NOVEL HYALURONIDASE INHIBITORS FOR THE PROMOTION OF REMYELINATION

用于促进髓鞘再生的新型透明质酸酶抑制剂

• 批准号: 8357867
• 负责人: Larry S. Sherman
• 金额: $ 5.82万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357867
• 关键词: Axon; Cell Maturation; Data; Demyelinating Diseases; Enzymes; Failure; Funding; Grant; Hyaluronan; Hyaluronidase; In Vitro; Indoles; Lesion; Multiple Sclerosis; Mus; Myelin; National Center for Research Resources; Neuraxis; Neurologic; Oligodendroglia; Patients; Pharmaceutical Preparations; Polysaccharides; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Source; Stem cells; Testing; United States National Institutes of Health; cost; inhibitor/antagonist; novel

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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表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（OPC）可以在中枢神经系统（CNS）中变成髓磷脂形成少突胶质细胞（OL）。 OPCs 迁移至多发性硬化症 (MS) 患者的脱髓鞘病变处，但通常无法成熟为对脱髓鞘轴突进行髓鞘再生的 OL。 髓鞘再生失败会导致多发性硬化症患者长期神经功能缺损。我们之前发现一种称为透明质酸 (HA) 的多糖在多发性硬化症患者病变中积聚。我们的初步数据表明，OPC 表达透明质酸酶，即分解 HA 的酶，并且 HA 的分解产物抑制 OPC 成熟为形成髓磷脂的 OL。此外，这些 HA 分解产物会抑制髓鞘再生，而抑制透明质酸酶活性的药物可以促进 OPC 体外成熟。 我们的假设是，髓鞘再生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) 鉴定吲哚甲酰胺和其他抑制透明质酸酶活性并促进 OPC 体外成熟的衍生物。 (2) 测试全身性抑制透明质酸酶活性是否会促进患有实验诱发的脱髓鞘疾病的小鼠的髓鞘再生。