Cytokine mediated oligodendrocyte injury

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The pathophysiologic mechanism of white matter injury in periventricular leukomalacia (PVL) is not understood. Multiple factors, including oxygen free radicals, glutamate, and pro-inflammatory cytokines, likely contribute to injury of developing oligodendrocytes. The focus of this project is to elucidate the mechanism of action of cytokine mediated injury to developing oligodendrocytes, define their role in vivo as mediators of injury of developing white matter, and devise strategies to protect oligodendrocytes from cytokine mediated injury. Our overall hypothesis is that systemic or locally produced cytokines injure developing oligodendrocytes and that this toxicity is potentially relevant mechanism in PVL. To address this hypothesis we will pursue the following specific aims: 1. To determine the influence of IFN-gamma, TNF-alpha, or LPS (endotoxin) or survival of cells in the oligodendrocyte lineage. Hypothesis: Specific pro-inflammatory cytokines or LPS directly and specifically mediate injury to developing oligodendrocytes; 2. To determine the role of LPS-activated astrocytes, microglia and macrophages as mediators of death to developing oligodendrocytes. Hypothesis: LPS indirectly causes death of cells in the oligodendrocyte lineage by inducing an intermediate cell to produce factors toxic to developing oligodendrocytes; and 3. To determine the molecular pathway of IFN-gamma mediated oligodendroglial death. Hypothesis: The molecular mechanism of cytokine mediate mediated oligodendrocyte death occurs by induction or activation of specific death domain containing signaling molecules or by induction of reactive oxygen intermediated, or both. 4. To determine if endotoxin or IFN-gamma, that cause injury of cells in the oligodendrocyte lineage in vitro, will induce death of those cells and hypomyelination when injected stereotactically in vivo into developing cerebral white matter. Hypothesis: Characteristics of the PVL lesion can be reproduced in animals by focal introduction of specific IFN-gamma or endotoxin.