Alcohol (ethanol) is a teratogen known to have diverse effects on brain and craniofacial development. Recent studies provide strong support for interference with Sonic hedgehog (Shh) signaling as a critical molecular event in Fetal Alcohol Spectrum Disorder (FASD). However, the mechanism for Shh interference is unknown and resulting abnormal phenotypes remain incompletely defined. For the current investigation, our overall goal is to determine whether ethanol-mediated interference with the function of key morphogenic proteins (especially Shh) in the extracellular matrix (ECM) underlies ethanol's teratogenicity, as well as documenting the dysmorphology that results from this interference. This innovative and novel work will focus on agrin, a major basement membrane and transmembrane HSPG for which our laboratory has extensive research experience. It will employ a model system that holds particular promise for identification of ethanol's teratogenic mechanisms, the developing zebrafish. Previous studies have shown that exposure of zebrafish embryos to ethanol results in brain and ocular dysmorphology, as well as behavioral defects. In previous studies, our laboratory has shown that loss of agrin function in zebrafish leads to microphthalmia. This appears to be mediated by disrupted Fgf and Shh signaling. Our preliminary studies also demonstrate that agrin gene expression in zebrafish eyes is diminished in response to ethanol exposure, and suggest that agrin knockdown and ethanol exposure may share a common pathway to produce ethanol-mediated ocular defects. Thus, the underlying hypothesis of this proposal is that agrin is a CNS target of embryonic ethanol exposure, with perturbed agrin function resulting in interference with normal Shh and/or Fgf signaling following ethanol exposure. This hypothesis will be tested in the following specific aims: 1) To test the hypothesis that CNS phenotypes induced in the zebrafish by embryonic ethanol exposure and agrin loss-of-function are comparable;2) To test the hypothesis that ethanol-induced diminution in agrin gene expression disrupts Shh and/or Fgf signaling, ultimately contributing to developmental abnormalities associated with FASD;and 3) To test the hypothesis that embryonic ethanol exposure in zebrafish disrupts GABAergic and dopaminergic neuron differentiation as a consequence of perturbed Shh, Fgf, and/or agrin function. Ultimately, these studies will begin to provide insight into the molecular basis of FASD, using zebrafish as a new model for the study of FASD.

Public Health Relevance

This project is relevant to public health as maternal alcohol use is a leading cause of mental retardation in the western world. This proposal will seek to understand the underlying mechanisms of the pathological basis of maternal alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AA019767-03
Application #
8381566
Study Section
Special Emphasis Panel (ZAA1-DD)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$45,199
Indirect Cost
$14,659
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Crews, Fulton T; Vetreno, Ryan P (2016) Mechanisms of neuroimmune gene induction in alcoholism. Psychopharmacology (Berl) 233:1543-57
Crews, Fulton T; Vetreno, Ryan P; Broadwater, Margaret A et al. (2016) Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior. Pharmacol Rev 68:1074-1109
Vetreno, Ryan P; Yaxley, Richard; Paniagua, Beatriz et al. (2016) Adult rat cortical thickness changes across age and following adolescent intermittent ethanol treatment. Addict Biol :
Vetreno, Ryan P; Crews, Fulton T (2015) Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning. Front Neurosci 9:35
Liu, Yao; Chen, Hao; Sun, Zheng et al. (2015) Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma. Cancer Lett 361:164-73
Zou, Jian Y; Crews, Fulton T (2014) Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling. PLoS One 9:e87915
Qin, Liya; Crews, Fulton T (2014) Focal thalamic degeneration from ethanol and thiamine deficiency is associated with neuroimmune gene induction, microglial activation, and lack of monocarboxylic acid transporters. Alcohol Clin Exp Res 38:657-71
Vetreno, Ryan P; Broadwater, Margaret; Liu, Wen et al. (2014) Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain. PLoS One 9:e113421
Qin, Liya; Liu, Yuxin; Hong, Jau-Shyong et al. (2013) NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia 61:855-68
Crews, Fulton T; Qin, Liya; Sheedy, Donna et al. (2013) High mobility group box 1/Toll-like receptor danger signaling increases brain neuroimmune activation in alcohol dependence. Biol Psychiatry 73:602-12

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