Sphingolipids in Ethanol-Induced Neuronal Apoptosis

乙醇诱导的神经元凋亡中的鞘脂

• 批准号: 6968021
• 负责人: Mariko Saito
• 金额: $ 16.73万
• 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/6968021
• 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)：酒精诱导发育中的大脑中的神经细胞凋亡退化被认为是胎儿酒精综合征的原因之一。几项使用动物模型的研究表明，鞘糖脂(神经节苷脂、中性鞘糖脂、鞘磷脂、神经酰胺等)调节细胞的存活和凋亡过程。我们假设酒精诱导发育中的大脑细胞凋亡是由细胞鞘磷脂介导或修饰的。因此，通过给予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，将改变乙醇所致的神经毒性。在目标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)是否能减轻乙醇诱导的新生C57BL/6小鼠脑内神经变性。我们还将使用从C57BL76小鼠获得的培养小脑颗粒神经元来检测神经节苷脂和LIGA20对乙醇诱导的细胞凋亡的影响。在目标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说，我们将使用动物和细胞培养模型来检测乙醇诱导的鞘脂组分和代谢酶的变化。此外，还将分析鞘磷脂代谢酶抑制剂对乙醇诱导的细胞凋亡的影响。最后，基于神经节苷脂通过改变鞘磷脂代谢来减轻乙醇诱导的细胞凋亡的假设，在乙醇存在和不存在的情况下，神经节苷脂对神经鞘脂谱和相关酶的影响将被检测。这些研究可能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(或影响鞘脂新陈代谢的试剂)的治疗应用，以减轻乙醇对发育中的大脑的不利影响。