Role of Dysregulated Sphingolipid Metabolism in Alcohol- and Cigarette Smoke-Induced White Matter Degeneration

鞘脂代谢失调在酒精和香烟烟雾引起的白质变性中的作用

• 批准号: 10412015
• 负责人: Emine Yalcin
• 金额: --
• 依托单位: PROVIDENCE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412015
• 关键词: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; Accounting; Address; Adverse effects; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Atrophic; Automobile Driving; Axon; Behavior; Behavioral; Biochemical; Bioinformatics; Biometry; Brain Injuries; Cardiovascular Diseases; Ceramides; Cerebrum; Chronic; Cognition; Cognitive; Disease; Dose; Energy Metabolism; Ensure; Environment; Enzymes; Ethanol; Experimental Models; Exposure to; Female; Functional disorder; Gene Delivery; Gene Expression; Goals; Heavy Drinking; Homeostasis; Human; Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Injury; Insulin; Insulin-Like Growth Factor I; Lead; Link; Lipids; Long-Term Effects; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Memory; Mentors; Metabolic; Metabolic Pathway; Metabolism; Methodology; Modeling; Molecular; Myelin; Nature; Nerve Degeneration; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neuronal Plasticity; Neurons; Nitrosamines; Oligodendroglia; Oxidative Stress; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Pharmacology; Publishing; Rattus; Research; Research Training; Resources; Role; Scientist; Severities; Signal Transduction; Smoke; Smoker; Smoking; Somatomedins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingolipids; Sphingomyelinase; Sphingomyelins; Stress; Substance abuse problem; Testing; Therapeutic Intervention; Tissue Microarray; Tissues; Tobacco; Tobacco smoke; Veterans; White Matter Disease; alcohol effect; alcohol exposure; analytical tool; base; biological adaptation to stress; career; cerebral atrophy; chronic respiratory disease; cigarette smoke; cigarette smoke-induced; cigarette smoking; cytotoxic; dihydroceramide desaturase; enzyme activity; expectation; experience; experimental study; exposure to cigarette smoke; in vivo; lipidomics; mRNA Expression; male; mass spectrometric imaging; multiplex assay; myelin degeneration; neurobehavioral test; neuroinflammation; neurotoxic; oxidative damage; prevent; problem drinker; protein expression; relating to nervous system; response; serine palmitoyltransferase; substance use; tobacco smoke exposure; tool; white matter

Chronic heavy alcohol consumption and daily cigarette smoking are the most prevalent substance use problems among U.S. Veterans. In addition to chronic respiratory and cardiovascular diseases and malignancies, heavy drinking and smoking damage the brain and cause neurocognitive and behavioral deficits that are accompanied by neurodegeneration. Cerebral white matter is a major target of both types of exposure, and lead to atrophy with degeneration of myelin which is needed to ensure efficient neuronal conductivity to carry out most functions including executive. Previous studies have shown that alcohol and cigarette smoke exposures impair signal transduction through insulin and insulin like growth factor (IGF) networks that regulate oligodendrocyte functions needed to generate and maintain myelin. Damaged myelin exposes axons, rendering them vulnerable to oxidative injury including by alcohol or tobacco smoke. In addition, oligodendrocyte functions can be further compromised via activation of neuroinflammatory and oxidative stress responses, dysregulation of energy metabolism, and alterations in the expression of sphingolipids. Corresponding declines in sphingomyelin contribute to cognitive decline and neuronal plasticity while increases in ceramide have neurotoxic effects that worsen the impairments in insulin/IGF signaling needed for oligodendrocyte survival and myelin-related functions. The proposed research will utilize robust experimental models of chronic plus binge alcohol and cigarette smoke exposures to characterize their nature and mechanisms of white matter degeneration, oligodendrocyte dysfunction, and cognitive decline. In addition, molecular, biochemical and tissue-based approaches will be used to characterize key abnormalities linked to progression of ethanol/tobacco smoke induced pathological alterations in sphingomyelin and ceramide expression. This mentored research and training will incorporate state-of-the-art methodology including matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry, tissue microarrays, multiplex assays of mRNA and protein expression, bio- informatics, and experimental model manipulation to address hypothesis-driven questions about white matter disease pathogenesis and mechanistic approaches to treat or reduce severity of its degeneration caused by chronic alcohol and tobacco smoke exposures. My research plan is organized under three specific aims to: 1) characterize the independent and additive or interactive effects of chronic plus binge ethanol and cigarette smoke exposures on cognitive-behavioral function, white matter atrophy, and myelin sphingolipid expression; 2) examine the roles of impaired insulin/IGF signaling through PI3K-Akt pathways and associated neuroinflammation, oxidative stress, and abnormalities in sphingolipid metabolizing enzyme activity or gene expression; and 3) utilize in vitro, ex vivo, and in vivo approaches to test the hypothesis that the adverse effects of alcohol and tobacco smoke exposures can be remediated or prevented by molecular or pharmacologic inhibition of sphingomyelin degradation and ceramide accumulation in cerebral white matter.

慢性大量饮酒和每天吸烟是最普遍的药物使用问题 在美国退伍军人中。除了慢性呼吸道和心血管疾病和恶性肿瘤外， 饮酒和吸烟会损害大脑，并引起伴随的神经认知和行为缺陷 通过神经变性。脑白质是两种类型的暴露的主要目标，并导致萎缩 随着髓磷脂的变性，需要确保有效的神经元电导率以执行大多数功能 包括高管。先前的研究表明，酒精和香烟烟雾暴露损害信号 通过胰岛素和胰岛素类似生长因子（IGF）网络转导的调节少突胶质功能的网络 需要产生和维持髓鞘。受损的髓鞘会暴露轴突，使它们容易受到伤害 氧化损伤，包括酒精或烟草烟雾。另外，少突胶质细胞功能可以进一步 通过激活神经炎症和氧化应激反应，能量失调而受到损害 代谢和鞘脂表达的改变。鞘磷脂的相应下降 有助于认知能力下降和神经元可塑性，而神经酰胺的增加具有神经毒性作用， 少突胶质细胞生存和髓磷脂相关的胰岛素/IGF信号传导的损害恶化 功能。拟议的研究将利用慢性加酒精的强大实验模型和 香烟烟雾暴露以表征其白质变性的性质和机制， 少突胶质细胞功能障碍和认知能力下降。另外，分子，生化和基于组织 方法将用于表征与乙醇/烟草烟雾进展有关的关键异常 诱导的鞘磷脂和神经酰胺表达的病理改变。这项指导的研究和培训 将结合最先进的方法，包括基质辅助激光解吸/电离（MALDI） 成像质谱法，组织微阵列，mRNA和蛋白质表达的多重测定，生物 信息学和实验模型操纵以解决有关白质假设驱动的问题 疾病的发病机理和机械方法治疗或减少其变性的严重程度 慢性酒精和烟草烟雾暴露。我的研究计划是根据以下三个特定目的组织的：1） 表征慢性乙醇和香烟烟的独立和添加或互动效果 对认知行为功能，白质萎缩和髓鞘鞘脂表达的暴露； 2） 检查通过PI3K-AKT途径和相关的胰岛素/IGF信号受损的作用 鞘脂代谢酶或基因的神经炎症，氧化应激和异常 表达; 3）利用体外，离体和体内方法来检验以下假设。 可以通过分子或药物来补救或预防酒精和烟草烟雾暴露 抑制鞘磷脂降解和神经酰胺在脑白质中的积累。