Prenatal alcohol exposure induces a range of disorders called fetal alcohol spectrum disorders (FASD). One of the most severe consequences of prenatal alcohol exposure is the damage to the developing brain. Ethanol triggers apoptotic neurodegeneration in the newborn rodent brain during the period of rapid synaptogenesis that corresponds to human brain development during the last trimester of pregnancy and for several years after birth. The ethanol-induced neuronal loss in newborn rodents is likely to explain some of the neuropathological conditions observed in FASD. However, mechanisms of ethanol-induced neuronal loss in the developing rodent brain are not fully understood. Elucidation of these mechanisms would contribute to the development of therapeutic applications for FASD. This proposal is aimed at elucidating the mechanisms of ethanol-induced neuronal loss using the brains of postnatal day 7 (P7) C57BLl6 mice, which show robust apoptotic neurodegeneration upon acute exposure to ethanol. Our previous studies indicate that ethanol affects brain lipid metabolism and signal transduction pathways. Specifically, we have shown ethanol-induced elevation in ceramide (a mediator of apoptosis) and ethanol-induced perturbation of the AMP-activated protein kinase (AMPK) pathway and the phosphoinositol 3-kinase (PI3K)/Akt pathway (a survival pathway). In this application, we propose to test our hypothesis that ethanol-induced lipid alteration-specifically ceramide elevationtriggers or enhances apoptosis in the developing brain in concert with ethanol-induced perturbation of the AMPK and P13K1Akt pathway.
In Aim 1, changes in the cellular and subcellular localization of sphingolipids affected by ethanol will be examined because this would give insight into the roles of these lipids.
In Aim 2, enzymes and regulators responsible for ethanol-induced ceramide elevation will be sought, and the effects of the inhibition of ceramide elevation on ethanol-induced apoptosis will be examined. These studies will reveal the functions of sphingolipids in ethanol-induced apoptosis in the developing brain, and will offer bases for future therapeutic strategies for FASD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015355-05
Application #
7860622
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Reilly, Matthew
Project Start
2004-12-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$377,563
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
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Chakraborty, Goutam; Saito, Mitsuo; Shah, Relish et al. (2012) Ethanol triggers sphingosine 1-phosphate elevation along with neuroapoptosis in the developing mouse brain. J Neurochem 121:806-17
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Saito, Mariko; Chakraborty, Goutam; Mao, Rui-Fen et al. (2010) Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain. Neurochem Res 35:651-9

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