Cytokine mediated oligodendrocyte injury

脑室周围白质软化症（PVL）中白色物质损伤的病理生理机制尚不清楚。多种因素，包括氧自由基，谷氨酸和促炎细胞因子，可能有助于发育中的少突胶质细胞的损伤。本项目的重点是阐明细胞因子介导的发育中少突胶质细胞损伤的作用机制，确定其在体内发育中白色物质损伤的介导者的作用，并设计策略以保护少突胶质细胞免受细胞因子介导的损伤。我们的总体假设是，全身或局部产生的细胞因子损伤发育中的少突胶质细胞，这种毒性是PVL的潜在相关机制。为了解决这个假设，我们将追求以下具体目标：1。确定IFN-γ、TNF-α或LPS（内毒素）或少突胶质细胞谱系中细胞存活的影响。假设：特异性促炎细胞因子或LPS直接特异性介导发育中少突胶质细胞的损伤; 2.确定LPS激活的星形胶质细胞、小胶质细胞和巨噬细胞作为发育中少突胶质细胞死亡介质的作用。假设：LPS通过诱导中间细胞产生对发育中的少突胶质细胞有毒的因子而间接引起少突胶质细胞谱系中的细胞死亡;以及3.探讨IFN-γ介导的少突胶质细胞死亡的分子途径。假设：细胞因子介导的少突胶质细胞死亡的分子机制是通过诱导或激活含有信号传导分子的特定死亡结构域或通过诱导活性氧介导的，或两者。4.确定在体外引起少突胶质细胞谱系细胞损伤的内毒素或IFN-γ在体内立体定向注射到发育中的脑白色物质中时是否会诱导这些细胞死亡和髓鞘形成不足。假设：PVL病变的特征可以通过局部引入特异性IFN-γ或内毒素在动物中重现。

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.