Cellular mechanisms of fetal white matter injury

胎儿脑白质损伤的细胞机制

• 批准号: 8289741
• 负责人: Stephen Arthur Back
• 金额: $ 37.73万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289741
• 关键词: Acute; Animal Model; Anisotropy; Appearance; Architecture; Atrophic; Axon; Back; Biological Markers; Brain Injuries; CD44 gene; Caring; Cell Cycle Progression; Cell Death; Cell Lineage; Cerebral Ischemia; Cerebral Palsy; Cerebrovascular Circulation; Cerebrum; Cessation of life; Chronic; Cognitive; Development; Diffuse; Electroencephalography; Extracellular Matrix; F2-Isoprostanes; Failure; Glial Fibrillary Acidic Protein; Gliosis; Histopathology; Human; In Situ; Injury; Ischemia; Lead; Learning Disabilities; Lesion; Life; Magnetic Resonance Imaging; Measurement; Microspheres; Modeling; Necrosis; Neonatal; Nervous System Physiology; Neuroglia; Neurologic; Neuronal Injury; Neurons; Oxidative Stress; Periventricular Leukomalacia; Periventricular white matter injury; Population; Pre-Clinical Model; Predisposition; Pregnancy; Premature Birth; Recurrence; Relative (related person); Research Personnel; Resistance; Risk; Seizures; Sensitivity and Specificity; Sheep; Staging; Survivors; Testing; Time; astrogliosis; axonal degeneration; cell type; cerebral hypoperfusion; disability; fetal; gray matter; in utero; insight; myelination; neuroimaging; neuron loss; oxidative damage; prevent; progenitor; spastic motor deficit; white matter; white matter injury

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.

描述（由申请人提供）：人类脑室周围白质损伤（PWMI）是脑损伤的主要形式，也是早产幸存者脑瘫的主要原因。随着新生儿护理的进步，弥漫性髓鞘形成障碍和脑灰质萎缩正在成为与 PWMI 相关的主要病变。我们在早产羊胎中开发了一种子宫内脑缺血模型，该模型保留母胎单位并产生一系列急性和慢性脑损伤，与早产幸存者中所见的情况非常相似。急性白质损伤的好发性是由晚期少突胶质细胞 (OL) 祖细胞 (preOL) 的区域分布来定义的，这些祖细胞被发现选择性地容易遭受缺血。因此，我们假设前OLs的急性变性耗尽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和前OLs数量的增加同时发生，尽管存在大量完整的轴突，但前OLs重新填充病变但无法分化和髓鞘化。这些意外的发现提出了另一种总体假设，即髓鞘形成失败与弥漫性神经胶质增生和 OL 成熟在髓鞘形成前阶段的停滞有关。我们进一步假设，在 OL 阶段，前 OL 成熟的停滞，对缺血高度敏感，使白质对复发性缺血持续敏感。我们的方法与之前的研究有很大不同，因为我们将采用我们先前在发育人类白质中表征的 OL 谱系和其他神经细胞类型的全谱发育标记物来定义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，通过应用脑电图、磁共振成像和定量脑血流研究，对白质和灰质损伤的进展进行综合定量区域和时间组织病理学分析。该项目完成后，我们期望获得关于引发慢性 PWMI 正常髓鞘形成失败的发病机制的基本新见解。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，以恢复早产幸存者的正常髓鞘形成以及潜在的神经功能。