CNS Development & Alcohol: Microglia-Neuron Interactions

描述（由申请人提供）：胎儿酒精综合征和相关疾病是智力迟钝的主要已知原因。了解产前酒精暴露的神经病理学是至关重要的。由于对酒精破坏神经元发育的了解有限，缺乏预防脑损伤的方法。为了解决这一知识空白，我们正在研究神经元-胶质细胞相互作用在发育过程中酒精介导的神经毒性中的作用。小胶质细胞是唯一重要的，因为它们介导神经元保护或病理激活，神经元死亡。我们的初步研究表明，暴露于单一剂量的酒精新生大鼠产生显着的小胶质细胞的损失在发展中的小脑。在存活的小胶质细胞中，酒精改变细胞形态并诱导活化抗原的表达，提示病理活化。使用小胶质细胞培养物，我们发现酒精诱导小胶质细胞凋亡，并且酒精诱导的小胶质细胞死亡可以通过激活PPARgamma信号通路来阻断。 为了进一步这些发现，本研究将调查的整体假设，即酒精破坏小胶质细胞-神经元的相互作用，通过诱导小胶质细胞凋亡和病理性小胶质细胞活化，有助于酒精神经毒性在发育中的大脑。将使用补充的体内和体外模型来检验这一假设。本提案的具体目标是：1.确定酒精诱导的小胶质细胞死亡是否与发育中小脑的神经元凋亡有关。2.确定酒精是否诱导小胶质细胞的病理激活，以及酒精诱导的小胶质细胞激活是否与发育中小脑的神经元凋亡相关。3.确定酒精对发育中的小胶质细胞的有害影响是否会破坏小胶质细胞和神经元之间的相互作用，并导致酒精神经毒性。4.确定酒精对发育中小脑的小胶质细胞和神经元的有害影响是否涉及抑制PPARgamma信号传导。这些研究的结果将提供更好地了解酒精干扰小胶质细胞和神经元之间的关系在发展过程中。这些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学提供新的治疗策略。

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.