因此，迫切需要确定各种因素。 控制重新髓鞘形成的物质。成人脑中的少突胶质细胞前体细胞(OPC)是主要来源之一 少突胶质细胞重新髓鞘形成。然而，在慢性脱髓鞘中，它们对于重新髓鞘形成是无效的 耗尽和/或阻碍它们的成熟。使用生物信息学分析和髓鞘再分化的组合 在小鼠身上的研究中，我们发现了一种新的7*)介体？途径，高表达的GPNMB 与其受体CD44一起作用于脱髓鞘。GPNMB是一种跨膜蛋白，可被 蛋白水解酶分为胞内区(GPNMB-ICD)和胞外区(GPNMB-ECD)。而GPNMB-ICD可以 通过转位到细胞核，释放的GPNMB-ECD发挥自分泌或 旁分泌信号通过分别与同一细胞或相邻细胞中的CD44受体相互作用而实现。在第一个 目的：我们将确定GPNMB在少突胶质前体细胞和第二代细胞中的细胞自主功能。 目的：我们将确定内源性和外源性GPNMB信号对下列OPC的联合作用 铜试剂可致脱髓鞘。总之，这些研究不仅将有助于阐明分子机制 参与成人OPC的成熟，但也可能确定促进再髓鞘形成的治疗靶点。

ABSTRACT Loss of oligodendrocytes gives rise to demyelination, ultimately resulting in axonal degeneration and debilitating clinical outcomes in diseases like Multiple Sclerosis. While remyelination can prevent neurodegeneration, there are currently no approved therapies for promoting remyelination. Thus, there is an urgent need to identify factors that control remyelination. Oligodendrocyte progenitor cells (OPCs) in the adult brain are one of the key sources of remyelinating oligodendrocytes. However in chronic demyelination, they are inefficient for remyelination due to depletion and/or a block in their maturation. Using a combination of bioinformatic analysis and remyelination studies in mice, we discovered a novel mediator of the 7*)? pathway, Gpnmb which is highly expressed along with its receptor CD44 in response to demyelination. Gpnmb is a transmembrane protein that is cleaved by proteases into an intracellular domain (Gpnmb-ICD) and an ectodomain (Gpnmb-ECD). While Gpnmb-ICD can signal intrinsically by translocating to the nucleus, the released Gpnmb-ECD functions as an autocrine or paracrine signal by interacting with CD44 receptor in the same cell or a neighboring cell respectively. In the first aim, we will define the cell-autonomous function of Gpnmb in oligodendrocyte progenitor cells and in the second aim, we will determine the combined effect of intrinsic and extrinsic Gpnmb signaling on OPCs following cuprizone induced demyelination. Together, these studies will not only help elucidate the molecular mechanisms involved in maturation of adult OPCs but may also identify therapeutic targets for promoting remyelination.