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

描述（由申请人提供）：人脑室周围白色物质损伤（PWMI）是脑损伤的主要形式，也是早产幸存者因脑瘫导致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。慢性PWMI的范围包括囊性坏死病变（脑室周围白质软化，PVL）和与反应性星形胶质细胞增多相关的弥漫性正常髓鞘形成障碍。尽管受影响的婴儿数量很大，但慢性PWMI的细胞和分子基础尚不清楚，也没有在相关动物模型中进行研究。虽然有相当多的证据表明，脑H-1发生在危重早产儿谁维持PWMI，H-1，急性白色物质损伤和慢性髓鞘形成障碍之间的病理生理关系仍然知之甚少。因此，对产生慢性白色物质损伤的细胞和分子事件的定义是推进预防性治疗的关键。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。在与人类PWMI相关的围产期大鼠模型中，我们将定义H-I后晚期OL祖细胞（preOL）的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。因此，我们推测，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。我们的方法与以前的研究有显著的不同，因为我们将采用我们以前在发育人白色物质中表征的OL谱系特异性标志物的全谱来定义H-1触发慢性前OL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.