Alcohol use disorders : transcriptomic and bioinformatic approaches
Creators: name: Ferguson, Laura Brockway
name: 0000-0003-3274-412X
Publisher: name: The University of Texas at Austin
Year: 2018
Subjects: subject: Gene expression
subject: Alcohol use disorder
subject: Alcoholism
subject: Transcriptome
subject: Bioinformatics
subject: FOS: Computer and information sciences
subject: FOS: Computer and information sciences
subject: Systems biology
subject: Network pharmacology

description: Excessive alcohol consumption causes widespread, persistent changes throughout the brain and body. These molecular and cellular adaptations are thought to be the mechanisms by which neurons and glia adapt to chronic alcohol use. These adaptations can eventually lead to Alcohol Use Disorder (AUD) depending on genetic predisposition and environmental factors including stress, age of drinking onset, and access to alcohol. Gene expression is believed to be the means by which these adaptations occur. There are now multiple transcriptome studies of brain from animals with genetic differences in alcohol traits, and after alcohol exposure in rodents and humans. Such studies often use gene network approaches to identify collections of the many and varied molecular targets of alcohol, providing a framework to investigate the multifaceted nature of alcohol’s effects on the brain. I apply network-based approaches to propose novel treatments and offer mechanistic insight into AUD. In the first part of this dissertation, I determined the transcriptomic effects of pharmacological and genetic perturbations that affect alcohol consumption, hypothesizing that these effects on gene expression are important for modulating alcohol-related behaviors. I initially explored the actions of a class of transcriptional regulators, PPAR agonists, that decrease alcohol consumption. I defined their effects on brain and liver gene expression and identified a strong neuronal signature associated with dopamine, neuropeptide, and glutamatergic pathways. Next, I characterized brain gene expression patterns from 7 brain regions from a genetic mouse model of intense, binge-like drinking (HDID-1 mice). These studies highlighted the importance of the extended amygdala in regulating binge drinking and suggested possible convergence with gene network changes observed in postmortem brain from patients with AUD. I applied transcriptome-based computational approaches that integrated the gene networks affected in HDID-1 mice and by chemical compounds, and validated that the top 2 candidates decreased alcohol intake in vivo. This dissertation provides insight into potential molecular facilitators of AUD and represents the first evidence for transcriptome-based drug discovery to target an addiction-related trait. The tools and approaches outlined here offer strategies to study molecular mechanisms underlying complex diseases and renewed opportunities to discover new or repurpose existing compounds to expedite treatment options In the first part of this dissertation, I determined the transcriptomic effects of pharmacological and genetic perturbations that affect alcohol consumption, hypothesizing that these effects on gene expression are important for modulating alcohol-related behaviors. I initially explored the actions of a class of transcriptional regulators, PPAR agonists, that decrease alcohol consumption. I defined their effects on brain and liver gene expression and identified a strong neuronal signature associated with dopamine, neuropeptide, and glutamatergic pathways. Next, I characterized brain gene expression patterns from 7 brain regions from a genetic mouse model of intense, binge-like drinking (HDID-1 mice). These studies highlighted the importance of the extended amygdala in regulating binge drinking and suggested possible convergence with gene network changes observed in postmortem brain from patients with AUD. I applied transcriptome-based computational approaches that integrated the gene networks affected in HDID-1 mice and by chemical compounds, and validated that the top 2 candidates decreased alcohol intake in vivo. This dissertation provides insight into potential molecular facilitators of AUD and represents the first evidence for transcriptome-based drug discovery to target an addiction-related trait. The tools and approaches outlined here offer strategies to study molecular mechanisms underlying complex diseases and renewed opportunities to discover new or repurpose existing compounds to expedite treatment options