Studies performed during the previous grant period established that the IRS-1 mediated signal transduction pathway was important in promoting cell growth and survival particularly in the context of insulin and IGF-1 stimulation, and that ethanol exposure profoundly inhibits growth factor signaling through this pathway. In addition, we delineated some of the differential effects of ethanol on insulin/IGF-1 stimulated signaling as they pertain to different cell types and cellular functions. In this regard, we observed that ethanol inhibits insulin-stimulated survival but has little adverse effects on DNA synthesis in neuronal cells. This phenomenon was linked to the prominent inhibition of insulin-stimulated IRS-1-PI3K-Akt pathway and relative preservation of downstream signaling through Erk MAPK. In preliminary studies, we found that the IRS-1-PI3K pathway is also an important mediator of neuronal migration, and that the effects are mediated through the aspartyl (asparaginyl)-beta-hydroxylase (AAH) gene, which we isolated. We have demonstrated that expression of the AAH gene is regulated by insulin/IGF-1 stimulated signaling through IRS-1-PI3K, and that ethanol inhibition of neuronal migration may be mediated by its inhibitory effects on insulin/IGF-1 stimulated cyclin-dependent kinase 5 (cdk-5) activity and PI3K-Akt-Gsk-3 phosphorylation. In addition, we have obtained preliminary evidence that the effects of AAH in promoting neuronal migration are mediated through downstream Notch signaling pathways. These observations are particularly exciting because cdk-5 and Notch have known roles in neuronal migration during development. In this application, we propose to utilize chronic gestational and in vitro exposure models in hypothesis-driven experiments that are organized under the following 3 specific aims:
Specific Aim #1 : Evaluate the effects of ethanol on insulin/IGF-1 stimulated signaling in relation to neuronal migration;
Specific Aim #2 : Characterize the regulation of insulin/IGF-1 stimulated AAH expression and AAH-mediated neuronal migration;
Specific Aim #3 : Define the upstream and downstream signaling pathways that mediate neuronal migration and that are inhibited by ethanol. Importantly, the third Specific Aim will link AAH gene expression to upstream signaling through cdk-5, and downstream signaling through Notch, and evaluate the effects of ethanol on these mechanisms. We expect that the results from these investigations will demonstrate the mechanisms by which chronic gestational exposure to ethanol inhibits insulin/IGF-1 stimulated signaling through IRS-1 and its associated downstream effector molecules, leading to impaired neuronal migration during development.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Gentry, Thomas
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Rhode Island Hospital (Providence, RI)
United States
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Mandelbaum, David E; Arsenault, Amanda; Stonestreet, Barbara S et al. (2018) Neuroinflammation-Related Encephalopathy in an Infant Born Preterm Following Exposure to Maternal Diabetic Ketoacidosis. J Pediatr 197:286-291.e2
de la Monte, Suzanne M; Tong, Ming; Wands, Jack R (2018) The 20-Year Voyage Aboard the Journal of Alzheimer's Disease: Docking at 'Type 3 Diabetes', Environmental/Exposure Factors, Pathogenic Mechanisms, and Potential Treatments. J Alzheimers Dis 62:1381-1390
de la Monte, Suzanne M (2017) Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer's Disease. Drugs 77:47-65
Tong, Ming; Leão, Raiane; Vimbela, Gina V et al. (2017) Altered temporal lobe white matter lipid ion profiles in an experimental model of sporadic Alzheimer's disease. Mol Cell Neurosci 82:23-34
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
de la Monte, Suzanne M; Tong, Ming; Schiano, Irio et al. (2017) Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer's Disease. J Alzheimers Dis 55:849-864
Andreani, Tomas; Tong, Ming; Gundogan, Fusun et al. (2016) Differential Effects of 3rd Trimester-Equivalent Binge Ethanol and Tobacco-Specific Nitrosamine Ketone Exposures on Brain Insulin Signaling in Adolescence. J Diabetes Relat Disord 1:
Re, Edward; Tong, Ming; de la Monte, Suzanne M (2016) Tobacco Nitrosamine Exposures Contribute to Fetal Alcohol Spectrum Disorder Associated Cerebellar Dysgenesis. International journal of biology 8:10-21
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

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