Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of mental retardation in the USA. Ethanol impairs neuronal survival and function by two major mechanisms: 1) it inhibits insulin signaling required for viability, metabolism, synapse formation, and acetylcholine production;and 2) it functions as a neurotoxicant, causing oxidative stress, DNA damage and mitochondrial dysfunction. Ethanol inhibition of insulin signaling is mediated at the insulin receptor (IR), and caused by impaired binding and attendant reductions in the transmission of survival signals. In addition, increased activation of phosphatases that reverse IR tyrosine kinase and PI3 K activities, exacerbates ethanol?s inhibitory effects on neuronal survival. In contrast, the neurotoxicant effects of ethanol promote DNA damage, and are likely caused by DNA adduct formation through production and accumulation of acetaldehyde, a major metabolite of ethanol. Therefore, chronic in utero ethanol exposure produces a dual state of CNS insulin resistance and oxidative stress. Preliminary studies showed that: 1) genetic or chemical depletion of CNS IR causes FASD-like morphologic, biochemical, and molecular defects; 2) CNS insulin resistance-related impairments can be reduced by treatment with insulin-sensitizers i.e. PPAR agonists;and 3) FASD-associated CNS abnormalities may persist or progress leading to functional deficits in adolescents. In this competing renewal application, experiments proposed in 3 specific aims will characterize the long-term consequences of chronic gestational exposure to ethanol, focusing on early and late adolescence, and determine the degrees and mechanisms in which PPAR agonist treatments prevent or reduce long-term CNS abnormalities caused by chronic in utero exposure to ethanol.
Aim #1 will characterize the long-term consequences of brain insulin resistance in early and late adolescent rats following chronic in utero exposure to ethanol.
Aim #2 will utilize an in vitro model of primary cerebellar neuron cultures generated from control and ethanol-exposed rat pups to characterize the effects of PPAR agonists on neuronal survival and function.
Aim #3 will take advantage of information gained in Aim #2 to optimize an in vivo approach for PPAR agonist therapeutic rescue of the long-term adverse effects of chronic in utero ethanol exposure in relation to CNS neuronal survival and function in early and late adolescence. Graded in utero ethanol exposures will be used to determine if the therapeutic effectiveness of PPAR agonists varies with ethanol dose. In addition, experiments will address the role of gender in relation to the nature and severity of ethanol-induced CNS abnormalities and responsiveness to PPAR agonists. The experimental design is translational because it utilizes a therapeutic strategy that realistically could be applied to humans.
We have linked fetal alcohol spectrum disorder-associated brain abnormalities to insulin resistance and oxidative stress in neurons. Preliminary data suggest that prenatal alcohol exposure may cause persistent or progressive neuronal injury in adolescent brains, and therefore, we now propose to characterize the degree to which pre-natal alcohol exposure causes long-lasting adverse effects on brain function. Our second goal is to evaluate treatments that target the underlying causes of ethanol-mediated brain abnormalities and assess their effectiveness in preventing structural and functional impairments in adolescent brains following chronic prenatal alcohol exposure.
|Nunez, Kavin; Kay, Jared; Krotow, Alexander et al. (2016) Cigarette Smoke-Induced Alterations in Frontal White Matter Lipid Profiles Demonstrated by MALDI-Imaging Mass Spectrometry: Relevance to Alzheimer's Disease. J Alzheimers Dis 51:151-63|
|de la Monte, Suzanne M; Tong, M; Agarwal, A R et al. (2016) Tobacco Smoke-Induced Hepatic Injury with Steatosis, Inflammation, and Impairments in Insulin and Insulin-Like Growth Factor Signaling. J Clin Exp Pathol 6:|
|Deochand, Chetram; Tong, Ming; Agarwal, Amit R et al. (2016) Tobacco Smoke Exposure Impairs Brain Insulin/IGF Signaling: Potential Co-Factor Role in Neurodegeneration. J Alzheimers Dis 50:373-86|
|Yalcin, Emine; de la Monte, Suzanne (2016) Tobacco nitrosamines as culprits in disease: mechanisms reviewed. J Physiol Biochem 72:107-20|
|Yalcin, Emine B; de la Monte, Suzanne M (2015) Review of matrix-assisted laser desorption ionization-imaging mass spectrometry for lipid biochemical histopathology. J Histochem Cytochem 63:762-71|
|Borgas, Diana L; Gao, Jin-Song; Tong, Ming et al. (2015) Potential Role of Phosphorylation as a Regulator of Aspartyl-(asparaginyl)-Î²-hydroxylase: Relevance to Infiltrative Spread of Human Hepatocellular Carcinoma. Liver Cancer 4:139-53|
|Zabala, Valerie; Tong, Ming; Yu, Rosa et al. (2015) Potential contributions of the tobacco nicotine-derived nitrosamine ketone (NNK) in the pathogenesis of steatohepatitis in a chronic plus binge rat model of alcoholic liver disease. Alcohol Alcohol 50:118-31|
|Tong, Ming; Yu, Rosa; Deochand, Chetram et al. (2015) Differential Contributions of Alcohol and the Nicotine-Derived Nitrosamine Ketone (NNK) to Insulin and Insulin-Like Growth Factor Resistance in the Adolescent Rat Brain. Alcohol Alcohol 50:670-9|
|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|
|Borgas, Diana L; Gao, Jin-Song; Tong, Ming et al. (2015) Regulation of Aspartyl-(Asparaginyl)-Î²-Hydroxylase Protein Expression and Function by Phosphorylation in Hepatocellular Carcinoma Cells. J Nat Sci 1:|
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