# Gain of function mutations in inflammasome related genes in human and experimental alcoholic liver disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $329,168

## Abstract

Alcohol abuse is a leading cause of morbidity and mortality worldwide. The deleterious
effects of alcohol abuse on the liver leads to pathologically distinct entities: steatosis,
steatohepatitis (ASH), fibrosis and cirrhosis. NLRP3 inflammasome is a multi-protein
cytoplasmic complex that serves as pattern recognition receptor and has emerged as key
mediator of inflammation, and cell death. The NLRP3 inflammasome senses damage-
associated molecular patterns and induces secretion of IL-1β and IL-18 that may be
destructive to tissues. We, and others, have recently shown that hepatic caspase 1 activation
occurs during the development of ASH and nonalcoholic steatohepatitis (NASH) and this
activation appears to be mediated through the NLRP3 inflammasome. These studies
demonstrated that caspase 1 plays an important role in inflammation and fibrosis during ASH
and NASH development while IL-1 receptor antagonist ameliorates ASH in mice. A role for
NLRP3 inflammasome gain-of-function mutations was initially described in a group of rare
autoinflammatory monogenic conditions. Subsequently, multiple gene polymorphisms have
been described and some have been implicated in common chronic inflammatory conditions
including Crohn's disease and rheumatoid arthritis. In particular, two common polymorphisms
affecting 15-20% of general population have been shown to result in gain-of-function
phenotype associated with moderately increased IL-1β levels.
Based on these preliminary data we propose the CENTRAL HYPOTHESIS that 1) NLRP3 is
required for the progression of ethanol-induced fatty liver to ASH and fibrosis in mice; 2)
Genetic variation in NLRP3-inflammasome expression predicts progression and/or severity
of ALD and response to IL-1-based therapy in ASH. To investigate this hypothesis our
proposal has following SPECIFIC AIMS. First: Determine the role of NLRP3 inflammasome
activation on ALD progression from fatty liver to steatohepatitis and fibrosis. Second:
Determine the role of genetic variations of NLRP3 inflammasome resulting in gain-of-function
phenotypes in susceptibility to ALD and response to IL-1-based therapy in patients with ALD.
To address these central issues, we have put together a Multi-PI investigative team including
a Pioneered Scientist in Inflammasome Biology, and Experts in Cell Death, Fibrosis and
Alcoholic Liver Disease Pathology. The results of these studies will uncover crucial aspects
of NLRP3 inflammasome biology and its contribution to liver pathology in ALD that may lead
to novel diagnostic and therapeutic strategies for patients with this disease.

## Key facts

- **NIH application ID:** 10237244
- **Project number:** 5R01AA024206-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ariel Feldstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $329,168
- **Award type:** 5
- **Project period:** 2017-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237244

## Citation

> US National Institutes of Health, RePORTER application 10237244, Gain of function mutations in inflammasome related genes in human and experimental alcoholic liver disease (5R01AA024206-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10237244. Licensed CC0.

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