# Modeling human alcohol abuse in mice with a common SLC6A3 regulatory variant

> **NIH NIH R21** · MCLEAN HOSPITAL · 2020 · $235,750

## Abstract

Modeling human alcohol abuse in mice with a common SLC6A3 regulatory variant
 Project Abstract
The purpose of this R21 research is to model for stress-regulated alcohol consumption through generating a
clinically-related SLC6A3 regulatory mutation in mice. Such work will not only facilitate investigations of causality
recapitulation and signaling pathway delineation for gene-environment interaction, but also precipitate disease
progression prediction and genome editing-based cure development. Collaboratively among eight groups in four
countries, we recently uncovered a stress-sensitive common variant in the human dopamine transporter (DAT)
gene (SLC6A3) which is implicated in a clinical symptom of alcohol use disorder (AUD). Understanding such a
genetic disorder may indeed provide novel insights into the pathogenic mechanisms underlying AUD. How does a
common variant regulate alcohol consumption in a stress-dependent manner? It is well known that AUD is a
phenotypically complex disease but the central theme is excessive consumption of alcohol. AUD has not only a
polygenic etiology but also environmental attribution so that to clarify the genetics-stress interaction in regulation of
alcohol consumption remains a key in delineating the disease mechanism.
 In our pilot studies, we find that a common variant, DNPiB, in SLC6A3 is associated with reduced levels of
alcohol consumption among different populations and among patients with AUD. At a molecular level, DNPiB is
recognized by a stress-responsive transcription factor. We hypothesize that individuals carrying DNPiB will
consume more alcohol in the presence of stress than in the absence of stress. This makes it an attractive case for
developing DNPiB-based precision medicine for AUD.
 The present project aims to generate and study knock-in mice carrying DNPiB vs DNPiA as a control, allowing
us to answer questions regarding mechanisms as well as clinical utilities linking DAT’s environmental genomics
with AUD that could not otherwise be answered. Expression pattern and level of DAT in the brain will be examined
by immunohistochemistry with techniques ongoing in our lab. We will characterize the DNPiB vs DNPiA mice in
general terms such as body weight and maternal behavior. Neurochemical assays of DAT function will measure DA
uptake. Importantly, we will examine stress-related ethanol intake and preference.
 DAT plays a role in a spectrum of stress- and DA-related diseases such as PTSD, schizophrenia, autism
spectrum disorder, attention deficit hyperactivity disorder, PD, depression and substance use disorders. By
representing all humans, the DNPiB vs DNPiA model will flexibly allow a better understanding of how environment-
regulated SLC6A3 activity is involved in these complex diseases, developmentally and environmentally, and more
importantly, provide a platform for in vivo genomic repair.

## Key facts

- **NIH application ID:** 9929520
- **Project number:** 5R21AA026663-02
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** Zhicheng Carl Lin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $235,750
- **Award type:** 5
- **Project period:** 2019-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929520

## Citation

> US National Institutes of Health, RePORTER application 9929520, Modeling human alcohol abuse in mice with a common SLC6A3 regulatory variant (5R21AA026663-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9929520. Licensed CC0.

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