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

长期大量饮酒和每天吸烟是最普遍的物质使用问题 在美国退伍军人中。除了慢性呼吸系统和心血管疾病以及恶性肿瘤外，重型 饮酒和吸烟会损害大脑，导致神经认知和行为缺陷，并伴随而来 由神经退化引起的。脑白质是两种类型暴露的主要目标，并导致萎缩 髓鞘变性，这是确保有效的神经元传导性来执行大多数功能所必需的 包括高管。先前的研究表明，接触酒精和香烟烟雾会削弱信号。 通过胰岛素和胰岛素样生长因子(IGF)网络调节少突胶质细胞的功能 产生和维持髓鞘所需的。受损的髓鞘暴露出轴突，使它们容易受到 氧化损伤，包括由酒精或烟草烟雾引起的。此外，少突胶质细胞的功能还可以进一步 通过激活神经炎性和氧化应激反应，能量调节失调而受到损害 神经鞘脂的代谢和表达的变化。神经鞘磷脂的相应下降 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， 加重少突胶质细胞生存和髓鞘相关所需的胰岛素/胰岛素样生长因子信号的损害 功能。这项拟议的研究将利用长期酗酒和酗酒的稳健实验模型 香烟烟雾暴露，以表征其白质退化的性质和机制， 少突胶质细胞功能障碍和认知功能减退。此外，分子、生化和组织基础 将使用方法来表征与酒精/烟草烟雾进展有关的关键异常 诱导神经鞘磷脂和神经酰胺表达的病理改变。这是对研究和培训的指导 将采用最先进的方法，包括基质辅助激光解吸/电离(MALDI) 成像质谱学，组织微阵列，信使核糖核酸和蛋白质表达的多重分析，生物 信息学和实验模型操作，以解决假设驱动的关于白质的问题 该病的发病机制及治疗或减轻其退变严重程度的机制 长期接触酒精和烟草烟雾。我的研究计划组织在三个具体目标下：1) 描述长期酗酒和香烟烟雾的独立和相加或相互作用的影响 暴露于认知行为功能、白质萎缩和髓鞘鞘脂表达；2) 研究PI3K-Akt信号通路在胰岛素/胰岛素样生长因子信号转导中的作用 神经炎症、氧化应激和鞘磷脂代谢酶活性或基因异常 表达；以及3)利用体外、体外和体内的方法来检验假设的不良影响 酒精和烟草烟雾暴露可以通过分子或药物来补救或预防 抑制脑白质中鞘磷脂的降解和神经酰胺的积累。

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.