# Autophagy in Alcoholic Pancreatitis

> **NIH NIH U01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $344,250

## Abstract

Project Summary 
Alcohol abuse is a major risk factor in initiating pancreatitis in humans and in rodents. Experimental evidence
indicates that alcohol consumption leads to the destabilization of lysosomes and increases zymogen fragility in
acinar cells. Cells can adapt and protect themselves by removing these damaged lysosomes and zymogen
granules (ZGs) by autophagy and lysosomal biogenesis. However, these protective mechanisms are impaired
after chronic alcohol consumption. Cannabinoid receptor 2 (CB2) agonists have potent anti-inflammatory
effects and protect against experimental pancreatitis in mice. However, the underlying molecular mechanisms
by which CB2 agonists protect against pancreatitis are not known. Moreover, what is also missing is the
availability of CB2 agonists with optimal pharmacokinetics and absence of major toxicity as tested in relevant
alcoholic pancreatitis models. In our preliminary studies, we established a novel alcohol pancreatitis mouse
model using the recently established chronic plus acute alcohol binge (Gao-binge) protocol. Gao-binge induces
significant pathogenesis in mouse pancreas, including edema, increased ZGs, elevated expression of
inflammatory cytokines, increased infiltration of inflammatory cells and release of pancreatic enzymes
(amylase and lipase) into the blood. We also demonstrated that Gao-binge decreases expression of pancreatic
cannabinoid receptor 2 (CB2) and inactivates TFEB, a master regulator of lysosomal biogenesis. A selective
CB2 agonist activates TFEB in mouse pancreas and increases autophagic flux in cultured acinar cells. Here
we propose a novel hypothesis that ethanol metabolism leads to decreased CB2 expression and impaired
TFEB-mediated lysosomal biogenesis, insufficient autophagy, accumulation of fragile ZGs, damaged
lysosomes, and subsequent pancreatitis. Our long-term goal is to understand the molecular mechanisms for
alcohol impairment of lysosomal biogenesis in pancreatic acinar cells, in order to identify steps in the repair
pathway that are points for intervention in alcoholic pancreatitis. The objective of this proposal is to understand
how CB2 agonists activate TFEB-mediated lysosomal biogenesis and selective zymophagy and lysophagy to
protect against alcohol-induced pancreatitis. Using complimentary expertise in CB2 receptor
pharmacology/toxicology (NIAAA intramural research program) and modeling of lysosomal biogenesis and
alcoholic pancreatitis in vitro and in vivo (University of Kansas Medical Center) we propose to test a set of
novel, highly selective and orally available CB2 agonists assuring quick translation toward clinical application
for the treatment of alcoholic pancreatitis. We will determine how the selective CB2 agonists activate TFEB-
mediated lysosomal biogenesis and their ability to improve the insufficient autophagy to remove damaged
lysosomes and ZGs induced by chronic alcohol consumption. This proposal brings together research expertise
that will address...

## Key facts

- **NIH application ID:** 10189453
- **Project number:** 5U01AA024733-05
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Wen-Xing Ding
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,250
- **Award type:** 5
- **Project period:** 2017-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189453

## Citation

> US National Institutes of Health, RePORTER application 10189453, Autophagy in Alcoholic Pancreatitis (5U01AA024733-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189453. Licensed CC0.

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