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Impact of Ethanol Drinking on ALK and STAT3 Signaling in the Mouse Brain

thesis
posted on 01.12.2020, 00:00 by Kana Hamada
Alcohol use disorder (AUD) is a difficult disorder to treat. Identifying relevant signaling pathways in the brain may be useful for finding new pharmacological targets to treat AUD. The receptor tyrosine kinase ALK activates the transcription factor STAT3 in response to ethanol exposure in vitro. Here, we demonstrate ALK activation and upregulation of known STAT3 target genes (Socs3, Gfap, and Tnfrsf1a) in the prefrontal cortex (PFC) and ventral hippocampus (vHPC) of mice after 4 days of binge-like ethanol drinking. To investigate the behavioral relevance of activated STAT3, we treated mice with a STAT3 inhibitor, stattic, and observed that they drank less ethanol compared with vehicle-treated mice. Finally, to identify novel ethanol-induced target genes downstream of ALK-STAT3, we analyzed the NIH LINCS L1000 database for gene signature overlap between ALK inhibitor (alectinib and NVP-TAE684) and STAT3 inhibitor (niclosamide) treatments on cell lines. This signature was then compared to genes that were differentially expressed in the PFC of mice after binge-like drinking. We found 95 unique gene candidates and examined them for STAT3 binding motifs in their promoters. Fifty-seven of the 95 genes had STAT3 motifs. We validated by qPCR that expression of putative STAT3 target genes Nr1h2, Smarcc1, Smarca4, and Gpnmb were increased in the PFC or vHPC after binge-like drinking. Together these results demonstrate activation of the ALK-STAT3 signaling pathway in the brain after binge-like ethanol consumption, identify putative novel ethanol-responsive STAT3 target genes, and suggest that STAT3 inhibition may be a potential method to reduce binge drinking in humans.

History

Advisor

Lasek, Amy W

Chair

Brodie, Mark S

Department

Psychiatry

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Brady, Scott T Pandey, Subhash C Roitman, Jamie D

Submitted date

December 2020

Thesis type

application/pdf

Language

en

Exports