HYALURONATE IN AGING-RELATED GLIOSIS AND DEMYELINATION

透明质酸在衰老相关神经胶质增生和脱髓鞘中的作用

• 批准号: 7561900
• 负责人: Larry S. Sherman
• 金额: $ 1.47万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561900
• 关键词: Age; Aging; Astrocytes; Brain; CD44 gene; Cell physiology; Chronic; Computer Retrieval of Information on Scientific Projects Database; Condition; Data; Demyelinating Diseases; Demyelinations; Elderly; Extracellular Matrix; Funding; Future; Gliosis; Glycoproteins; Glycosaminoglycans; Goals; Grant; Impaired cognition; Institution; Myelin Sheath; Nerve Degeneration; Neuraxis; Neuroglia; Oligodendroglia; Primates; Protein Overexpression; Research; Research Personnel; Resources; Rodent; Source; Testing; United States National Institutes of Health; age related; aging brain; astrogliosis; base; cognitive change; hyaluronate; insight; normal aging; receptor; white matter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this study is to understand the contribution of the glycosaminoglycan hyaluronate (HA) to demyelination and gliosis in the aging central nervous system (CNS). Age-related changes in cortical white matter have been implicated in cognitive impairment. These changes include alterations in astrocytes that mimic reactive gliosis and the breakdown of myelin sheaths. In neurodegenerative conditions, glial cells overexpress the CD44 transmembrane glycoprotein, a receptor for HA. We recently found that chronic CD44 overexpression by oligodendrocytes results in increased HA and progressive demyelinating disease, while alterations in the HA-based extracellular matrix promote reactive astrogliosis. Our preliminary data suggest that many of the changes in CD44 expression and HA distribution that occur in neurodegenerative conditions also occur in the aging brain. These findings support the hypothesis that CD44 and HA accumulation are induced during the course of normal aging and may contribute to aging-related demyelination and astrogliosis. Here, we will test this hypothesis by (1) examining how HA accumulates in the aging primate and rodent CNS; and (2) testing the requirement for CD44 in promoting gliosis and related cognitive changes in the aging rodent brain. These studies will provide substantial insight into the contribution of CD44 and HA to alterations in elderly white matter, and will provide substantial preliminary data for a larger, future proposal aimed at determining how targeting HA and CD44 can reverse altered glial cell function and, ultimately, cognitive impairment.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 本研究的目的是了解糖胺聚糖透明质酸 (HA) 对衰老中枢神经系统 (CNS) 脱髓鞘和神经胶质增生的影响。 皮质白质的年龄相关变化与认知障碍有关。 这些变化包括模仿反应性神经胶质增生的星形胶质细胞的改变和髓鞘的破坏。 在神经退行性疾病中，神经胶质细胞过度表达 CD44 跨膜糖蛋白（HA 的受体）。 我们最近发现少突胶质细胞慢性 CD44 过度表达会导致 HA 增加和进行性脱髓鞘疾病，而基于 HA 的细胞外基质的改变会促进反应性星形胶质细胞增生。我们的初步数据表明，神经退行性疾病中发生的 CD44 表达和 HA 分布的许多变化也发生在衰老的大脑中。这些发现支持这样的假设：CD44 和 HA 积累是在正常衰老过程中诱导的，可能导致衰老相关的脱髓鞘和星形胶质细胞增生。在这里，我们将通过（1）检查HA如何在衰老的灵长类动物和啮齿动物中枢神经系统中积累来检验这一假设； (2)测试CD44在促进衰老啮齿动物大脑神经胶质增生和相关认知变化方面的需求。 这些研究将深入了解 CD44 和 HA 对老年白质改变的贡献，并将为未来更大的提案提供大量初步数据，该提案旨在确定靶向 HA 和 CD44 如何逆转胶质细胞功能的改变，并最终逆转认知障碍。