Sphingolipids in Ethanol-Induced Neuronal Apoptosis

产前酒精暴露会诱发一系列称为胎儿酒精谱系障碍（FASD）的疾病。产前酒精暴露的最严重后果之一是对发育中的大脑的损害。乙醇在快速突触形成期间触发新生啮齿动物大脑中的凋亡性神经变性，这与妊娠最后三个月和出生后几年的人类大脑发育相对应。新生啮齿类动物中乙醇诱导的神经元损失可能解释FASD中观察到的一些神经病理学状况。然而，在发育中的啮齿动物大脑中乙醇诱导的神经元损失的机制尚未完全了解。阐明这些机制将有助于开发FASD的治疗应用。该提议旨在使用出生后第7天（P7）C57 BL 16小鼠的脑阐明乙醇诱导的神经元损失的机制，所述小鼠在急性暴露于乙醇时显示出强烈的凋亡性神经变性。我们前期的研究表明乙醇影响脑脂质代谢和信号转导通路。具体来说，我们已经表明乙醇诱导的神经酰胺（细胞凋亡的介质）和乙醇诱导的AMP激活蛋白激酶（AMPK）途径和磷酸肌醇3-激酶（PI 3 K）/Akt途径（生存途径）的扰动的升高。在这项应用中，我们提出了我们的假设，即乙醇诱导的脂质变化，特别是神经酰胺elevationtriggers或增强细胞凋亡在发育中的大脑与乙醇诱导的AMPK和P13 K1 Akt通路的扰动。在目标1中，将检查受乙醇影响的鞘脂的细胞和亚细胞定位的变化，因为这将深入了解这些脂质的作用。在目标2中，将寻找负责乙醇诱导的神经酰胺升高的酶和调节剂，并将检查神经酰胺升高对乙醇诱导的细胞凋亡的抑制作用。这些研究将揭示鞘脂在乙醇诱导的发育中脑细胞凋亡中的作用，并为FASD的未来治疗策略提供依据。

Prenatal alcohol exposure induces a range of disorders called fetal alcohol spectrum disorders (FASD). One of the most severe consequences of prenatal alcohol exposure is the damage to the developing brain. Ethanol triggers apoptotic neurodegeneration in the newborn rodent brain during the period of rapid synaptogenesis that corresponds to human brain development during the last trimester of pregnancy and for several years after birth. The ethanol-induced neuronal loss in newborn rodents is likely to explain some of the neuropathological conditions observed in FASD. However, mechanisms of ethanol-induced neuronal loss in the developing rodent brain are not fully understood. Elucidation of these mechanisms would contribute to the development of therapeutic applications for FASD. This proposal is aimed at elucidating the mechanisms of ethanol-induced neuronal loss using the brains of postnatal day 7 (P7) C57BLl6 mice, which show robust apoptotic neurodegeneration upon acute exposure to ethanol. Our previous studies indicate that ethanol affects brain lipid metabolism and signal transduction pathways. Specifically, we have shown ethanol-induced elevation in ceramide (a mediator of apoptosis) and ethanol-induced perturbation of the AMP-activated protein kinase (AMPK) pathway and the phosphoinositol 3-kinase (PI3K)/Akt pathway (a survival pathway). In this application, we propose to test our hypothesis that ethanol-induced lipid alteration-specifically ceramide elevationtriggers or enhances apoptosis in the developing brain in concert with ethanol-induced perturbation of the AMPK and P13K1Akt pathway. In Aim 1, changes in the cellular and subcellular localization of sphingolipids affected by ethanol will be examined because this would give insight into the roles of these lipids. In Aim 2, enzymes and regulators responsible for ethanol-induced ceramide elevation will be sought, and the effects of the inhibition of ceramide elevation on ethanol-induced apoptosis will be examined. These studies will reveal the functions of sphingolipids in ethanol-induced apoptosis in the developing brain, and will offer bases for future therapeutic strategies for FASD.