# Regulation of responses to alcohol by the SWI/SNF chromatin remodeling complex

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $343,125

## Abstract

PROJECT SUMMARY
An individual's initial level of response (LR) to ethanol (their naïve sensitivity) is highly heritable, and LR
strongly predicts lifetime liability to develop alcohol dependence. The genes that regulate LR are therefore
important targets for study, but despite intense investigation, they remain poorly understood. One limitation is
that it has been difficult to apply what we learn about the genes affecting level of response in model organisms
to identifying liability loci in human gene association studies. Here, we solve this problem by beginning with
candidate genes initially identified in human studies and by using a genetic model to define the biological
mechanisms by which these genes are likely to regulate LR and, subsequently, abuse liability. Recently, allelic
variation in members of the SWI/SNF chromatin-remodeling protein complex has been associated with a
diagnosis of alcohol dependence in humans. The goal of this proposal is to elucidate the mechanism by which
this complex controls ethanol responses, and, because the SWI/SNF complex regulates transcription, to
determine the downstream genes that mediate these effects. We study the molecular mechanisms by which
SWI/SNF influences the neuronal response to ethanol using the genetic model organism, Caenorhabditis
elegans. C. elegans is an excellent model for these studies, because there is striking conservation between the
machinery of nervous system function in humans and worms, and there are rich genetic resources available to
experimentally manipulate nervous system function in worms. C. elegans behavior is affected by relevant
doses of ethanol, and genes that modify ethanol responses in worms also modify ethanol responses, including
drinking behavior, in mammals. We have found that altering the function of the SWI/SNF complex in
C. elegans alters acute behavioral responses to ethanol, demonstrating that the role of SWI/SNF in modifying
the effects of ethanol is conserved. We will determine the specific neurons and neural circuits in which the
SWI/SNF complex is required for acute ethanol responses, which will implicate specific neurotransmitter
systems in these functions. Second, we will use whole genome expression analysis to identify genes that are
regulated by the SWI/SNF complex in differentiated neurons; these will be candidates for mediators of acute
ethanol responses. Finally, we will use genetic and behavioral analysis to identify the genes that are
responsible for the acute behavioral response to ethanol, and determine the biological mechanisms by which
they regulate ethanol responses. Together, these studies will provide novel insight into the biological
processes that regulate the level of response to ethanol, a phenotype that is predictive of the development of
alcohol dependence. Importantly, this work will also provide new candidate genes for liability loci that can be
examined in human populations for association with liability to develop alcohol dependen...

## Key facts

- **NIH application ID:** 9970372
- **Project number:** 5R01AA024482-05
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** JILL C BETTINGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2016-08-05 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970372

## Citation

> US National Institutes of Health, RePORTER application 9970372, Regulation of responses to alcohol by the SWI/SNF chromatin remodeling complex (5R01AA024482-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970372. Licensed CC0.

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