CEREBRAL DYSGENESIS AFTER PERINATAL HYPOXIA/ISCHEMIA

本提案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。SZ细胞在围产期组成性分裂生成神经元和神经胶质。因此，破坏或扰乱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。基于我们广泛的特征，可以做出一些预测，关于在大脑发育的关键时期，H/I侮辱将如何影响这些祖细胞。特异性目的1将研究预测H/I将改变SZ中增殖细胞的速率或数量。特异性目标2将决定H/I是否杀死SZ中的细胞。将进行实验以确定坏死性死亡与凋亡性死亡的比例，并揭示其死亡的机制。由于每个祖细胞都有可能产生100多个子细胞，因此即使是少数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是否会破坏来自SZ的祖细胞迁移的速度或模式。H/I损伤会干扰或破坏未成熟细胞用于迁移的径向神经胶质网络，这可能会改变正常大脑发育过程中细胞运动的精确时间或方向。最后，特异性靶4将确定在H/I损伤后是否存在异常细胞分化。通过改变发育中的大脑的微环境，围产期的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侮辱影响上述所有参数。这些实验的完成将揭示室管膜下区损伤是如何导致围产期人类婴儿缺氧/缺血性损伤的。

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.