# Brain microRNA-mRNA regulatory networks and alcohol use disorders

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $352,996

## Abstract

PROJECT SUMMARY/ABSTRACT
Alcohol use disorders (AUDs) are characterized by compulsive and uncontrolled alcohol use, leading to social
and occupational impairments. While genetic variation can result in an increased risk of AUDs, chronic alcohol
consumption can independently lead to alcohol tolerance and dependence. However, it is unknown how
chronic alcohol consumption alters gene expression and leads to neuroadaptations underlying AUDs. There is
evidence that small noncoding microRNAs (miRNAs), which regulate target gene (or mRNA) expression at the
posttranscriptional level, are abundant in the brain and play important roles in a variety of biological processes
such as neuronal differentiation and synapse formation and plasticity. Additionally, each miRNA can regulate
the expression of a number of different target mRNAs and each mRNA can be targeted by different miRNAs.
Thus, brain miRNAs that regulate the expression of alcohol-responsive mRNAs may act upstream of alcohol-
induced neuroadaptations. The objective of the proposed study is to identify dysregulated miRNAs and their
target mRNAs in the brains of AUD subjects and generate AUD-associated miRNA-mRNA regulatory
networks. The central hypothesis is that AUD-associated miRNAs interact with target mRNAs in reward-related
brain regions, forming miRNA-mRNA regulatory networks that are critical for AUD development. This
hypothesis will be tested by pursuing three specific aims: (1) identify differentially expressed miRNAs and
mRNAs in at least eight reward-related brain regions (prefrontal cortex, nucleus accumbens, ventral tegmental
area, hippocampus, amygdala, putamen, caudate, and cerebellum) of AUD subjects using next-generation
sequencing (miRNA-Seq and mRNA-Seq); (2) generate AUD-associated miRNA-mRNA regulatory networks in
reward-related brain regions using integrated bioinformatics analyses; and (3) refine AUD-associated miRNA-
mRNA regulatory networks by validating the predicted miRNA-mRNA pairs using experimental approaches,
such as high throughput 3' UTR reporter assays in cell lines and miRNA-mRNA interaction analyses in human
embryonic stem cell (hESC)-derived GABAergic cortical neurons (as an in vitro cellular model). The proposed
research is significant because it will identify and validate AUD-associated miRNA-mRNA regulatory networks
in reward-related brain regions, thus improving our understanding of the epigenetic mechanisms of AUDs. The
proposed research is innovative because advanced technologies (such as next-generation sequencing, state-
of-the-art bioinformatics programs for miRNA-mRNA network construction, high-throughput 3' UTR reporter
assay, and miRNA-mRNA interaction modeling in stem cell-derived neurons) will be used. Our long-term goal
is to develop novel pharmacological treatment for AUDs by targeting specific miRNAs and their target genes.

## Key facts

- **NIH application ID:** 9976401
- **Project number:** 5R01AA025080-05
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Huiping Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,996
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976401

## Citation

> US National Institutes of Health, RePORTER application 9976401, Brain microRNA-mRNA regulatory networks and alcohol use disorders (5R01AA025080-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976401. Licensed CC0.

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