# Protective Signaling Pathway in Alcohol-Induced Pancreatitis

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $184,261

## Abstract

Principal Investigator/Program Director (Last, first, middle): KO, Tien C., MD
PROJECT SUMMARY
 Chronic alcohol consumption is the most common cause of chronic pancreatitis (CP), a devastating
fibro-inflammatory disease of the pancreas with no effective therapy. The unmet need for CP therapy is
largely due to fundamental gaps in our understanding of the complex mechanisms that regulate CP
progression. Transforming growth factor (TGF)-β and bone morphogenetic protein (BMP), members of the
TGF-β superfamily, play pro- and anti-fibrogenic roles, respectively, in CP. Gremlin1 (Grem1), a prominent
endogenous BMP antagonist, is elevated in CP. Grem1 can be experimentally induced by TGF-β, alcohol
metabolite and cerulein in vitro in pancreatic stellate cells (PSCs), the key effector cells in CP. Grem1 can
block BMP signaling in these cells. Thus, a balance between BMP and TGF-β signaling through Grem1
regulation may dictate CP progression. The objective of this proposal is to understand the protective role
of BMP signaling during the disease progression. This study will take both in vivo approach by employing
two alcohol (A)-induced CP mouse models in conditional BMP receptor and Grem1 knockout mice, and in
vitro approach by using PSCs for mechanistic studies. Human pancreatic cells and tissue samples will be
utilized for validating key findings from mouse studies. Two Specific Aims will be pursued. Specific Aim 1
determines the anti-fibrogenic effects of BMP signaling in alcohol-induced chronic pancreatitis by
evaluating whether blocking BMP signaling exacerbates CP and how BMP signaling opposes TGF-β
signaling. Specific Aim 2 investigates the mechanisms of suppression of BMP signaling in alcohol-induced
chronic pancreatitis by examining whether Grem1 knockout ameliorates CP, how alcohol enhances Grem1
expression, and whether Grem1 levels correlate with TGF-β and BMP signaling in human CP. The
proposed study is expected to provide mechanistic insights into a novel protective key signaling pathway
in CP, which will lead to a better understanding of the disease progression and innovative approaches to
CP therapy.
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## Key facts

- **NIH application ID:** 9917676
- **Project number:** 5R21AA027014-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** TIEN C KO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,261
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917676

## Citation

> US National Institutes of Health, RePORTER application 9917676, Protective Signaling Pathway in Alcohol-Induced Pancreatitis (5R21AA027014-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9917676. Licensed CC0.

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