# Innate immune signaling in alcoholic liver disease

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $367,500

## Abstract

Both Alzheimer's disease and heavy alcohol use cause dementia and their interaction on neuroinflammation, a
key element in the pathogenesis of these conditions, is yet to be understood. We hypothesize that the
Interferon Regulatory Factor 3 (IRF3) and the Stimulator of Interferon Genes (STING) signaling pathways are
common and potentially synergistic in AD and alcohol-related neuroinflammation. IRF3 is a nuclear regulatory
factor in Type I Interferon (IFN-I) induction and IFN-Is were recently shown to regulate neuroinflammation and
neurodegeneration in AD. Because evaluation of AD dementia and neurodegeneration in mice models is
based on behavioral assessments, we propose to build new resources in our laboratory for behavioral tests.
The Specific Aims of this study are: 1. To test the role of STING and IRF3 signaling pathways in alcohol-
induced neuroinflammation and regulation of the expression of AD proteins by: a) Evaluating the effects of
chronic alcohol feeding with and without binge on neuroinflammation in wild-type, IRF3-, STING- and cGAS-
deficient mice on mRNA and protein expression of pro-inflammatory cytokine genes, inflammasome activation,
IRF3 phosphorylation, IFN-I induction and microglia activation/polarization in the brain; b) Assessing the
expression levels of AD-associated proteins in the cortex and hippocampus of wild type, IRF3-, STING- and
cGAS-deficient mice after excessive alcohol intake with and without alcohol binge; c) Exploring the effects of
chronic alcohol administration with and without alcohol binge on neuroinflammation, STING activation, IRF3
phosphorylation and IFN-I activation in AD transgenic mice (hAPPJ20) compared to WT mice; d) Testing
effects of pharmacologic inhibition of IRF3 or STING on alcohol-induced neuroinflammation in wild-type mice.
Aim 2 is to establish resources and an infrastructure in our laboratory for a mouse behavioral phenotyping
platform to test cognitive and social impairments associated with AD, including the Morris Water maze test for
assessment of hippocampal-dependent spatial learning and memory formation, the novel object recognition
test as an index of recognition memory, the open field test as a measure of anxiety and locomotor activity, and
the resident intruder aggression task and three-chamber test to evaluate sociability. Experiments proposed in
this supplement will explore novel signaling molecules in alcohol-induced neuroinflammation and interactions
between alcohol use and key pathways in the biology of neuroinflammation and AD dementia. The proposed
studies are within the scope of the parent grant and parallel investigation of the cGAS-STING-IFN-I pathways
between alcohol-induced neuroinflammation and alcoholic liver disease will provide another unique insight into
alcohol-induced organ damage. Our studies will reveal new potential therapeutic targets in the dual insult of
alcohol use and Alzheimer's disease on the brain and dementias.

## Key facts

- **NIH application ID:** 10123147
- **Project number:** 3R01AA017729-10S1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Gyongyi Szabo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,500
- **Award type:** 3
- **Project period:** 2019-09-23 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123147

## Citation

> US National Institutes of Health, RePORTER application 10123147, Innate immune signaling in alcoholic liver disease (3R01AA017729-10S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123147. Licensed CC0.

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