CNS Development & Alcohol: Microglia-Neuron Interactions

描述(由申请人提供)：胎儿酒精综合症和相关疾病是导致智力低下的主要已知原因。了解产前酒精暴露的神经病理学是至关重要的。由于对酒精对神经元发育的干扰了解有限，缺乏预防脑损伤的方法。为了解决这一知识差距，我们正在调查神经元-神经胶质相互作用在发育过程中酒精介导的神经毒性中的作用。小胶质细胞特别重要，因为它们介导神经元保护，或在病理激活的情况下，神经元死亡。我们的初步研究表明，新生大鼠暴露于单一剂量的酒精会导致发育中的小脑中显著的小胶质细胞丢失。在存活的小胶质细胞中，酒精改变了细胞的形态并诱导了激活的抗原的表达，这表明是病理性的激活。利用小胶质细胞培养，我们发现酒精诱导小胶质细胞凋亡，酒精诱导的小胶质细胞死亡可以通过激活PPAR-Gamma信号通路而被阻断。 为了进一步推进这些发现，本研究将探讨酒精破坏小胶质细胞-神经元相互作用的总体假设，即酒精通过诱导小胶质细胞凋亡和病理性小胶质细胞激活，导致酒精对发育中的大脑的神经毒性。体内和体外的互补模型将被用来检验这一假设。这项建议的具体目的是：1.确定酒精诱导的小胶质细胞死亡是否与发育中的小脑神经元凋亡有关。2.确定酒精是否诱导了小胶质细胞的病理性激活，以及酒精诱导的小胶质细胞激活是否与发育中的小脑神经元的凋亡有关。3.确定酒精对发育中的小胶质细胞的有害影响是否破坏了小胶质细胞与神经元之间的相互作用，并导致了酒精的神经毒性。4.确定酒精对发育中的小脑小胶质细胞和神经元的有害影响是否与抑制PPAR-γ信号有关。这些研究的结果将提供更好的理解酒精对发育过程中小胶质细胞和神经元之间关系的干扰。这一知识的应用可能为预防或治疗与产前酒精暴露相关的神经病理提供新的治疗策略。

DESCRIPTION (provided by applicant): Fetal alcohol syndrome and related disorders are the leading known cause of mental retardation. Understanding the neuropathology of prenatal alcohol exposure is critical. Methods for preventing the brain damage are lacking due to limited understanding of alcohol disruption of neuronal development. To address this gap in knowledge, we are investigating the role of neuronal-glial interactions in alcohol-mediated neurotoxicity during development. Microglia are uniquely important because they mediate neuronal protection or, with pathologic activation, neuronal death. Our pilot studies reveal that exposure of neonatal rats to a single alcohol dose produces significant microglial loss in the developing cerebellum. In the surviving microglia, alcohol alters cell morphology and induces expression of activated antigens, suggesting pathological activation. Using microglial cultures, we found that alcohol induces microglial apoptosis and that alcohol-induced microglial cell death could be blocked by activation of the PPARgamma signaling pathway. To further these discoveries, this study will investigate the overall hypothesis that alcohol disruption of microglial-neuronal interactions, through induction of microglial apoptosis and pathologic microglial activation, contributes to alcohol neurotoxicity in the developing brain. Complementary in vivo and in vitro models will be used to test this hypothesis. Specific aims of this proposal are to: 1. Determine whether alcohol-induced microglial cell death is associated with neuronal apoptosis in the developing cerebellum. 2. Determine whether alcohol induces pathological activation of microglia and if alcohol-induced microglial activation is associated with neuronal apoptosis in the developing cerebellum. 3. Establish whether the deleterious effects of alcohol on developing microglia disrupt interactions between microglia and neurons and contribute to alcohol neurotoxicity. 4. Establish whether the deleterious effects of alcohol on microglia and neurons in the developing cerebellum involve suppression of PPARgamma signaling. Results of these studies will provide better understanding of alcohol interference with the relationship between microglia and neurons during development. Application of this knowledge may provide new therapeutic strategies for prevention or treatment of the neuropathology associated with prenatal alcohol exposure.