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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

基本信息

批准号：
10259938
负责人：
Emine Yalcin
金额：
--
依托单位：
PROVIDENCE VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10259938
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 Image Impaired cognition Impairment In Vitro Individual Inflammation Injury Insulin Insulin-Like Growth Factor I Lead Link Lipids Long-Term Effects Lung diseases 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 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 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

项目摘要

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.

长期大量饮酒和每天吸烟是最普遍的物质使用问题