Sphingolipids in Ethanol-Induced Neuronal Apoptosis

乙醇诱导的神经元凋亡中的鞘脂

• 批准号: 7099621
• 负责人: Mariko Saito
• 金额: $ 18.95万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099621
• 关键词: apoptosis; brain; cellular pathology; developmental neurobiology; enzyme activity; enzyme inhibitors; ethanol; gangliosides; immunocytochemistry; laboratory mouse; lipolysis; neural degeneration; neurons; neuroprotectants; neurotoxins; protein structure function; sphingolipids; statistics /biometry; terminal nick end labeling; tissue /cell culture; western blottings

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.

描述（由申请人提供）：发育中的大脑中乙醇诱导的凋亡神经退行性变性被认为是胎儿酒精综合征的原因。使用动物模型的几项研究表明，鞘脂脂（神经节，中性糖脂脂，鞘磷脂，神经酰胺等）介导了生存和凋亡的细胞过程。我们假设乙醇诱导的发育中的脑凋亡是由细胞鞘脂介导或修饰的。因此，通过给予外源鞘脂或操纵内源性鞘脂代谢来改变细胞鞘脂的变化会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神经节的半合成衍生物）是否会衰减新生儿C57BL/6小鼠脑中乙醇诱导的神经变性。我们还将使用从C57BL76小鼠获得的培养的小脑颗粒神经元来检查神经节苷脂和LIGA20对乙醇诱导的凋亡的影响。在AIM 2中，为了检查乙醇诱导的细胞凋亡的假设是由内源性鞘脂介导或修饰的，将使用动物和细胞培养模型来检查乙醇诱导的鞘脂型的变化以及代谢酶的变化。还将分析鞘脂 - 代谢酶对乙醇诱导凋亡的抑制剂的影响。最后，基于以下假设，即通过修饰鞘脂代谢来减轻乙醇诱导的凋亡，在存在和不存在乙醇的情况下，将检查神经节剂对鞘脂型和相关酶的影响。这些研究可能将鞘脂鉴定为影响乙醇诱导的凋亡途径的重要因素，并可能导致鞘脂的治疗应用（或影响鞘脂代谢的试剂）减轻乙醇在发育中的不良影响。