The major causes of periventricular leukomalacia (PVL) in the premature infant are: 1) cerebral ischemia/reperfusion compounded by cerebral vascular immaturity and impaired autoregulation; and/or 2) maternofetal bacterial infection that triggers an inflammatory/cytokine response in the fetal brain. In the first grant cycle, our neuropathologic studies in human PVL demonstrated evidence for extensive free radical injury to premyelinating oligodendrocytes (pre-OLs) that is presumably triggered by cerebral ischemia and infection acting in concert. These studies also implicated critical roles for activated microglia and reactive astrocytes in contributing to or ameliorating this injury. Moreover, we found that PVL is associated with injury to gray matter sites critical to cognitive function, thus suggesting that this injury contributes to the long-term neurological handicaps in premature infants. The overall hypothesis of this Project is that nitrative and oxidative injury plays a major role in the pathogenesis of PVL and its associated injury in vulnerable gray matter sites. In six specific aims, we will examine in depth cellular features of nitrative and oxidative injury in PVL to vulnerable pre-OLs and now neurons, including subplate neurons. We also will determine factors in oligodendrocyte, astrocytic, microglial, and neuronal development that potentially place the immature white matter at risk. Under the auspices of our PVL Tissue Bank, we will accrue and analyze tissue samples with single- and double-labeled immunocytochemistry, in situ hybridization for mRNA, and western blot analysis for selected parameters related to free radical biology and injury, as well as the inflammatory response. The proposed specific aims, hypotheses, and approaches build upon the first cycle's findings in PVL, yet are novel and have the potential to lead to new insights into its pathogenesis. A full understanding of the cellular basis of PVL in the human brain is essential for establishing basic underlying mechanisms in directly relevant experimental models, in turn ultimately resulting in therapeutic interventions for testing in clinical trials.
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