NOVEL HYALURONIDASE INHIBITORS FOR THE PROMOTION OF REMYELINATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 少突胶质前体细胞(OPC)可以在中枢神经系统(CNS)中成为髓鞘形成的少突胶质细胞(OLs)。在多发性硬化症(MS)患者中，OPC迁移到脱髓鞘病变，但通常不能成熟为使脱髓鞘轴突重新髓鞘的OL。髓鞘再生失败会导致多发性硬化症患者长期的神经功能障碍。我们之前发现，一种名为透明质酸(HA)的多糖在多发性硬化症患者的皮损中积累。我们的初步数据表明，OPC表达透明质酸酶，这种酶可以分解HA，而HA的分解产物抑制OPC成熟为髓鞘形成的OL。此外，这些HA分解产物抑制再髓鞘形成，一种抑制透明质酸酶活性的药物可以在体外促进OPC成熟。我们的假设是，重新髓鞘形成失败可以通过药物阻断透明质酸酶活性来逆转。在这里，我们的目标是： (1)鉴定吲哚甲酰胺及其他在体外抑制透明质酸酶活性和促进OPC成熟的衍生物。 (2)检测全身抑制透明质酸酶活性是否促进实验性脱髓鞘疾病小鼠的重新髓鞘形成。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Oligodendrocyte progenitor cells (OPCs) can become myelin-forming oligodendrocytes (OLs) in the central nervous system (CNS). OPCs migrate to demyelinating lesions in patients with multiple sclerosis (MS) but often fail to mature into OLs that remyelinate demyelinated axons. Remyelination failure leads to long-term neurological deficits in MS patients. We previously found that a polysaccharide called hyaluronan (HA) accumulates in MS patient lesions. Our preliminary data indicate that OPCs express hyaluronidases, enzymes that break-down HA, and that breakdown products of HA inhibit the maturation of OPCs into myelin-forming OLs. Furthermore, these HA breakdown products inhibit remyelination and a drug that inhibits hyaluronidase activity can promote OPC maturation in vitro. Our hypothesis is that remyelination failure can be reversed by pharmacologically blocking hyaluronidase activity. Here, we aim to: (1) Identify indole carboxamide and other derivatives that inhibit hyaluronidase activity and promote OPC maturation in vitro. (2) Test if systemic suppression of hyaluronidase activity promotes remyelination in mice with experimentally-induced demyelinating diseases.