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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 少突胶质细胞祖细胞（OPC）可以成为中枢神经系统（CNS）中形成髓磷脂的少突胶质细胞（OLS）。 OPC迁移到多发性硬化症患者（MS）的患者中脱髓鞘病变，但通常无法成熟成脱髓鞘轴突的OL。 再髓衰竭导致MS患者的长期神经缺陷。我们以前发现，一种称为透明质酸（HA）的多糖会在MS患者病变中积聚。我们的初步数据表明，OPC表达透明质酸酶，破裂HA的酶以及HA的分解产物抑制OPC的成熟到形成髓磷脂形成的OLS中。此外，这些HA分解产物抑制了透明度和抑制透明质酶活性的药物可以在体外促进OPC成熟。 我们的假设是，可以通过药理阻断透明质酸酶活性来逆转透明失败。 在这里，我们的目标是： （1）确定吲哚羧酰胺和其他抑制透明质酶活性并在体外促进OPC成熟的衍生物。 （2）测试透明质酸酶活性的全身抑制是否会通过实验诱导的脱髓鞘疾病促进小鼠的透明度。