Fetal alcohol spectrum disorder (FASD) is one of the leading causes of mental retardation, and thus is a major public health concern. The developing central nervous system (CNS) is particularly sensitive to alcohol. One of the most deleterious effects of developmental alcohol exposure is the permanent loss of neurons in the CNS. The cellular/molecular mechanisms underlying ethanol-induced neuronal death remain unclear. During the last decade, mitochondria damage and oxidative stress have been believed to play an important role in the pathogenesis of ethanol-associated CNS injury. However, mitochondria damage does not fully explain ethanol neurotoxicity. The effects of ethanol on other cellular organelles receive little attention, and the connection between mitochondria damage and other organelle dysfunction is poorly understood. This grant proposal attempts to fill this gap and investigate the effect of ethanol on the interaction between the endoplasmic reticulum (ER) and autophagy. ER stress is induced in various physiological and pathological conditions where the accumulation of unfolded proteins or disruption of ER Ca2+ homeostasis occurs. Autophagy, a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, is induced to alleviate cytotoxicity during ER stress. We have demonstrated that ethanol induces ER stress in developing neurons. We hypothesize that ethanol neurotoxicity is partially caused by the induction of ER stress and the simultaneous impairment of the protective autophagic pathway. As a corollary, we propose that activation of autophagy pathways during ethanol exposure can ameliorate ethanol cytotoxicity;contrarily, inhibition of autophagy exacerbates the effect of ethanol. To test this hypothesis, we will first determine whether ethanol inhibits ER stress- triggered autophagy. Next, we will activate or inhibit the autophagic pathway by pharmacological or genetic approaches and determine whether the modulation of autophagic pathways ameliorates or exacerbates ethanol cytotoxicity. Our hypothesis is novel and the proposed study is significant;it will offer new insight into the effect of ethanol on the endoplasmic reticulum and lysosomal degradation pathways. It will provide a potential avenue for alleviating ethanol cytotoxicity.

Public Health Relevance

Prenatal exposure to alcohol causes profound damages to the developing brain. Fetal alcohol syndrome is the leading cause of mental retardation. One of the most deleterious effects of developmental alcohol exposure is the permanent loss of neurons in the brain. However, it remains unclear how alcohol kills immature neurons. The endoplasmic reticulum (ER) is an organelle that processes proteins and stores calcium. We have shown that ethanol causes ER injury. Autophagy, a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, is induced to alleviate cytotoxicity during ER damage. Our study will test a novel hypothesis that alcohol neurotoxicity is partially caused by ER damage and simultaneous impairment of the protective autophagic pathway. Our study will offer novel insight into the effect of alcohol on the ER and lysosomal degradation pathways. It may provide a new therapeutic avenue.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA019693-01
Application #
7960921
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Regunathan, Soundar
Project Start
2010-07-10
Project End
2012-06-30
Budget Start
2010-07-10
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$218,143
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Ji, Zhe; Fan, Zhiqin; Zhang, Ying et al. (2014) Thiamine deficiency promotes T cell infiltration in experimental autoimmune encephalomyelitis: the involvement of CCL2. J Immunol 193:2157-67
Luo, Jia (2014) Autophagy and ethanol neurotoxicity. Autophagy 10:2099-108
Alimov, Alexander; Wang, Haiping; Liu, Mei et al. (2013) Expression of autophagy and UPR genes in the developing brain during ethanol-sensitive and resistant periods. Metab Brain Dis 28:667-76
Wang, Haiping; Bower, Kimberly A; Frank, Jacqueline A et al. (2013) Hypoxic preconditioning alleviates ethanol neurotoxicity: the involvement of autophagy. Neurotox Res 24:472-7
Meng, Ya; Yong, Yue; Yang, Guang et al. (2013) Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism. J Neurochem 126:805-18
Luo, Jia (2012) The role of GSK3beta in the development of the central nervous system. Front Biol (Beijing) 7:212-220
Wang, Xin; Ke, Zunji; Chen, Gang et al. (2012) Cdc42-dependent activation of NADPH oxidase is involved in ethanol-induced neuronal oxidative stress. PLoS One 7:e38075
Luo, Jia (2012) Mechanisms of ethanol-induced death of cerebellar granule cells. Cerebellum 11:145-54
Chen, Gang; Ke, Zunji; Xu, Mei et al. (2012) Autophagy is a protective response to ethanol neurotoxicity. Autophagy 8:1577-89
Ke, Zunji; Wang, Xin; Liu, Ying et al. (2011) Ethanol induces endoplasmic reticulum stress in the developing brain. Alcohol Clin Exp Res 35:1574-83

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