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 ...