# Mechanisms of mechanically-induced acute pancreatitis

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $362,250

## Abstract

Abstract
The pancreas is extremely sensitive to mechanical injury. Physical manipulation of the pancreas can initiate a
series of cellular events leading to premature zymogen activation and eventually pancreatitis. Why the
pancreas is so sensitive to mechanical stress and the mechanism by which mechanical force causes
pancreatitis were unknown until we discovered that pancreatic acinar cells express mechanically-activated ion
channels. The dominant mechanically-activated channel in the pancreas is the cation channel Piezo1. We
recently demonstrated that increasing pressure within the pancreatic duct, under conditions that resemble the
clinical condition of endoscopic retrograde cholangiopancreatography (ERCP), caused pancreatitis in mice and
these effects could be blocked by the Piezo1 antagonist, GsMTx4. Moreover, selective acinar cell-specific
genetic deletion of Piezo1 protected mice against pressure-induced pancreatitis. Thus, activation of
mechanically sensitive ion channels in pancreatic acinar cells is a previously unrecognized cause of
pancreatitis, however, the mechanisms by which Piezo1 activation causes pancreatitis is unknown. As a
cation channel, Piezo1 activation produces a rapid influx of extracellular calcium into the cell. Abnormal
calcium regulation within the pancreatic acinar cell perturbs zymogen granule and lysosome function and is
thought to be an early process in the development of pancreatitis. It is possible that Piezo1 induces
pancreatitis by disturbing normal calcium homeostasis. Our preliminary data also indicate that mechanical
activation of pancreatic acinar cells disrupts mitochondrial function and stimulates intracellular trypsin
activation. Therefore, to assess the pathophysiological role of Piezo1 in the pancreas we will (1) establish the
relationship between mechanoactivation and calcium signaling in pancreatic acinar cells, (2) determine the
effects of mechanical activation on mitochondrial function and energy metabolism and (3) characterize the
contribution of mechanically sensitive ion channel activation to premature zymogen activation and generation
of inflammatory mediators in pancreatic acinar cells. We will use a combination of animal, cell biological, and
complimentary genetic and pharmacological tools to characterize mechanoactivation of pancreatic acinar cells.
These studies will unveil the fundamental mechanisms that cause pancreatitis when pressure is applied to the
gland and are relevant to clinical conditions such as surgical manipulation, abdominal trauma, ERCP, and
gallstone induced duct obstruction and may provide a novel target for preventing pancreatitis in which
manipulation of the gland is anticipated.

## Key facts

- **NIH application ID:** 9873033
- **Project number:** 5R01DK120555-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Rodger A. Liddle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,250
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873033

## Citation

> US National Institutes of Health, RePORTER application 9873033, Mechanisms of mechanically-induced acute pancreatitis (5R01DK120555-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9873033. Licensed CC0.

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