Cellular mechanisms of fetal white matter injury

胎儿脑白质损伤的细胞机制

• 批准号: 7475817
• 负责人: Stephen Arthur Back
• 金额: $ 33.69万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475817
• 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; Disruption; 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; cell type; cerebral hypoperfusion; disability; fetal; gray matter; in utero; insight; myelination; neuroimaging; neuron loss; 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，该模型保留了母体-胎儿单位，并产生了一系列急性和慢性脑损伤，与早产幸存者中所见非常相似。急性白色物质损伤的偏好是由晚期少突胶质细胞（OL）祖细胞（preOL）的区域分布确定的，这些祖细胞被发现对缺血选择性地敏感。因此，我们假设前OL的急性变性耗尽了髓鞘形成所需的成熟OL的白色物质。然而，随着白色损伤的发展，髓鞘形成失败与弥漫性星形胶质细胞增生和不断扩大的前OL群体相一致，前OL群体重新填充病变，但尽管存在许多完整的轴突，但未能分化和髓鞘形成。这些意想不到的发现表明了另一种总体假设，即髓鞘形成失败与弥漫性胶质增生和髓鞘形成前阶段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，前OL成熟的停滞使白色物质对复发性缺血的持续敏感性易感。我们的方法是一个显着的偏离，从以前的研究中，我们将采用全谱的发展标志物的OL谱系和其他神经细胞类型的特点，我们以前在开发人类白色物质，以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，允许整合的定量区域和时间的白色和灰质损伤的进展与EEG，MRI和定量脑血流研究的应用组织病理学分析。在这个项目完成后，我们希望获得基本的新见解的发病机制，触发慢性PWMI的正常髓鞘形成失败。我们的长期目标是利用这种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。