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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类脑室周围白质损伤(PWMI)是脑损伤的主要形式，也是早产幸存者脑性瘫痪导致终身神经残疾的主要原因。在早产儿的大脑中，当缺氧-缺血(H-L)、母婴感染等侮辱损伤脑白质时，存在一个脆弱性窗口。我们建议在围产期大鼠和人类中定义新的机制，通过这种机制，急性白质损伤导致细胞外基质水平的神经血管单位紊乱，从而扰乱正常的髓鞘生成。我们将检验这一总体假设，即H-L后早产白质对慢性髓鞘形成障碍的偏好与触发慢性反应性星形细胞增多症的前驱OL的急性退变有关。我们的初步数据表明，反应性胶质化导致糖胺聚糖透明质酸(HA)的积聚，HA可以阻止Preol成熟。我们推测，反应性星形细胞增多症阻止了易感前白质残留池的正常成熟，阻止了正常的髓鞘形成，并通过一种涉及HA积聚的机制导致白质易损性增加的持续状态，延迟性前白质死亡。

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. 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 will test 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.