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.
Prenatal alcohol exposure induces a full range of clinical abnormalities called fetal alcohol spectrum disorders (FASD) (Riley and McGee 2005). One of the most severe consequences of prenatal alcohol exposure is the disruption of brain development and the resulting neurobehavloral disturbances. This includes a reduction in cognitive abilities, the most common manifestation of FASD. FASD affects nearly one in 100 births (Sampson 1997), and the cost of dealing with the consequences of prenatal alcohol exposure is estimated at $4 billion per year in the United States (Harwood 2000). However, effective treatments for FASD, aside from abstinence from alcohol, have been underdeveloped. To seek strategies that prevent or alleviate the negative effects of alcohol, it is necessary to investigate the mechanisms of alcohol-induced neurodevelopmental injuries. For this purpose, animal models have been used frequently, as human studies are limited because of ethical constraints. One effective animal model is to administer alcohol acutely to postnatal day 7 (P7) mice (Olney 2002). It has been shown that alcohol 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 (lkonomidou 2000;Olney 2002). The alcohol-induced neuronal loss in newborn rodents is likely to explain the reduced brain mass and some of the neurobehavioral disturbances observed in FASD. This proposal is aimed at elucidating the mechanisms of ethanol-induced neuronal loss using P7 C57BU6 mice as a model for FASD. During these studies, the neuroprotective effects of a variety of agents (modulators of sphingolipid metabolism and AMPK activators) will b~ tested against alcohol-induced neurodegeneration, Completion of the projects would ~ffer a foundation for future therapeutic strategies for FASD. 14PHS 39812590
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