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。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 少突胶质细胞祖细胞（Oligodendrocyte progenitor cells，OPCs）在中枢神经系统（central nervous system，CNS）中可分化为髓鞘形成的少突胶质细胞（oligodendrocyte，OLs）。OPCs迁移到多发性硬化症（MS）患者的脱髓鞘病变，但通常不能成熟为使脱髓鞘轴突再生的OL。 再髓鞘化失败导致MS患者的长期神经功能缺损。我们以前发现一种叫做透明质酸（HA）的多糖在MS患者的病变中积累。我们的初步数据表明，OPCs表达透明质酸酶，分解HA的酶，HA的分解产物抑制OPCs成熟为髓鞘形成OL。此外，这些HA分解产物抑制髓鞘再生，并且抑制透明质酸酶活性的药物可以促进体外OPC成熟。 我们的假设是，髓鞘再生失败可以通过阻断透明质酸酶活性来逆转。 在这里，我们的目标是： （一） 鉴定吲哚甲酰胺和其他衍生物，抑制透明质酸酶活性，促进体外OPC成熟。 （二） 测试透明质酸酶活性的全身抑制是否促进实验诱导脱髓鞘疾病小鼠的髓鞘再生。

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.