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

人类脑室周围白质损伤(PWMI)是脑损伤的主要形式，也是最常见的 早产幸存者脑性瘫痪致终生神经残疾的原因。在早产儿中 人脑在缺氧缺血时存在脆弱性窗(H-L)，母婴感染及 其他侮辱会损害大脑白质。慢性PWMI的范围包括囊性坏死性病变。 (脑室周围白质软化，PVL)和与反应性相关的正常髓鞘形成的弥漫性失败 星形细胞增多症。尽管有大量受影响的婴儿，慢性PWMI的细胞和分子基础 是未知的，并且还没有在相关的动物模型中进行研究。尽管存在相当多的证据 危重早产儿发生脑H-L的病理生理机制 H-L与急性脑白质损伤和慢性髓鞘紊乱的关系仍然较差 明白了。因此，导致慢性脑白质损伤的细胞和分子事件的定义是， 这是推进预防性治疗的迫切需要。我们建议在围产期大鼠中定义新的机制 和人类急性白质损伤导致神经血管单位在 破坏正常髓鞘生成的细胞外基质。在与人类相关的围产期大鼠模型中 PWMI，我们将确定H-L后晚期OL祖细胞(PreOL)急性退变的机制 会引发正常髓鞘形成的慢性中断。我们将检验总体假设，即 H-L术后早产白质致慢性髓鞘损伤与急性退行性变有关 引发慢性反应性星形细胞增多症的前驱OLS。我们的初步数据表明，反应性胶质细胞增多症会导致 糖胺聚糖透明质酸(HA)的积累以及HA能阻止Preol成熟。我们 因此，假设反应性星形细胞增多症阻止了残余池的正常成熟。 易感的前OLS，阻止正常的髓鞘形成，并导致持续的易感性增加的状态 脑白质通过参与HA蓄积的机制延缓Preol死亡。我们的 方法与以前的研究有很大的不同，因为我们将使用全范围的OL 我们以前在人类白质发育过程中描述的谱系特异性标记，以定义 H-L引发慢性胎盘变性和髓鞘衰竭的机制。

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.