# Regulation of biliary growth and fibrosis by melatonin

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $289,480

## Abstract

Project Summary/Abstract
Cholangiocytes are the target cells in cholangiopathies; such as, primary biliary cirrhosis (PBC) and primary
sclerosing cholangitis (PSC), which are characterized by the damage and proliferation of cholangiocytes. In
cholestatic liver diseases, cholangiocytes, through the products of their cellular activation, are implicated as
the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary
injury. While advances have been made to further our understanding of the neuroendocrine factors that
modulate biliary proliferation and fibrosis during cholestasis, unfortunately, viable therapies for the
management of cholangiopathies remain elusive. Our previous studies have revealed that cholangiocytes
express the enzymes necessary to synthesize and secrete melatonin and that melatonin plays a role in
regulating biliary hyperplasia during cholestasis. Our overall objective is to determine the molecular
mechanisms by which biliary proliferation and fibrosis are regulated by the melatonin/MT1/MT2/GPR50
signaling axis. Our central hypothesis, based upon the strong preliminary data, is that biliary proliferation
and fibrosis are differentially regulated by the melatonin/melatonin receptor (MT1 or MT2)-signaling axis in
the presence/absence of MT1 or MT2. The central hypothesis was formulated on the basis that knockout of
MT1 and MT2 resulted in differential responses of the biliary epithelium to extrahepatic cholestasis. As such,
we found: (i) a significant increase of biliary proliferation and fibrosis in MT2 knockout mice during BDL; and
(ii) a substantial reduction in biliary proliferation and fibrosis in MT1 knockout mice following BDL. miRNA
PCR array analysis of cholangiocytes from BDL MT2 knockout and Mdr2-/- mice exposed to prolonged
darkness (that increases melatonin secretion) revealed alterations in the expression levels of miRNAs (miR-
125b, let-7a, miR-200b and miR-181a/b) that will be evaluated as potential targets to regulate biliary
proliferation and fibrosis through the melatonin/MT1/MT2/GPR50 signaling axis. To test our central
hypothesis, we propose two Specific Aims: (1) disruption of the melatonin/MT1/MT2/GPR50 signaling axis
alters biliary proliferation and liver fibrosis during cholestasis and (2) biliary proliferation and liver fibrosis is
regulated by the melatonin/MT1/MT2/GPR50 signaling axis via miRNA-regulated proliferative and pro-
fibrogenic mechanisms. The successful completion of the studies may provide tools for the development of
novel treatment paradigms targeting the melatonin/MT1/MT2/GPR50 signaling axis during chronic liver
diseases.

## Key facts

- **NIH application ID:** 9994291
- **Project number:** 5R01DK115184-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Gianfranco D Alpini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $289,480
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994291

## Citation

> US National Institutes of Health, RePORTER application 9994291, Regulation of biliary growth and fibrosis by melatonin (5R01DK115184-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9994291. Licensed CC0.

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