# BLR&D Research Career Scientist Award

> **NIH VA IK6** · RLR VA MEDICAL CENTER · 2021 · —

## Abstract

Bile duct epithelial cells (i.e., cholangiocytes) are the target cells in cholangiopathies such as primary biliary
cholangitis (PBC), primary sclerosing cholangitis (PSC), and cholangiocarcinoma (CCA), which are
diseases characterized by the damage, proliferation and neoplastic transformation of cholangiocytes.
These cholestatic liver diseases (characterized by coordinated proliferation/damage of biliary epithelial
cells) along with other cholangiopathies represent a major clinical challenge due to the lack of effective
therapeutic interventions resulting in the need for liver transplantation during end-stage liver disease.
Management of cholangiopathies (including drug- or viral-induced liver injury) represents one of the major
challenges for Veterans Health. Targeting the neuroendocrine factors that respond to cholestasis resulting
from tissue injury may help limit inflammation and fibrosis that occur during hepatobiliary damage. There
is a critical need to understand the neuroendocrine triggers of cholangiocyte growth and their responses
to damage during cholestasis, which will help identify key signaling pathways that represent viable targets
for the development of effective therapeutic agents. Our long-term research goal is to develop an
understanding of the neuroendocrine factors and signaling mechanisms regulating biliary growth during
cholestasis, fatty liver and alcohol-induced liver disease, which will provide a foundation for the discovery
of prevention and new pharmaceutical interventions for cholangiopathies and liver diseases characterized
by hepatic fibrosis. For my current funded VA Merit Award, the central hypothesis is based upon the
postulate that the secretin/secretin receptor (Sct/SR) axis signaling is key for mediating the proliferative
and activated profibrogenic biliary phenotype that contributes to the progression of hepatic steatosis and
fibrosis during the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis
(NASH). In addition, my research program is funded by multiple collaborative NIH R01 grants that explore
various aspects of the regulation of biliary growth and hepatic fibrosis by neuroendocrine factors such as
secretin, melatonin, serotonin and miRNAs in models of cholestasis, NAFLD, and alcohol-induce liver
disease. My collaborative effort with multiple VA investigators has been high productive and has resulted
in many publications in high impact journals. The exploration of the neuroendocrine features of
cholangiocytes will provide new avenues for the development of therapeutic interventions for these
diseases. Our contribution is significant since this is a critical step to provide translational knowledge for
the development of therapies for cholangiopathies. These findings will also have broader implications for
other hepatic diseases characterized by hepatic fibrosis.

## Key facts

- **NIH application ID:** 10265373
- **Project number:** 5IK6BX004601-03
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Gianfranco D Alpini
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265373

## Citation

> US National Institutes of Health, RePORTER application 10265373, BLR&D Research Career Scientist Award (5IK6BX004601-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10265373. Licensed CC0.

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