Cellular mechanisms of fetal white matter injury

描述（由申请人提供）：人脑室周围白质损伤（PWMI）是脑损伤的主要形式，也是早产幸存者脑瘫的主要原因。随着新生儿护理的进步，弥漫性髓鞘发育障碍和脑灰质萎缩正在成为与PWMI相关的主要病变。我们在早产胎羊中开发了一种子宫内脑缺血模型，该模型保留了母胎单位，并产生了一系列急性和慢性脑损伤，与早产儿幸存者的情况非常相似。晚期少突胶质细胞（OL）祖细胞（preOLs）的区域分布确定了急性白质损伤的偏好，这些祖细胞被发现对缺血具有选择性易感。因此，我们假设，前OLs的急性变性消耗了髓鞘形成所需的成熟OLs的白质。然而，随着白质损伤的发展，髓鞘形成失败与弥漫性星形胶质细胞增生同时发生，尽管存在大量完整的轴突，但preol群体的扩大会重新填充病变，但无法分化和髓鞘形成。这些出乎意料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瘤和髓鞘形成前阶段OL成熟的停滞有关。我们进一步假设，在这个对缺血高度敏感的OL阶段，阻止OL前成熟，使白质对复发性缺血具有持续的易感性。我们的方法与以前的研究有很大的不同，因为我们将利用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形成失败的细胞机制。我们将开发第一个大型动物模型，利用脑电图、MRI和定量脑血流研究，对白质和灰质损伤的进展进行综合定量的区域和时间组织病理学分析。在这个项目完成后，我们期望对慢性PWMI中引发正常髓鞘形成失败的发病机制获得新的基本见解。我们的长期目标是利用这种临床前模型来测试新的转化策略，以恢复正常的髓鞘形成，并可能恢复早产幸存者的神经功能。

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.