Oligodendrocyte Loss Following Early Ischemic Injury

描述（由申请人提供） 胎儿对发育中的CNS的缺血性损伤导致不可逆的 破坏性的功能后果，如在脑瘫中观察到的那些。一 这种早期缺血性损伤的标志是有髓神经细胞的急剧减少， 白色物质。我们建议使用一个强大的胎儿缺血模型， 利用生物化学和免疫学工具， 少突胶质细胞成熟，以确定胎儿受影响的确切事件 缺血性损伤正常的少突胶质细胞发育涉及许多 关键的调节事件，其中只有一些似乎受到胎儿 缺血根据初步数据，我们假设， 缺血性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 前体在第一个目标中，我们将确定以下具体阶段： 胎儿缺血性损伤后少突胶质细胞谱系细胞丢失 这一假设是，这种伤害改变了生长因子的表达， 少突胶质细胞的发育在第二个目标中，我们将测试假设 产前缺血损伤减少了 少突胶质细胞前体在第三个目标中，我们将量化少突胶质细胞 缺血性损伤后前体细胞死亡，并测试几种 不同鉴定的调节分子在少突胶质细胞诱导中的作用 细胞死亡这些研究利用胎儿缺血模型来鉴定 在少突胶质细胞成熟过程中易受损伤的事件， 失去了白色物质。该项目的完成将确定候选人 这些分子将用于开发新的治疗药物， 用于治疗常见和毁灭性的儿科CNS问题的干预措施。

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.