Sphingolipids in Ethanol-Induced Neuronal Apoptosis

乙醇诱导的神经元凋亡中的鞘脂

• 批准号: 7860622
• 负责人: Mariko Saito
• 金额: $ 37.76万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860622
• 关键词: 5' -AMP-activated protein kinase; Acetyl-CoA Carboxylase; Acute; Affect; Antibodies; Apoptosis; Apoptotic; Astrocytes; Birth; Brain; Cell Survival; Cells; Ceramidase; Ceramides; Cerebellum; Development; Disease; Enzymes; Ethanol; Ethanol Metabolism; Ethanol toxicity; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fluorescence; Future; Gangliosides; Glycogen Synthase Kinases; Hippocampus (Brain); Human; Immunohistochemistry; Link; Lipids; Mediator of activation protein; Membrane Microdomains; Metabolism; Microglia; Mitochondria; Modeling; Mus; Nerve Degeneration; Neurons; Newborn Infant; Okadaic Acid; Oligodendroglia; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Predisposition; Pregnancy; Protein phosphatase; Reporting; Rodent; Role; SRE-1 binding protein; Signal Transduction Pathway; Sphingolipids; Sphingomyelinase; Subcellular Fractions; Testing; Therapeutic; Third Pregnancy Trimester; Toxic effect; Triglycerides; alcohol content; alcohol effect; alcohol sensitivity; base; caspase-3; cell type; dihydroceramide desaturase; inhibitor/antagonist; insight; lipid metabolism; nerve stem cell; neuron apoptosis; neuron loss; phosphatase inhibitor; postnatal; serine palmitoyltransferase; synaptogenesis; therapeutic development

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.

产前接触酒精会诱发一系列称为胎儿酒精谱系障碍 (FASD) 的疾病。产前接触酒精最严重的后果之一是对发育中的大脑造成损害。在快速突触发生期间，乙醇会引发新生啮齿动物大脑中的细胞凋亡性神经变性，这对应于妊娠最后三个月和出生后几年的人类大脑发育。新生啮齿动物中乙醇引起的神经元损失可能解释了 FASD 中观察到的一些神经病理状况。然而，乙醇引起啮齿动物大脑发育中神经元损失的机制尚不完全清楚。阐明这些机制将有助于 FASD 治疗应用的开发。该提案旨在利用出生后第 7 天 (P7) C57BL16 小鼠的大脑阐明乙醇诱导的神经元损失的机制，这些小鼠在急性暴露于乙醇时表现出强烈的凋亡性神经变性。我们之前的研究表明乙醇会影响脑脂质代谢和信号转导途径。具体来说，我们发现乙醇诱导的神经酰胺（细胞凋亡介质）升高，以及乙醇诱导的 AMP 激活蛋白激酶 (AMPK) 途径和磷酸肌醇 3-激酶 (PI3K)/Akt 途径（生存途径）的扰动。在本申请中，我们建议检验我们的假设，即乙醇诱导的脂质改变（特别是神经酰胺升高）与乙醇诱导的 AMPK 和 P13K1Akt 通路扰动相一致，可触发或增强发育中大脑的细胞凋亡。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因子，并检查抑制神经酰胺升高对乙醇诱导的细胞凋亡的影响。这些研究将揭示鞘脂在乙醇诱导的发育中大脑细胞凋亡中的功能，并为未来 FASD 的治疗策略提供基础。

项目成果

Ethanol triggers sphingosine 1-phosphate elevation along with neuroapoptosis in the developing mouse brain.

• DOI: 10.1111/j.1471-4159.2012.07723.x
• 发表时间: 2012-06
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Chakraborty G;Saito M;Shah R;Mao RF;Vadasz C;Saito M
• 通讯作者: Saito M

Involvement of sphingolipids in ethanol neurotoxicity in the developing brain.

• DOI: 10.3390/brainsci3020670
• 发表时间: 2013-04-26
• 期刊: Brain sciences
• 影响因子: 3.3
• 作者: Saito M;Saito M
• 通讯作者: Saito M

Ethanol alters lipid profiles and phosphorylation status of AMP-activated protein kinase in the neonatal mouse brain.

乙醇改变新生小鼠大脑中的脂质谱和 AMP 激活蛋白激酶的磷酸化状态。

• DOI: 10.1111/j.1471-4159.2007.04836.x
• 发表时间: 2007
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Saito,Mariko;Chakraborty,Goutam;Mao,Rui-Fen;Wang,Ray;Cooper,ThomasB;Vadasz,Csaba;Saito,Mitsuo
• 通讯作者: Saito,Mitsuo

Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain.

• DOI: 10.1007/s11064-009-0116-4
• 发表时间: 2010-04
• 期刊: NEUROCHEMICAL RESEARCH
• 影响因子: 4.4
• 作者: Saito, Mariko;Chakraborty, Goutam;Mao, Rui-Fen;Paik, Sun-Mee;Vadasz, Csaba;Saito, Mitsuo
• 通讯作者: Saito, Mitsuo

Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain.

小鼠大脑发育过程中乙醇诱导的细胞凋亡性神经变性过程中 GM2 神经节苷脂的升高。

• DOI: 10.1111/j.1471-4159.2012.07710.x
• 发表时间: 2012
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Saito,Mitsuo;Chakraborty,Goutam;Shah,Relish;Mao,Rui-Fen;Kumar,Asok;Yang,Dun-Sheng;Dobrenis,Kostantin;Saito,Mariko
• 通讯作者: Saito,Mariko