Cellular mechanisms of fetal white matter injury

胎儿脑白质损伤的细胞机制

• 批准号: 7317124
• 负责人: Stephen Arthur Back
• 金额: $ 32.51万
• 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/7317124
• 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）：人脑周期白质损伤（PWMI）是脑损伤的主要形式，是早产幸存者中脑瘫的主要原因。随着新生儿护理的进步，弥漫性髓鞘障碍和脑灰质萎缩正在成为与PWMI相关的主要病变。我们在早产胎羊中发展了一个脑缺血的子宫模型，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，与早产幸存者相似。急性白质损伤的偏见是由晚期寡胶质细胞（OL）祖细胞（Preols）的区域分布定义的，这些分布被认为有选择性地容易患缺血。因此，我们假设preols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，随着白质损伤的发展，髓鞘衰竭与弥漫性的星形胶质细胞增多症和不断扩大的pre醇种群，尽管存在大量完整的轴突，但仍无法区分病变，但无法区分和髓鞘。这些意外的发现表明，髓鞘化失败与弥漫性神经胶质病有关和在疗程前阶段的成熟造成的替代性总体假设。我们进一步假设在这个OL阶段停滞preol成熟，这极易受到缺血的影响，使白质易于持续存在复发性缺血的敏感性。我们的方法与以前的研究有很大的不同，因为我们将采用OL谱系的全部发育标志物以及以前由我们在开发人类白质中特征的其他神经细胞类型来定义慢性髓鞘衰竭的细胞机制。我们将开发第一个大型动物模型，该模型允许通过脑电图，MRI和定量脑血流流量研究的使用，对白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，我们希望获得对致病机制的基本新见解，从而触发慢性PWMI正常髓鞘化的失败。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，以恢复正常的髓鞘形成，并可能在早产幸存者中神经功能。