# Impaired autophagy, mitochondrial dysfunction, and inflammation in pancreatitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $402,233

## Abstract

Summary/Abstract
 Pancreatitis is a potentially fatal disease of exocrine pancreas, with obscure pathogenesis and no specific or
efficient treatment available. Excessive/unresolving inflammation is a major determinant of pancreatitis severity
but its mechanisms are poorly understood. Recent findings in experimental and genetic models have uncovered
key pathogenic roles of impaired autophagy and mitochondrial dysfunction in acinar cell damage driving
pancreatitis; disordering of these pathways is also prominent in human disease. Blockade/impairment of
pancreatic autophagy initiates inflammation in genetic models, such as pancreas-specific knockout of the key
autophagy mediator ATG5. Conversely, enhancing autophagic efficiency (or normalizing mitochondrial function)
ameliorates the inflammatory response in experimental pancreatitis. These findings strongly indicate that normal
autophagy restricts inflammation in pancreatitis; however, the underlying mechanisms are unknown.
 We hypothesize that a key mechanism linking impaired autophagy to inflammation in pancreatitis is acinar
cell mitochondrial dysfunction; and further, that this mechanism is mediated by the increase in acinar cell
mitochondrial (mt)ROS and mtDNA release. We posit that these effectors activate major proinflammatory
pathways: NF-κB, triggering the expression of cytokines/chemokines in acinar cells and thus initiating the
inflammatory response; the DNA-sensing cGAS-STING-TBK1 pathway in macrophages, resulting in production
of type I IFNs; and inflammasome activation in macrophages, resulting in massive production of IL-1β and IL-
18. The proposed studies will use genetic and pharmacologic approaches to elucidate the roles of these
pathways. The hypothesis will be tested in 3 Specific Aims:
 1). Determine the effects of impaired autophagy on mitochondrial dysfunction and pancreatic inflammation
in genetic and experimental models of pancreatitis.
 2). Investigate macrophage cGAS-STING-TBK1 pathway activation caused by impaired autophagy in
genetic and experimental models of pancreatitis.
 3). Investigate the role of (canonical) inflammasome pathway in macrophage activation caused by impaired
autophagy and mitochondrial dysfunction.
 Our proposed studies will determine the mechanisms linking impaired autophagy and mitochondrial
dysfunction to macrophage-driven inflammatory response of pancreatitis. The studies will identify molecular
targets in these pathways that could be amenable for pharmacologic intervention to alleviate the inflammatory
response of pancreatitis.

## Key facts

- **NIH application ID:** 10345131
- **Project number:** 1R01DK131111-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ILYA GUKOVSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,233
- **Award type:** 1
- **Project period:** 2022-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10345131

## Citation

> US National Institutes of Health, RePORTER application 10345131, Impaired autophagy, mitochondrial dysfunction, and inflammation in pancreatitis (1R01DK131111-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10345131. Licensed CC0.

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