Sphingolipids in Ethanol-Induced Neuronal Apoptosis

描述（由申请人提供）：在发育中的大脑中乙醇诱导的凋亡性神经变性被认为是胎儿酒精综合征的一个原因。一些动物模型研究表明，鞘脂（神经节脂苷、中性鞘脂、鞘磷脂、神经酰胺等）介导细胞的生存和凋亡过程。我们假设乙醇诱导的发育中的脑细胞凋亡是由细胞鞘脂介导或修饰的。因此，通过施用外源性鞘脂或通过操纵内源性鞘脂代谢来改变细胞鞘脂谱将改变乙醇诱导的神经毒性。在Aim 1中，我们将测试外源性神经节苷脂和LIGA20 （GM1神经节苷脂的半合成衍生物）是否会减弱新生C57BL/6小鼠大脑中乙醇诱导的神经变性。我们还将利用C57BL76小鼠培养的小脑颗粒神经元，研究神经节苷脂和LIGA20对乙醇诱导的细胞凋亡的影响。在Aim 2中，为了验证乙醇诱导的细胞凋亡是由内源性鞘脂介导或修饰的假设，我们将使用动物和细胞培养模型来检测乙醇诱导的鞘脂谱和代谢酶的变化。鞘脂代谢酶抑制剂对乙醇诱导的细胞凋亡的影响也将被分析。最后，基于神经节苷脂通过改变鞘脂代谢来缓解乙醇诱导的细胞凋亡的假设，我们将在乙醇存在和不存在的情况下研究神经节苷脂对鞘脂谱和相关酶的影响。这些研究可能会确定鞘脂是影响乙醇诱导的细胞凋亡途径的重要因素，并可能导致鞘脂（或影响鞘脂代谢的试剂）的治疗应用，以减轻乙醇对发育中的大脑的不良影响。

DESCRIPTION (provided by applicant): Ethanol-induced apoptotic neurodegeneration in the developing brain is considered a cause of fetal alcohol syndrome. Several studies using animal models indicate that sphingolipids (gangliosides, neutral glycosphingolipids, sphingomyelin, ceramide, etc.) mediate the cellular processes of survival and apoptosis. We hypothesize that ethanol-induced apoptosis in the developing brain is mediated or modified by cellular sphingolipids. Consequently, alteration of cellular sphingolipid profiles by the administration of exogenous sphingolipids or by the manipulation of endogenous sphingolipid metabolism would modify the ethanol-induced neurotoxicity. In Aim 1, we will test whether exogenous gangliosides and LIGA20 (a semisynthetic derivative of GM1 ganglioside) attenuate ethanol-induced neurodegeneration in the neonatal C57BL/6 mouse brain. We will also examine the effects of gangliosides and LIGA20 on ethanol-induced apoptosis using cultured cerebellar granule neurons obtained from C57BL76 mice. In Aim 2, in order to examine the hypothesis that ethanol-induced apoptosis is mediated or modified by endogenous sphingolipids, ethanol-induced changes in sphingolipid profiles and in metabolizing enzymes will be examined using animal and cell culture models. The effects of inhibitors of sphingolipid-metabolizing enzymes on ethanol-induced apoptosis will also be analyzed. Finally, based on the hypothesis that gangliosides alleviate ethanol-induced apoptosis through modifications of sphingolipid metabolism, the effects of gangliosides on sphingolipid profiles and related enzymes will be examined in the presence and absence of ethanol. These studies may identify sphingolipids as important factors affecting the ethanol-induced apoptotic pathway, and may lead to therapeutic applications of sphingolipids (or reagents affecting sphingolipid metabolism) that alleviate the adverse effects of ethanol on the developing brain.