Cellular Mechanisms of Fetal White Matter Injury

胎儿白质损伤的细胞机制

• 批准号: 6850130
• 负责人: Stephen Arthur Back
• 金额: $ 23.72万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6850130
• 关键词: biomarker; brain circulation; brain injury; cerebral ischemia /hypoxia; cerebral palsy; cytotoxicity; embryo /fetus; fluorescence microscopy; free radicals; high performance liquid chromatography; immunocytochemistry; myelinopathy; oligodendroglia; oxidative stress; sheep; terminal nick end labeling

DESCRIPTION (provided by applicant): Periventricular leukomalacia (PVL) is the major form of brain injury in the premature infant. During critical illness, PVL is related to hypoxia-ischemia, and results in cerebral palsy, the leading cause of chronic neurological disability in survivors of premature birth. Since the death of oligodendrocyte (OL) progenitors could explain the myelination disturbances that are the major pathological feature of PVL, we studied a true fetal model to determine the acute response of the white matter to ischemia. Graded selective periventricular white matter injury was produced via a well-established in utero model in the 0.65 gestation sheep that mimics acute global cerebral ischemia. Injury is accompanied by death of OL progenitors and suggests an explanation for the developmental specificity of PVL. We will test the hypothesis that the predilection of cerebral white matter to injury is primarily related to maturation-dependent vulnerability of oligodendrocyte (OL) progenitors whose death is related to free radical toxicity from oxidative stress, and secondarily that such stress occurs at distinct sites of particularly marked blood flow disturbances during the course of global cerebral hypoperfusion-reperfusion. Our approach is a significant departure from previous studies in that we will focus on cellular mechanisms of white matter injury. We will precisely determine the relative susceptibility of successive stages in the OL lineage to death from in utero ischemia with OL lineage-specific markers. A multidisciplinary approach will integrate recent advances in immunohistochemistry, in situ analysis of regional cerebral blood flow with fluorescent microspheres, and oxidant biochemistry to investigate mechanisms of free radical-mediated white matter injury. Our long term objectives are to define the pathophysiologic relationships among ischemia, acute white matter damage and mechanisms of oligodendroglial vulnerability in periventricular white matter. The specific aims to be studied are: (1) Determine whether the susceptibility of the OL lineage to global ischemia in utero is maturation-dependent. (2) Determine the extent and spatial distribution of the acute global ischemia and its relationship to regions of cerebral white matter injury. (3) Determine molecular mechanisms of oxidative stress related to the pathogenesis of cerebral white matter injury from global ischemia. Upon completion of this project, we hope to gain insight into strategies to prevent PVL by understanding intrinsic features of the OL progenitor which influence susceptibility to free radical-mediated injury from ischemia.

描述（由申请人提供）：脑室周围白质软化症（PVL）是早产儿脑损伤的主要形式。危重病期间，PVL 与缺氧缺血有关，并导致脑瘫，这是早产幸存者慢性神经功能障碍的主要原因。由于少突胶质细胞 (OL) 祖细胞的死亡可以解释髓鞘形成障碍（PVL 的主要病理特征），因此我们研究了真实的胎儿模型，以确定白质对缺血的急性反应。通过模拟急性全脑缺血的 0.65 妊娠绵羊的成熟子宫内模型产生分级选择性脑室周围白质损伤。损伤伴随着 OL 祖细胞的死亡，这为 PVL 的发育特异性提供了解释。我们将检验以下假设：脑白质易受损伤主要与少突胶质细胞 (OL) 祖细胞的成熟依赖性脆弱性有关，少突胶质细胞祖细胞的死亡与氧化应激产生的自由基毒性有关，其次，这种应激发生在大脑白质的不同部位。在全脑低灌注-再灌注过程中，血流紊乱尤其明显。我们的方法与之前的研究有很大不同，因为我们将重点关注白质损伤的细胞机制。我们将使用 OL 谱系特异性标记物精确确定 OL 谱系的连续阶段对子宫内缺血死亡的相对易感性。多学科方法将整合免疫组织化学、荧光微球局部脑血流原位分析和氧化生物化学的最新进展，以研究自由基介导的白质损伤的机制。 我们的长期目标是确定缺血、急性白质损伤和脑室周围白质少突胶质细胞脆弱性机制之间的病理生理关系。研究的具体目的是：（1）确定OL谱系对子宫内整体缺血的易感性是否具有成熟依赖性。 (2)确定急性全脑缺血的范围和空间分布及其与脑白质损伤区域的关系。 (3)确定与全脑缺血引起的脑白质损伤发病机制相关的氧化应激的分子机制。该项目完成后，我们希望通过了解 OL 祖细胞的内在特征来深入了解预防 PVL 的策略，这些特征影响对自由基介导的缺血损伤的易感性。