# Regulation of pancreatitis severity

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2023 · —

## Abstract

This proposal will continue the topic of our current Merit Award and examine a relatively recently described
secretory protein, renalase, which appears to have a potent and novel protective role in acute pancreatitis (AP).
AP has an incidence of up to 5/10,000 in the U.S. population, but is much more common in Veterans. It can
cause death in 30% of those with severe disease, and is the most common reason for hospitalization for
individuals with gastrointestinal disease in the U.S. Since AP is often caused by alcohol abuse, cigarette
smoking, and increases in incidence with age, it is frequently encountered in our Veteran population. During this
funding period we published a manuscript that examined most of our current Merit Aims on renalase in
experimental murine AP and showed that: 1) Plasma renalase levels fell dramatically at the onset of AP and
rebounded much higher than basal levels during recovery, 2) Genetic deletion of renalase was associated with
worse experimental AP, 3) Administering recombinant renalase (rRNLS) reduced experimental AP severity in
vivo even when given after disease onset, 4) rRNLS could act directly on pancreatic acinar cells to reduce injury,
5) The protective effects of renalase on acinar cells is mediated by a specific plasma-membrane calcium export
pump (PMCA4b). Our preliminary studies in clinical AP suggest that plasma renalase levels also falls in human
AP and may reflect disease severity. Here we propose to extend these observations with 3 specific aims that will
examine the following questions: 1) Does renalase also affect recovery from acute pancreatitis? 2) What
mechanisms account for the rapid decrease in plasma renalase and appearance in the kidney in experimental
AP and the subsequent increases in plasma renalase during recovery? 3) Do plasma binding proteins interact
with RNLS and how might it affect its biology? These issues are relevant when considering renalase as a
potential AP therapy because the data could serve as a guide for its future administration by showing benefits
when given well after disease onset to promote recovery. The plasma levels of renalase may be a prognostic
factor for AP severity and could also guide therapies including administering renalase. The following preliminary
data provides a scientific foundation for pursuing these questions and aims. First, we find that severe human AP
is associated with levels of plasma renalase that are persistently lower than baseline, indicating a deficient. We
propose to examine the levels of plasma renalase in other murine AP models, including one that causes severe
disease, to determine whether they conform to the patterns in human. In mice with genetic deletion of renalase,
we find that AP recovery is delayed. The human and AP model findings led us to predict that renalase may be act
to both reduce the acute AP severity and enhance recovery- we will test this experimentally. Second, we
observe that during AP, the levels of renalase in the kidn...

## Key facts

- **NIH application ID:** 10514593
- **Project number:** 5I01BX003250-07
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Fred Sanford Gorelick
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-07-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514593

## Citation

> US National Institutes of Health, RePORTER application 10514593, Regulation of pancreatitis severity (5I01BX003250-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10514593. Licensed CC0.

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