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

长期大量饮酒和每日吸烟是最普遍的物质使用问题 在美国退伍军人中。除了慢性呼吸道和心血管疾病以及恶性肿瘤外， 饮酒和吸烟会损害大脑，导致神经认知和行为缺陷， 神经退化大脑白色物质是这两种暴露的主要目标，并导致萎缩 髓鞘变性是确保有效的神经传导性以执行大多数功能所必需的 包括执行。先前的研究表明，酒精和香烟烟雾暴露损害信号 通过调节少突胶质细胞功能的胰岛素和胰岛素样生长因子（IGF）网络进行转导 产生和维持髓磷脂所必需的。受损的髓鞘暴露轴突，使它们容易受到 氧化损伤，包括酒精或烟草烟雾。此外，少突胶质细胞的功能可以进一步 通过激活神经炎症和氧化应激反应、能量调节障碍 代谢和鞘脂表达的改变。鞘磷脂的相应减少 导致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， 使少突胶质细胞存活所需的胰岛素/IGF信号传导和髓鞘相关的 功能协调发展的拟议的研究将利用慢性加酗酒的强大实验模型， 香烟烟雾暴露以表征它们的性质和白色物质变性的机制， 少突胶质细胞功能障碍和认知能力下降。此外，基于分子、生物化学和组织的 方法将用于描述与酒精/烟草烟雾进展相关的关键异常 诱导鞘磷脂和神经酰胺表达的病理改变。这指导了研究和培训 将采用最先进的方法，包括基质辅助激光解吸/电离（MALDI） 成像质谱，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作来解决关于白色物质的假设驱动的问题 疾病的发病机理和治疗或减轻其退化严重程度的机制方法 慢性酒精和烟草烟雾暴露。我的研究计划有三个具体目标：1） 表征慢性加酗酒酒精和香烟烟雾的独立和相加或交互作用 认知行为功能、白色物质萎缩和髓鞘鞘脂表达的暴露; 2） 研究受损的胰岛素/IGF信号通过PI 3 K-Akt途径的作用， 神经炎症、氧化应激和鞘脂代谢酶活性或基因异常 表达;和3）利用体外、离体和体内方法来测试以下假设： 酒精和烟草烟雾暴露可以通过分子或药理学方法进行补救或预防 抑制脑白色物质中鞘磷脂降解和神经酰胺蓄积。

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.