# Acinar Biology and Pancreatic Disease

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $338,526

## Abstract

Pancreatitis is the most common reason for GI-disease related hospital admissions with an economic impact
totaling $3.7 billion annually, yet few treatment options other than palliative care exist. The initiation of acute
pancreatitis is largely held to result from activation of proteolytic zymogens within the major cell type of the
gland, acinar cells. Damage of acinar cells results in a cytokine/chemokine-initiated inflammatory response that
may spread to other organ systems and can be fatal. Acinar cells undergo digestive enzyme secretion from a
major pathway termed the zymogen granule pathway, and less well recognized constitutive-like pathway
(CLP). The CLP utilizes anterograde endosomal trafficking to secrete small quantities of digestive enzymes,
and therefore has received only limited attention. Our published and preliminary data have uncovered a
previously unrecognized function for the CLP in 1) shaping ZG-mediated secretion, 2) controlling intracellular
zymogen activation, 3) maintaining expression of the transcription factor sXBP1 that is essential for acinar
differentiation, and 4) coordinating levels of autophagy in accordance with secretory activity. All of these
processes have been implicated in the development and progression of AP, yet how acinar cells integrate
these pathways, and the extent to which they are interdependent remains unclear. Tumor protein D52 plays a
pivotal role in regulating the CLP. We have determined that D52 is an autophagy protein that interacts with
ATG16L1, a major regulator of autophagy, that when mutated is the most common marker associated with
development of Crohn's disease. This proposal examines the overarching hypothesis that D52 regulation of
the CLP plays a central role in coordinating secretory function and high levels of autophagy necessary to
maintain acinar cell homeostasis. Aim 1 utilizes D52 knockout mice to test the hypothesis that D52-regulated
anterograde endosomal trafficking is essential to maintain acinar terminal differentiation, and that loss of D52-
mediated trafficking will negatively impact recovery from pancreatitis. Aim 2 will evaluate the mechanistic role
of the D52-ATG16L1 interaction in controlling acinar homeostasis both normally and during pancreatitis. Aim
3 will test the hypothesis that hypomophic mutation of ATG16L1 in mice will negatively impact pancreatic
acinar cell function making animals more susceptible to the development of AP in vivo. These studies should
provide critical insights essential to identify therapeutic targets and strategies aimed at treating pancreatitis.

## Key facts

- **NIH application ID:** 9921376
- **Project number:** 5R01DK070888-12
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** GUY E GROBLEWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,526
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921376

## Citation

> US National Institutes of Health, RePORTER application 9921376, Acinar Biology and Pancreatic Disease (5R01DK070888-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9921376. Licensed CC0.

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