CEREBRAL DYSGENESIS AFTER PERINATAL HYPOXIA/ISCHEMIA

这项建议的总体目标是建立围产期缺氧/缺血（H/I）如何影响室管膜下区（SZ）的神经干细胞。 SZ细胞在围产期组成性分裂产生神经元和神经胶质。 因此，破坏或干扰SZ细胞的损伤可能会破坏大脑的发育和功能。 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正常发育命运的数据。 基于我们广泛的表征，可以做出一些预测，以确定在大脑发育的这一关键时期，H/I损伤将如何影响这些祖细胞。 具体目标1将研究H/I将改变SZ中增殖细胞的速率或数量的预测。 具体目标2将确定H/I是否杀死SZ中的细胞。 将进行实验以确定坏死性与凋亡性死亡的比例，并揭示导致其死亡的机制。 由于每一个祖细胞都有可能产生100多个子代细胞，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是否会破坏祖细胞从SZ迁移的速率或模式。 H/I损伤会扰乱或破坏未成熟细胞用于迁移的放射状胶质网络，这可能会改变正常大脑发育期间发生的细胞运动的精确时间或方向。 最后，具体目标4将确定H/I损伤后是否存在异常细胞分化。 通过改变发育中大脑的微环境，围产期损伤也会改变决定细胞身份的信号。 虽然脑室周围出血是新生儿围产期窒息的常见后果，但这种损伤的后果尚未被仔细检查或认为重要。 我们的初步数据表明，H/I损伤影响上述所有参数。 这些实验的完成将揭示室管膜下区的损伤如何导致围产期人类婴儿的缺氧/缺血性损伤。

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). SZ cells divide constitutively during the perinatal period to generate neurons and glia. Insults that destroy or disturb SZ cells, therefore, 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 developmental 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 SZ. Specific aim 2 will determine whether H/I kills cells in the SZ. Experiments will be performed to establish the proportion of necrotic vs 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 microenvironment of the developing brain, perinatal insults also will change the signals that determine cell identity. While periventricular hemorrhage is a frequent consequence of perinatal asphyxia of the newborn, the consequences of this injury have not been closely examined or considered important. Our preliminary data indicate that H/I insults impact all of the parameters discussed above. Completion of these experiments will reveal how damage to the subependymal zone contributes to hypoxic/ischemic damage in the perinatal human infant.