A key concept of the program is that periventricular leukomalacia (PVL) results from ischemia/reperfusion that triggers free radical injury in vulnerable developing oligodendrocytes in perinatal white matter, and that, as a result developing oligodendrocytes die in part by apoptosis, thus resulting in decreased mature oligodendrocytes and impaired myelination. The overall hypothesis of the proposed study is that there is a specific vulnerability of developing oligodendrocytes to oxidative stress in the cerebral white matter in the period of greatest risk for PVL (24-32 weeks) which relates, at least in part, to a developmental lack of expression of antioxidant enzymes, and/or to the acquisition of iron necessary for oligodendrocyte differentiation. In baseline studies, we will determine the temporospatial maturation of oligodendrocytes in human cerebral white matter using immunocytochemical methods with markers to stage-specific oligodendrocytes, testing the hypothesis that the period of greatest risk for PVL coincides with a predominance of developing oligodendrocytes. We will also determine the developmental profile of selected antioxidant enzymes and markers of iron metabolism in human cerebral white matter using histochemistry, immunocytochemistry, and immunoblotting. Here we will test the hypotheses that antioxidant enzymes are expressed at low levels in immature white matter during the period of greatest risk for PVL, and that the appearance of markers of iron metabolism precedes the expression of antioxidant enzymes, thus denoting a developmental mismatch between potential sources of free radicals and the systems to clear them. In PVL itself, we will determine the densities of developing oligodendrocytes in white matter surrounding PVL, testing the hypothesis that there is a decrease in the density of developing oligodendrocytes, indicative of a targeted death and loss of these cells. We will also attempt to determine if developing oligodendrocytes undergo apoptosis in PVL. Finally, we will determine the involvement of selected cytokines in PVL with immunocytochemistry. The proposed studies should provide important insight into the roles of developing oligodendrocytes and factors related to oxidative stress in PVL directly within the human brain.
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