# Research Project 4: NF-κB–NRF2 Interplay Regulates Inflammation in Alcoholic Pancreatitis

> **NIH NIH P50** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $111,504

## Abstract

RESEARCH PROJECT 4 - ABSTRACT
Alcoholic pancreatitis remains a disorder with significant morbidity and mortality, with no available
treatments directed at the mechanisms of the disease. Inflammation is a major complication of
pancreatitis and, to a large extent, determines its severity. There has been a significant progress
in our understanding of the inflammatory response; however, this knowledge has not translated
into effective therapies for pancreatitis. Thus, there is an urgent need to develop new approaches
to reduce nonresolving/uncontrolled inflammation in pancreatitis, particularly in acute pancreatitis.
Our recent studies reveal that impaired autophagy plays a key role in the pathogenesis of non-
alcoholic and alcoholic pancreatitis. We propose to investigate the pathways linking autophagic
dysfunction to inflammation in alcoholic pancreatitis. Our preliminary results suggest that impaired
autophagy leads to oxidative stress (ROS increase) and accumulation of the multifunctional
adaptor/scaffold protein p62/SQSTM1 in acinar cells. ROS increase and p62 accumulation, in
turn, stimulate two major transcription factor pathways in exocrine pancreas, the pro-inflammatory
NF-κB and the antioxidant/anti-inflammatory NRF2. Importantly, we find that NF-κB suppresses
NRF2 activity, thus perpetuating the inflammatory response of alcoholic pancreatitis.
These preliminary findings support our hypothesis that the interplay between NRF2 and
NF-κB is a central mechanism regulating oxidative stress and inflammation in alcoholic
pancreatitis; and, further, that the imbalance between excessive NF-κB and insufficient
NRF2 activities drives the inflammatory response of pancreatitis. Proposed studies will
determine the mechanisms regulating pancreatic NF-κB–NRF2 circuit and its role in the
inflammatory response of alcoholic pancreatitis.
Results from the proposed studies will identify potential molecular targets, such as NRF2,
amenable for pharmacologic intervention to reduce inflammation and the severity of alcoholic
pancreatitis.

## Key facts

- **NIH application ID:** 10322381
- **Project number:** 5P50AA011999-24
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** HIDEKAZU TSUKAMOTO
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $111,504
- **Award type:** 5
- **Project period:** 1999-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322381

## Citation

> US National Institutes of Health, RePORTER application 10322381, Research Project 4: NF-κB–NRF2 Interplay Regulates Inflammation in Alcoholic Pancreatitis (5P50AA011999-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10322381. Licensed CC0.

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