BRAIN DEVELOPMENT & ETHANOL: MICROGLIAL PATHOGENESIS

干预胎儿酒精引起的广泛中枢神经系统病理 综合征是酒精研究人员的高度优先事项，也是长期目标 这个实验室。没有治疗与脑损伤相关的 胎儿乙醇暴露，因为细胞和分子机制， 乙醇引起的发育神经发病机制尚不清楚。 虽然多年的研究集中在神经元和大胶质细胞 乙醇引起的病理学，乙醇对一个重要的，主要的 直到这些之前，大脑中的细胞类型--微巨噬细胞--尚未被探索过 最近的研究。这是令人惊讶的，因为乙醇对小胶质细胞的损伤可能 在发育中的神经元群体中产生严重的后果。小胶质 直接与神经元和免疫系统沟通， 生存和功能。它们是对抗中枢神经系统损伤的第一道防线， 是脑内的主要免疫细胞，在细胞因子中具有活性。 分泌、活性氧物质分泌、抗原呈递和 吞噬作用 初步研究表明，在乙醇浓度下， 远远低于导致直接神经元死亡所需的水平。平行研究 小脑和小胶质细胞的培养导致了这样的假设， 乙醇在小胶质细胞中的发病机制通过特定的细胞机制发生：（1） 乙醇抑制小胶质细胞的发生和存活，（2）乙醇抑制 小胶质细胞成熟为了进一步减少成熟小胶质细胞的数量， (3)结果，小胶质细胞的活性和功能受损， (4)由于没有小胶质细胞的周转，受损的小胶质细胞 功能性在成年人中仍然存在。这项研究将确定的机制， 乙醇在小胶质细胞中的发病机制。的因果关系 将定义小胶质细胞病理学和神经元毒性之间的关系。的 小胶质细胞对致畸作用敏感的临界期 乙醇将被确定。急性、短暂或持续性的 将区分小胶质细胞群中的乙醇发病机理。 将确定乙醇活性的分子机制。的 乙醇活性的细胞内信号传导途径将是 操纵以阻断乙醇在小胶质细胞中的发病机制。块 乙醇诱导的小胶质细胞病理学可能提供了一个新的机会， 干预胎儿酒精暴露引起的脑损伤。

Intervention in the extensive CNS pathology that underlies fetal alcohol syndrome is a high priority for alcohol researchers and is the long-term goal of this laboratory. There is no treatment for the brain damage associated with fetal ethanol exposure since the cellular and molecular mechanisms by which ethanol causes developmental neuropathogenesis are not yet understood. Although many years of study have focused on the neuronal and macroglial pathology caused by ethanol, the impact of ethanol upon an important, major cell type in the brain - the microolial cell - has not been probed until these recent studies. This is surprising since ethanol damage to microglia may produce serious consequences within developing neuronal populations. Microglia communicate directly with neurons and the immune system to influence neuronal survival and function. They are the first line of defense against CNS insults, are the principal immune cells within the brain, and are active in cytokine secretion, reactive oxygen species secretion, antigen presentation and phagocytosis. Pilot studies reveal that damage to microglia occurs at ethanol concentrations far below that required to cause direct neuronal death. Parallel studies in the cerebellum and cultures of microglia have led to the HYPOTHESIS that ethanol pathogenesis in microglia occurs via specific cellular mechanisms: (1) ethanol inhibits microglial genesis and survival, (2) ethanol suppresses microglial maturation to further reduce the population of mature microglia, (3) the activity and functionality of microglia are impaired as a result, and (4) since there is no turnover of microglia, the impaired microglial functionality persists in the adult. This study will define the mechanisms of ethanol pathogenesis within the microglial population. A causal relationship between microglial pathology and neuronal toxicity will be defined. The critical period of microglial sensitivity to the teratogenic effects of ethanol will be determined. The acute, transient or persistent nature of ethanol pathogenesis within the microglial population will be distinguished. The molecular mechanisms of ethanol activity will be identified. The intracellular signaling pathways underlying ethanol activity will be manipulated in order to block ethanol pathogenesis in microglia. Block of ethanol-induced microglial pathology may provide a new opportunity to intervene in the brain damage caused by fetal ethanol exposure.