Cytokine mediated oligodendrocyte injury

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DESCRIPTION: Dr. Vartanian proposes to investigate the pathophysiologic mechanism of periventricular leukomalacia (PVL), with an overall hypothesis that systemic or locally produced cytokines injure developing oligodendrocytes and that this toxicity is a potentially relevant mechanism in PVL. He will focus on the toxicity of interferon-g (IFN-g) to oligodendrocytes, which is potentiated by TNF-a. In the first specific aim, Dr. Vartanian proposes to determine the influence of pro-inflammatory cytokines or endotoxin on survival of oligodendrocytes or their progenitors. Throughout this project he tests oligodendrocytes grown as progenitors or as maturing oligodendrocytes, with the hypothesis that the progenitors are more susceptible to damage. He will extend his preliminary studies on the effects of IFN-g and TNF-a to include the effects of IL-1b and IL-6. He will begin to design and test protective strategies for these experiments, using receptor immunoadhesins to compete for cytokine binding to the receptors on the oligodendrocytes or their progenitor cells. He will quantify cell numbers; amount of apoptosis, using several approaches; and amount of mitogenesis, using BrdU. These are interesting studies, which focus both on the mechanism of death of these cells in a perinatal damage paradigm, and also on a protective therapy to reduce cell death. These studies are important and likely to be completed effectively. In the second specific aim, Dr. Vartanian proposes to determine the role of astrocytes, microglia, endothelial cells and monocytes/macrophages as mediators of oligodendrocyte cell death. In these experiments, he will test whether cell-cell contact of oligodendrocytes and other cells induces different effects on the oligodendrocytes. He will quantify cell number, viability, and apoptosis. Using a transwell coculture system, he will then test whether conditioned media from microglia, astrocytes, macrophages or endothelial cells pretreated with cytokines or LPS will induce oligodendrocytes changes. Lastly, he will test whether specific inhibitors of cytokines or inhibitors of oxygen free radicals incubated with the oligodendrocytes can block effects of factors in the medium from these effector cells. In the last specific aim, Dr. Vartanian will determine if endotoxin or cytokines that cause injury to oligodendrocytes will induce oligodendrocyte cell death and hypomyelination when injected stereotactically.