The career objective of this proposal is to permit the candidate, an academic child neurologist and developmental neurobiologist, to establish an independent perinatal white matter injury research program. This award would permit the candidate to characterize a highly promising animal model of periventricular leukornalacia (PVL) and to gain facility with rapidly emerging molecular techniques in gene profiling by DNA microarrays. PVL is the predominant form of brain injury in the premature infant. PVL is related to hypoxia-ischemia (H-1) and results in cerebral palsy, the leading cause of neurological disability in survivors of neonatal intensive care. Since the death of oligodendrocyte (OL) precursors could explain the impaired myelination that characterizes PVL, we developed methods based on immunopanning for serum-free defined culture of rat OLs at successive stages in the OL lineage. We tested the susceptibility of CiLs to oxidative stress, a well-established sequela of H-1. Late OL progenitors (preOLs) were markedly more susceptible than mature OLs to death mediated by an oxidative stress pathway in which glutathione depletion triggers free radical toxicity in preOLs that is blocked by antioxidants. These results motivated us to examine the susceptibility of preOLs to H-1 in a well-established neonatal rat model of white matter injury. PreOLs in vivo were also highly susceptible to death, whereas early OL progenitors were markedly resistant, thus suggesting an explanation for the developmental specificity of PVL. Our overall hypothesis is that the cellular basis for PVL is a maturation-dependent susceptibility of OL precursors to death from H-1. Our long term objectives are to understand the mechanisms that predispose OL precursors to death from H-I and to establish whether there is a causal relationship between OL death and the genesis of myelination disturbances in the developing white matter.
The specific aims are to determine: (1) whether the susceptibility of OL precursors to H-I in vivo is maturation-dependent. (2) whether death of OL precursors from H-1 results in subsequent myelination disturbances. (3) how the mechanism of OL death from H-I differs from that of neurons in the neonatal brain. (4) the developmental gene expression profiles of cultured OLs subjected to oxidative stress. Through this work we will gain fundamental new insights into the cellular and molecular mechanisms that underlie neonatal white matter injury and, thereby, develop new strategies to prevent PVL.
Showing the most recent 10 out of 13 publications
