BRAIN DEVELOPMENT & ETHANOL: MICROGLIAL PATHOGENESIS

干预胎儿酒精所在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 这个实验室的。与脑损伤相关的脑损伤尚无治疗方法 胎儿酒精暴露的细胞和分子机制 乙醇导致发育神经发病机制尚不清楚。 尽管多年来的研究主要集中在神经元和大胶质细胞上 酒精引起的病理，对酒精的影响是重要的、重大的 大脑中的细胞类型--微泡细胞--在这些之前还没有被探索过 最近的研究。这是令人惊讶的，因为乙醇对小胶质细胞的损害可能 在发育中的神经元群体中产生严重后果。小胶质细胞 直接与神经元和免疫系统通信以影响神经元 生存和功能。他们是抵御中枢神经系统侮辱的第一道防线， 是大脑中的主要免疫细胞，并活跃在细胞因子中 分泌物、活性氧的分泌物、抗原提呈和 吞噬作用。 初步研究表明，乙醇浓度会对小胶质细胞造成损害。 远低于导致神经元直接死亡所需的水平。中国的平行研究 小脑和小胶质细胞的培养导致了这样的假设 酒精对小胶质细胞的致病作用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 小胶质细胞的成熟进一步减少了成熟小胶质细胞的数量， (3)小胶质细胞的活性和功能受到损害； (4)由于小胶质细胞没有周转，受损的小胶质细胞 这种功能在成年人身上仍然存在。这项研究将定义 酒精在小胶质细胞群体中的发病机制。因果关系 小胶质细胞病理学和神经元毒性之间的关系将被定义。这个 小胶质细胞对致畸效应敏感的临界期 乙醇将被测定。急性的、短暂的或持续性的 酒精在小胶质细胞群体中的发病机制将被区分开来。 乙醇活性的分子机制将被确定。这个 乙醇活性背后的细胞内信号通路将是 为了阻断酒精对小胶质细胞的致病作用而进行的操作。区块 乙醇诱导的小胶质细胞病理可能提供新的机会 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.