# Relative Contribution of Trypsin and Inflamation in Acute and Chronic Pancreatitis

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $540,673

## Abstract

Abstract
Pancreatitis, an inflammatory disease of pancreas, leads to more than 300,000 admissions to hospitals
in the United States alone. Despite decades of research there is no specific therapy for pancreatitis.
While the inflammation during acute pancreatitis is initiated in acinar cells, over disease course the
inflammation spills into systemic circulation. Uncontrolled systemic inflammation during acute
pancreatitis can lead to Systemic Inflammatory Response Syndrome (SIRS) and multi-organ failure,
which is the primary cause of morbidity and mortality. Thus strategies to control inflammation will lead
to development of specific therapy for acute pancreatitis. In the current proposal we will evaluate the
early intra-acinar events in pancreatitis that lead to activation of signaling pathways that mediate local
inflammation, eventually resulting in disease development. In the first aim, we will evaluate the role of
ADAMs, specifically ADAM-10/17 in spreading this local inflammation to systemic levels. ADAMs are
Zn2+ - dependent proteases that proteolytically cleave a wide variety of membrane-bound proteins.
Among these, ADAM-10 and -17 have been implicated in multiple inflammatory disorders but their role
has not been evaluated in pancreatitis. Intriguingly, our preliminary data suggest that treatment with
ADAM-10/17 inhibitor in a therapeutic setting, i.e. after initiation of injury, leads to decrease in
pancreatic and lung injury and inflammation in caerulein model of severe acute pancreatitis. As most of
the studies in acute pancreatitis perform prophylactic intervention, which is not clinically significant, the
current proposal is focused on evaluating this translationally relevant observation that has the potential
of being developed into a therapeutic strategy for pancreatitis. In the next aim, we will study how
induction of pancreatitis may result in activation of ER stress in the acinar cells and how this may lead
to activation of signaling pathways like AP-1 and NF-kB that are known to be associated with
inflammation. We will also evaluate the role of anti-microbial `Neutrophil Extracellular Traps' or NETs, in
acinar cell injury in the third aim, which will help us understand the vicious cycle of inflammation and
injury in pancreatitis. Since we are in possession of the unique T7 KO mice, we will be in a position to
evaluate the role of trypsin in these early intra-acinar events that will eventually help us in
understanding the local and systemic inflammation in the context of pancreatic injury.

## Key facts

- **NIH application ID:** 10125136
- **Project number:** 5R01DK093047-11
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Rajinder K Dawra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $540,673
- **Award type:** 5
- **Project period:** 2011-08-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125136

## Citation

> US National Institutes of Health, RePORTER application 10125136, Relative Contribution of Trypsin and Inflamation in Acute and Chronic Pancreatitis (5R01DK093047-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10125136. Licensed CC0.

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