CEREBRAL DYSGENESIS AFTER PERINATAL HYPOXIA/ISCHEMIA

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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.