# Neuroendocrine Regulation of Biliary Growth and Fibrosis

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2020 · $339,918

## Abstract

In cholestatic liver diseases, cholangiocytes, through the secretion of neuroendocrine factors, are the key
link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury.
Targeting the factors that respond to the mechanical stress resulting from tissue injury may limit
inflammation and liver fibrosis that occur in hepatobiliary damage and diseases such as primary biliary
cirrhosis (PBC), primary sclerosing cholangitis (PSC) and liver fibrosis. Although mechanical stress occurs
with biliary distention (commonly observed in PSC and extrahepatic cholestasis) and activates
cholangiocytes, the cellular and molecular mechanisms responsible for this activated neuroendocrine
phenotypes remain unclear. While advances have been made to further our understanding of the paracrine
and autocrine neuroendocrine factors that modulate biliary proliferation during cholestasis, unfortunately,
viable therapies for management of cholangiopathies remain elusive. There remains, therefore, a critical
need to understand the triggers of cholangiocyte growth and their responses to damage during cholestasis,
which may help identify key signaling pathways that represent viable targets for the development of
effective therapeutic agents. Preliminary data from the analysis of the activated neuroendocrine
cholangiocyte phenotypes demonstrated that: (i) cholangiocytes express serotonin receptors (5-HTR) (2A, 2B
and 2C); (ii) mechanical stress-dependent activation of 5-HTR2B stimulates 5-HT synthesis and secretion and
an activated neuroendocrine cholangiocyte phenotype in a PKA and miR-16 mediated mechanism; (iii)
activation of mechanosensitive 5-HTR2B signaling in concert with increased cholangiocyte expression and
secretion of FGF1 (regulated by miR-16) stimulates biliary proliferation during in vitro mechanical stress and
bile duct ligation (BDL). Based upon these findings, we propose the overall central hypothesis that the
mechanosensitive 5-HTè5-HTR2A/BCèFGF1 signaling axis is a key pathway responsible for mediating the
proliferative and profibrogenic cholangiocyte phenotype. This postulate will be tested in three specific aims,
which will demonstrate that: (i) mechanical stress-dependent 5-HT synthesis and release induces an
activated neuroendocrine and profibrogenic cholangiocyte phenotype mediated by activation of 5-HTR2A/B/C
receptor family; (ii) FGF1 secretion by cholangiocytes during cholestasis mediates biliary proliferation and
the activated neuroendocrine cholangiocyte phenotype in a 5-HTR2A/B/C receptor family and miR-16-
dependent autocrine/paracrine mechanism; and (iii) inhibition of the 5-HTR2A/B/CèFGF1 axis attenuates the
activated neuroendocrine biliary phenotype and fibrosis during cholestasis. Completion of proposed studies
will provide a framework for understanding how mechanical stimuli trigger local and systemic responses
mediate hepatobiliary fibrosis.

## Key facts

- **NIH application ID:** 9869004
- **Project number:** 5R01DK110035-04
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Gianfranco D Alpini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,918
- **Award type:** 5
- **Project period:** 2017-03-02 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869004

## Citation

> US National Institutes of Health, RePORTER application 9869004, Neuroendocrine Regulation of Biliary Growth and Fibrosis (5R01DK110035-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869004. Licensed CC0.

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