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Sphingolipids in Ethanol-Induced Neuronal Apoptosis

乙醇诱导的神经元凋亡中的鞘脂

基本信息

批准号：
7522857
负责人：
Mariko Saito
金额：
$ 37.02万
依托单位：
NATHAN S. KLINE INSTITUTE FOR PSYCH RES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7522857
关键词：
3-ketosphinganine 5&apos -AMP-activated protein kinase Acetic Acids Acetyl-CoA Carboxylase Acids Acridine Orange Actins Acute Acyl Coenzyme A Affect Aftercare Alcohols Alexa594 Ammonia Animal Model Animals Anterior Antibodies Antigens Apoptosis Apoptosis Inhibitor Apoptotic Area Astrocytes Atlases Attenuated Biological Assay Biotechnology Birth Brain Brain Mass Brain Stem Brain region Buffers Cell Death Cell Fractionation Cell Line Cell Nucleus Cell membrane Cells Centrifugation Ceramidase Ceramides Cerebellum Cerebral Ischemia Cerebrum Chemicals Chloroform Cholera Toxin Cleaved cell Clinical Cods Coenzyme A Cognitive Computer software Confocal Microscopy Cultured Cells Cyclohexanes Cytosol Data Decapitation Desipramine Detection Detergents Development Digitonin Dihydrosphingosine Dimethylarsinate Disease Dithiothreitol Dose Dyes Edetic Acid Energy Metabolism Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Ethanol Ethanol Metabolism Ethanol toxicity Ethics Event Experimental Designs Exposure to Family Fatty Acids Fatty-acid synthase Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fluorescence Foundations Freeze Drying Fumonisins Furuncles Future G(M2) Ganglioside Gangliosides Gas-Liquid Chromatography Generations Genes Glass Glial Fibrillary Acidic Protein Global Change Goat Gold Head Hexanes Hippocampus (Brain)Home environment Hour Human Hydrogen Peroxide Ice Image Imipramine Immunofluorescence Immunologic Immunoglobulin G Immunoglobulin M Immunohistochemistry Incubated Injection of therapeutic agent Injury Instruction Insulin Intraperitoneal Injections Iowa Ischemia Label Lateral Lead Left Length Link Lipids Lipofectamine Lithium Liver Location Manufacturer Name Measures Mediator of activation protein Medical Membrane Membrane Microdomains Metabolism Metformin Methanol Methods Microglia Microscope Milk Mitochondria Modeling Molecular Probes Monoclonal Antibodies Monoclonal Antibody R24 Mus Needles Nerve Degeneration Neuroblastoma Neurons Newborn Infant Nuclear Oligodendroglia Organ Oryctolagus cuniculus Outcome Palmitoyl Coenzyme A Pathway interactions Pentobarbital Sodium Peptides Percoll Perfusion Peripheral Peroxidases Phase Phosphate Buffer Phosphotransferases Pregnancy Preparation Procedures Protease Inhibitor Proteins Pyridoxal Phosphate RNA Interference Radioactivity Rattus Reaction Reagent Relative (related person)Reperfusion Therapy Reporting Research Research Design Resveratrol Rodent Role SRE-1 binding protein Saline Sampling Scanning Sep-Pak C18 Sepharose Serine Signal Transduction Signal Transduction Pathway Silver Staining Slice Small Interfering RNA Sodium Acetate Sodium Cholate Solutions Solvents Somatomedins Son of Sevenless Proteins Sphingolipids Sphingomyelinase Sphingomyelins Staging Staining method Stains Staurosporine Stroke Students Subcellular Fractions Substrate Specificity Sucrose Surface Syringes System Tail Techniques Technology Testing Therapeutic Thick Third Pregnancy Trimester Time Tissue Sample Tissues Treatment Protocols Triglycerides Triton X100 Tube United States Universities Valproate Sodium Voltage-Dependent Anion Channel Water Weight Western Blotting alcohol abstinence alcohol content alcohol effect ammonium hydroxide aqueous base brain tissue caspase-3 cell type cingulate cortex coomassie Brilliant Blue cost cranium cytochrome c density digital dihydroceramide dihydroceramide desaturase effective therapy enzyme activity fluoro jade human tissue in vivo inhibitor/antagonist injured inorganic phosphate insight instrument interest kainate lipid biosynthesis lipid metabolism methylcholine millimeter mind control molecular dynamics natural hypothermia nerve stem cell nestin protein neural precursor cell neurobehavioral neuron apoptosis neuron loss outer surface lipoprotein paraform polyacrylamide gels polyclonal antibody polyvinylidene fluoride postnatal prevent programs pup research study serine palmitoyltransferase synaptogenesis tau aggregation tau phosphorylation therapeutic development vector

项目摘要

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小鼠的大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。