CELLULAR DIFFERENTIATION

这项建议的总体目标是确定围产期缺氧/缺血(H/I)如何影响室管膜下区(SZ)的神经干细胞。干细胞在围产期活跃分裂，产生神经元和神经胶质细胞。因此，破坏或干扰SZ细胞的侮辱很可能会扰乱大脑的发育和功能。在过去的8年里，我和我的合作者收集了大量关于这些干细胞的正常发育命运的数据。根据我们广泛的描述，可以做出一些预测，说明在大脑发育的关键时期，H/I侮辱将如何影响这些祖细胞。具体目标1将调查H/I将改变SC中增殖细胞的速度或数量的预测。特定目标2将决定H/I是否杀死深圳的细胞。将进行实验，以确定坏死性死亡与凋亡性死亡的比例，并揭示它们死亡的机制。由于每个祖细胞都有可能生下100多个女儿，即使是少量增殖干细胞的死亡也可能对大脑发育产生巨大影响。具体目标3将确定H/I是否会扰乱深圳先祖迁徙的速度或模式。H/I损伤将干扰或破坏未成熟细胞用于迁移的放射状神经胶质网络，这可能会改变正常大脑发育过程中细胞运动的准确时间或方向。最后，特定的目标4将确定在H/I损伤后是否存在异常的细胞分化。通过改变发育中的大脑的微环境，围产期的侮辱也会改变决定细胞识别的信号。我们的初步数据表明，H/I侮辱会影响上述所有参数。因此，这些实验的完成应该可以深入了解围产期嗡嗡声大脑受到即使是轻微的H/I侮辱也会产生不利影响的机制。

The overall goal of this proposal is to establish how perinatal hypoxia/ischemia (H/I) affects the neural stem cells in the subependymal zone (SZ). The SC cells are actively dividing during the perinatal period to generate neurons and glia. Therefore, insults that destroy or disturb SZ cells will likely disrupt brain development and function. In the last 8 years my collaborators and I have collected a wealth of data on the normal development fates of these stem cells. Based on our extensive characterization, a number of predictions can be made as to how a H/I insult during this critical period of brain development will affect these progenitors. Specific aim 1 will investigate the prediction that H/I will alter the rate or number of proliferating cells in the SC. Specific aim 2 will determine whether H/I kills cells in the SZ. Experiments will be performed to establish the proportion of necrotic versus apoptotic deaths and to reveal the mechanisms responsible for their demise. Since each progenitor has the potential to produce over 100 daughters, the death of even a small number of proliferating stem cells could have a dramatic impact on brain development. Specific aim 3 will establish whether H/I will disrupt the rate or pattern of migration of progenitors from the SZ. A H/I insult will disturb or destroy the radial glial network that immature cells use for migration, and this will likely alter the precise timing or direction of cellular movements that occur during normal brain development. Finally, specific aim 4 will determine whether there is abnormal cell differentiation in the wake of a H/I insult. By altering the micro-environment of the developing brain, perinatal insults also will change the signals that determine cell identify. Our preliminary data indicate that H/I insults impact all of the parameters discussed above. Therefore, completion of these experiments should provide insight into the mechanisms whereby the perinatal hum brain is adversely influence by even mild H/I insults.