# 4/11 Neuroimmune and extracellular matrix interactions in alcohol consumption

> **NIH NIH U01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $439,725

## Abstract

Chronic alcohol consumption induces transcriptional changes in genes encoding structural components
and regulators of the extracellular matrix (ECM). The molecular mechanisms underlying these alterations and
the functional implications of altered ECM gene expression are not well understood in the context of excessive
alcohol drinking. We hypothesize that activation of the immune response-related transcription factor STAT3 in
astrocytes results in transcriptional changes in genes encoding ECM components, resulting in alterations in
ECM structure and function, synaptic changes, and increased ethanol intake. The proposed experiments will
address this hypothesis with three specific aims. In Specific Aim 1, we will use an unbiased approach to
determine changes in the cortical ECM proteome, or “matrisome” in mice that have chronically consumed
ethanol in a binge-like drinking protocol (drinking in the dark) for 6 weeks. Cutting-edge proteomics and
glycomics will be performed to quantitatively measure changes in cortical ECM. These results will be compared
to changes in ECM-related genes in existing and new INIA transcriptome datasets and the genes analyzed for
STAT3 binding motifs in their promoters. In Specific Aim 2, we will determine the role of astrocyte-expressed
STAT3 in alcohol consumption by conditionally knocking out Stat3 in astrocytes using floxed Stat3 mice and
the astrocyte-specific Cre line, Aldh1l1-CreERT2. Mice will be tested for binge-like ethanol consumption and
dependence-induced escalation of ethanol intake. Association of activated STAT3 with gene promoters in the
prefrontal cortex will also be determined after chronic binge-like drinking using chromatin immunoprecipitation
with an antibody to phosphorylated STAT3, followed by whole-genome DNA sequencing (ChIP-Seq). Finally,
we will determine the role of a specific ECM gene and putative STAT3 target, brevican (Bcan) in alcohol
consumption, by conditionally knocking out Bcan in astrocytes as described above. We will also reduce the
expression of Bcan in the prefrontal cortex of mice using viral-delivered shRNA and measure binge-like ethanol
intake. Brevican is localized perisynaptically and regulates synaptic plasticity. To determine if brevican is more
highly associated with synapses after chronic ethanol drinking and if synapse structure in the PFC is altered by
chronic ethanol, we will perform super-resolution microscopy with brevican antibody and antibodies to
excitatory and inhibitory synaptic markers in mice after chronic binge-like drinking. Within each Specific Aim,
we will integrate and collaborate with INIA-Neuroimmune and INIA-Stress investigators. The completion of
these Specific Aims will contribute to fundamental knowledge of the molecular and cellular mechanisms by
which chronic alcohol drinking alters the ECM and potentially provide new cellular targets to reduce excessive
alcohol consumption.

## Key facts

- **NIH application ID:** 10411112
- **Project number:** 2U01AA020912-12
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Amy Wolven Lasek
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $439,725
- **Award type:** 2
- **Project period:** 2011-09-05 → 2022-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411112

## Citation

> US National Institutes of Health, RePORTER application 10411112, 4/11 Neuroimmune and extracellular matrix interactions in alcohol consumption (2U01AA020912-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10411112. Licensed CC0.

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