Cellular mechanisms of fetal 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的主要原因。随着新生儿护理的进步，弥漫性髓鞘障碍和大脑灰质萎缩成为与PWMI相关的主要病变。我们在早产胎羊身上建立了一种宫内脑缺血模型，这种模型保留了母胎单位，并产生了一系列与早产幸存者非常相似的急性和慢性脑损伤。急性白质损伤的易感性由晚期寡树突状细胞(OL)前体细胞(PreOL)的区域分布确定，这些细胞被发现选择性地容易受到缺血的影响。因此，我们推测，前白质的急性变性会耗尽成熟白质中髓鞘形成所需的白质。然而，随着白质损伤的发展，髓鞘丧失与弥漫性星形胶质细胞增多症和不断扩大的前OL种群相吻合，这些前OL重新填充病变，但尽管存在大量完整的轴突，但无法分化和髓鞘形成。这些意想不到的发现提出了另一种总体假设，即髓鞘形成失败与弥漫性胶质细胞增多症和髓鞘前阶段OL成熟停滞有关。我们进一步假设，在这个对缺血高度敏感的OL阶段阻止Preol成熟，使白质易于持续地易受反复缺血的影响。我们的方法与以前的研究有很大的不同，因为我们将使用OL谱系和其他神经细胞类型的全谱发育标记物来确定慢性髓鞘失败的细胞机制，这是我们在发育人类白质时所描述的。我们将建立第一个大型动物模型，利用EEG、MRI和定量脑血流研究，对白质和灰质损伤的进展进行综合的区域和时间定量组织病理学分析。在这个项目完成后，我们希望对触发慢性PWMI正常髓鞘形成失败的发病机制有新的基本认识。我们的长期目标是利用这一临床前模型来测试新的翻译策略，以恢复早产幸存者的正常髓鞘形成和潜在的神经功能。

DESCRIPTION (provided by applicant): Human periventricular white matter injury (PWMI) is the major form of brain injury and the leading cause of cerebral palsy in survivors of premature birth. With advances in neonatal care, diffuse myelination disturbances and cerebral gray matter atrophy are emerging as the major lesions associated with PWMI. We developed in preterm fetal sheep an in utero model of cerebral ischemia that preserves the maternal- fetal unit and generates a spectrum of acute and chronic cerebral injury that closely resembles that seen in preterm survivors. The predilection for acute white matter injury was defined by the regional distribution of late oligdendrocyte (OL) progenitors (preOLs) that were found to be selectively vulnerable to ischemia. We, thus, hypothesized that the acute degeneration of preOLs depletes the white matter of mature OLs required for myelination. However, as white matter injury evolves, myelination failure coincides with diffuse astrogliosis and an expanding population of preOLs that re-populate the lesions but fail to differentiate and myelinate despite the presence of numerous intact axons. These unexpected findings suggest the alternative overall hypothesis that myelination failure is related to diffuse gliosis and an arrest of OL maturation at pre-myelinating stages. We further hypothesize that arrest of preOL maturation at this OL stage, that is highly susceptible to ischemia, predisposes the white matter to persistent susceptibility to recurrent ischemia. Our approach is a significant departure from previous studies in that we will employ the full spectrum of developmental markers of the OL lineage and other neural cell types previously characterized by us in developing human white matter to define cellular mechanisms of chronic myelination failure. We will develop the first large animal model that permits an integrated quantitative regional and temporal histopathological analysis of the progression of white and gray matter injury with the application of EEG, MRI and quantitative cerebral blood flow studies. Upon completion of this project, we expect to gain fundamental new insights into pathogenetic mechanisms that trigger a failure of normal myelination in chronic PWMI. Our long-term objectives are to utilize this pre-clinical model to test new translational strategies to restore normal myelination and, potentially, neurological function in survivors of premature birth.