ROLE OF EXTRACELLULAR MATRIX IN HYPOXIC-ISCHEMIC PERINATAL WHITE MATTER INJURY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 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， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 人类脑室周围白色物质损伤（PWMI）是脑损伤的主要形式，也是早产儿幸存者脑性瘫痪终身神经功能障碍的主要原因。在早产儿脑中，当缺氧缺血（H-I）、母-胎感染和其他损伤损害脑白色物质时，存在易损性窗口。我们建议在围产期大鼠和人类中定义新的机制，通过该机制急性白色物质损伤导致细胞外基质水平的神经血管单位破坏，从而破坏正常的髓鞘形成。我们正在检验总体假设，即H-I后早产儿白色物质对慢性髓鞘形成障碍的偏好与引发慢性反应性星形胶质细胞增多症的前OL急性变性有关。我们的初步数据表明，反应性神经胶质增生导致积累的糖胺聚糖透明质酸（HA）和HA可以阻止前OL成熟。我们假设反应性星形胶质细胞增多症阻止了易感前OL残留池的正常成熟，阻止了正常的髓鞘形成，并导致白色物质脆弱性增加的持续状态，通过涉及HA积累的机制延迟前OL死亡。

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. Human periventricular white matter injury (PWMI) is the predominant form of brain damage and the leading cause of life-long neurological disability from cerebral palsy in survivors of premature birth. In the premature human brain there is a window of vulnerability when hypoxia-ischemia (H-l), maternal-fetal infection and other insults damage cerebral white matter. We propose to define novel mechanisms in perinatal rat and human by which acute white matter injury leads to disruptions in the neurovascular unit at the level of the extracellular matrix that disrupt normal myelinogenesis. We are testing the overall hypothesis that the predilection of the preterm white matter to chronic myelination disturbances after H-l is related to the acute degeneration of preOLs that triggers chronic reactive astrocytosis. Our preliminary data suggest that reactive gliosis leads to the accumulation of the glycosaminoglycan hyaluronan (HA) and that HA can block preOL maturation. We hypothesize that reactive astrocytosis prevents the normal maturation of the residual pool of susceptible preOLs, arrests normal myelination and results in a persistent state of increased vulnerability of the white matter with delayed preOL death through a mechanism that involves HA accumulation.