Role of extracellular matrix in hypoxic-ischemic perinatal white matter injury

描述(申请人提供)：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。慢性PWMI的范围包括囊性坏死性病变(脑室周围白质软化，PVL)和与反应性星形细胞增多症相关的正常髓鞘弥漫性丧失。尽管有大量的婴儿受到影响，但慢性PWMI的细胞和分子基础尚不清楚，也没有在相关的动物模型中进行研究。虽然有相当多的证据表明脑H-L发生在持续PWMI的危重早产儿中，但H-L与急性脑白质损伤和慢性髓鞘紊乱之间的病理生理关系尚不清楚。因此，定义导致慢性脑白质损伤的细胞和分子事件对于推进预防性治疗是至关重要的。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。在一个与人类PWMI相关的围产期大鼠模型中，我们将确定H-L后晚期OL前体细胞(PreOL)急性变性触发正常髓鞘形成的慢性破坏的机制。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。因此，我们假设，反应性星形细胞增多症阻止了易感前狼疮残留池的正常成熟，阻止了正常的髓鞘形成，并通过参与HA积聚的机制导致白质易损性增加的持续状态，延迟性前狼疮死亡。我们的方法与以前的研究有很大的不同，因为我们将使用我们在发育人类白质时描述的全谱OL谱系特异性标记物来定义H-L触发慢性Preol变性和髓鞘形成失败的机制。

DESCRIPTION (provided by applicant): 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. The spectrum of chronic PWMI includes cystic necrotic lesions (periventricular leukomalacia, PVL) and a diffuse failure of normal myelination associated with reactive astrocytosis. Despite the large number of affected infants, the cellular and molecular basis for chronic PWMI is unknown and has not been studied in a relevant animal model. Although considerable evidence exists that cerebral H-l occurs in critically ill premature neonates who sustain PWMI, the pathophysiologic relationships among H-l, acute white matter damage and chronic myelination disturbances remain poorly understood. Definition of the cellular and molecular events that generate chronic white matter injury is, thus, critically needed to advance preventive therapies. 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. In a perinatal rat model relevant to human PWMI, we will define mechanisms by which acute degeneration of late OL progenitors (preOLs) after H-l triggers a chronic disruption of normal myelination. 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, therefore, 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. Our approach is a significant departure from previous studies in that we will employ the full spectrum of OL lineage-specific markers previously characterized by us in developing human white matter to define the mechanisms by which H-l triggers chronic preOL degeneration and myelination failure.