Oligodendrocyte Loss Following Early Ischemic Injury

描述(由申请人提供) 胎儿缺血对发育中的中枢神经系统的损害导致不可逆转和 破坏性的功能后果，如在脑性瘫痪中观察到的。一个 这种早期缺血性损伤的特点是髓鞘显著减少 白色物质。我们建议使用一种强大的胎儿缺血联合模型 使用生化和免疫学工具来识别不同的阶段 少突胶质细胞成熟以确定胎儿影响的确切事件 对缺血儿的侮辱。正常的少突胶质细胞发育涉及许多 关键的监管事件，其中只有一些似乎受到了胎儿 缺血症。我们假设，根据初步数据，怀特的损失 缺血损伤后的物质反映了调节分子的变化 控制少突胶质细胞的增殖、迁移和存活 先驱物。在第一个目标中，我们将确定在哪些具体阶段 胎儿缺血性损伤后少突胶质细胞系细胞丢失 假设侮辱改变了所需的生长因子的表达 用于少突胶质细胞的发育。在第二个目标中，我们将检验假设 这种产前缺血症减少了血管的增殖和迁移 少突胶质细胞前体细胞。在第三个目标中，我们将对少突胶质细胞进行量化 缺血性损伤后前体细胞死亡并测试几种 诱导少突胶质细胞的不同调控分子 细胞死亡。这些研究利用胎儿缺血的模型来识别 最终导致少突胶质细胞成熟的损伤易感性事件 脑白质的丢失。完成这个项目将确定候选人 将有助于开发新的治疗方法的分子 治疗常见和破坏性的儿童中枢神经系统问题的干预。

DESCRIPTION (provided by applicant) Fetal ischemic insult to the developing CNS results in irreversible and devastating functional consequences such as those observed in cerebral palsy. A hallmark of such early ischemic damage is a dramatic reduction in myelinated white matter. We propose to use a powerful model of fetal ischemia combined with biochemical and immunological tools that identify distinct stages in oligodendrocyte maturation to define the precise events affected by fetal ischemic insults. Normal oligodendrocyte development involves a number of crucial regulatory events, only some of which appear compromised by fetal ischemia. We hypothesize, based on preliminary data, that the loss of white matter after ischemic injury reflects changes in regulatory molecules that control the proliferation, migration and survival of oligodendrocyte precursors. In the first aim we will identify the specific stages at which oligodendrocyte lineage cells are lost following fetal ischemic insult and test the hypothesis that the insult alters the expression of growth factors required for oligodendrocyte development. In the second aim we will test the hypothesis that prenatal ischemic insult reduces the proliferation and migration of oligodendrocyte precursors. In the third aim we will quantify oligodendrocyte precursor cell death following ischemic insult and test the role of several different identified regulatory molecules in the induction of oligodendrocyte cell death. These studies utilize a model of fetal ischemia to identify the injury-susceptible events in oligodendrocyte maturation that eventually result in loss of white matter. Completion of this project will identify candidate molecules that will be useful for the development of novel therapeutic interventions for treating a common and devastating pediatric CNS problem.