Alcohol-related brain disease can cause neurocognitive and behavioral deficits linked to white matter degeneration with loss of myelin and fibers. Ethanol inhibits insulin/IGF signaling and dysregulates lipid metabolism and oligodendrocyte function (myelin maintenance, maturation, and gene expression). Correspondingly, chronic ethanol feeding (36% caloric) of adult Long Evans rats causes demyelination and degeneration of myelinated axons in frontal white matter. Preliminary studies enabled by my training in the de la Monte lab using MALDI imaging mass spectrometry (IMS) and UPLC-MS/MS revealed striking effects of ethanol on frontal lobe white matter lipid biochemistry, including sphingolipid content and profiles. Exposure of frontal lobe slice cultures to the ceramide species that accumulate in brains chronically exposed to high levels of ethanol inhibits insulin/IGF-1 signaling through Akt pathways, mitochondrial function, and myelin-associated glycoprotein expression. Independent reports further showed that toxic ceramides promote cell death neuro- inflammation, and oxidative stress, while Myriocin, a ceramide inhibitor, reverses many adverse effects of ethanol in liver and brain. My preliminary studies suggest that ethanol-induced biochemical abnormalities in white matter are detectable by MALDI-IMS and quantifiable by UPLC-MS/MS, and that specific regions of interest, such as corpus callosum, can be studied in situ. Results can be correlated with white matter pathology, impairments in insulin/IGF signaling, oligodendroglial myelin-associated gene/protein expression, and neurocognitive deficits. I hypothesize that chronic ethanol exposures will produce dose-dependent alterations in white matter sphingolipid content and profiles prior to structural damage, and that these effects will correlate with emergence of brain insulin/IGF resistance and impairments in oligodendrocyte expression of myelin-associated genes/proteins. My research is organized under 2 aims to: 1) characterize effects of chronic ethanol exposures on in situ (corpus callosum and frontal white matter) sphingolipid profiles using MALDI-IMS and UPLC-MS/MS, and correlate results with impairments in insulin signaling, myelin gene/protein expression, and cognitive function; and 2) assess therapeutic effects of insulin sensitizers (PPAR-?+? agonists) and Myriocin on ethanol-associated sphingolipid profiles (MALDI-IMS/UPLC-MS/MS), oligodendrocyte function (mRNA and protein), and spatial learning and memory (Morris Water Maze). The use of MALDI-IMS with UPLC-MS/MS is innovative because it can generate biochemical signatures of the ethanol-induced structural, molecular, and signal transduction abnormalities in white matter. These preclinical approaches could be adapted to human alcoholic brain studies. My research plan, together with the outstanding educational opportunities, mentoring, and community of alcohol-related researchers at Lifespan and Brown, will provide me with state-of-the-art training and education in multidisciplinary translational science which I need to launch my independent career in alcohol-related research.
During F32 funded training, I will be engaged in innovative multidisciplinary research on alcohol-induced white matter degeneration. The experimental approach includes the use of imaging mass spectrometry which will help define early biochemical signatures of white matter degeneration, and be correlated with impairments in insulin/IGF-1 signaling, oligodendrocyte myelin-associated gene/protein expression, and cognitive function. The research plan and training, strong mentoring, resource-filled environment, access to state-of-the-art experimental approaches, and outstanding alcohol-related research investigators in the community will equip me with the tools needed to embark upon an exciting and competitive academic career studying human and experimental models of alcohol-related neurodegeneration.
| de la Monte, Suzanne M; Kay, Jared; Yalcin, Emine B et al. (2018) Imaging mass spectrometry of frontal white matter lipid changes in human alcoholics. Alcohol 67:51-63 |
| Yalcin, Emine B; McLean, Tory; Tong, Ming et al. (2017) Progressive white matter atrophy with altered lipid profiles is partially reversed by short-term abstinence in an experimental model of alcohol-related neurodegeneration. Alcohol 65:51-62 |
| Yalcin, E B; Tong, M; de la Monte, S M (2016) Enzymatic Responses to Alcohol and Tobacco Nicotine-Derived Nitrosamine Ketone Exposures in Long Evans Rat Livers. Austin Liver 1: |
| Yalcin, Emine; de la Monte, Suzanne (2016) Tobacco nitrosamines as culprits in disease: mechanisms reviewed. J Physiol Biochem 72:107-20 |
| Yalcin, Emine B; Nunez, Kavin; Tong, Ming et al. (2015) Differential Sphingolipid and Phospholipid Profiles in Alcohol and Nicotine-Derived Nitrosamine Ketone-Associated White Matter Degeneration. Alcohol Clin Exp Res 39:2324-33 |
