# Molecular regulation of cholestasis in cholangiocytes

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $478,862

## Abstract

PROJECT SUMMARY
Cholestasis is a common manifestation of liver disease. Cholestasis often is due to disorders
specifically affecting cholangiocytes, which play a major role in bile secretion. They are responsible for
secretion of bicarbonate into bile and modulating the biliary contents of other constituents as well. The
type III inositol trisphosphate receptor (InsP3R-3) is the primary intracellular calcium release channel
in cholangiocytes and our previous studies have shown that apically-localized InsP3R-3 controls
bicarbonate secretion. We also found that in most ductular forms of human cholestasis and in multiple
animal models, there is loss of InsP3R-3 expression, underlying the importance of calcium
homeostasis in normal cholangiocyte function and its dysregulation in cholestasis. We hypothesize
that restoration of InsP3R-3 expression will ameliorate cholestasis and improve biliary bicarbonate
secretion. Thus the long term objective of this grant is to understand the molecular mechanisms of
InsP3R-3 regulation in normal and cholestatic liver and the therapeutic effect of restoration of InsP3R-
3 expression on liver function. To achieve this objective, the proposal will be implemented with the
following specific aims: (1) The molecular factors governing the regulation of InsP3R-3 gene
expression will be defined by studying the transcription factors (TFs) and microRNAs (miRs) that
regulate the InsP3R-3 promoter and mRNA respectively; (2) The cellular mechanisms that direct
InsP3R-3 to the subapical region of cholangiocytes including targeting sequences and interacting
proteins that lead to such localization will be established; (3) Molecular mechanisms that lead to loss
of InsP3R-3 expression and function in animal/human models of cholestasis (including InsP3R-3 KO
mice and CRISPR/Cas9-InsP3R-3-null human cholangiocytes) will be determined and verified in
human cholestatic liver. Further, we will investigate whether restoration of expression-specific
TFs/miRs-anti-miRs in cholestasis results in improvement of disease. Together, the data derived from
these studies will improve our understanding of the regulation of secretion in cholangiocytes, and
have the potential to lead to design of novel therapeutic approaches for the treatment of cholestatic
disorders.

## Key facts

- **NIH application ID:** 10151603
- **Project number:** 5R01DK112797-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** MICHAEL H NATHANSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $478,862
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151603

## Citation

> US National Institutes of Health, RePORTER application 10151603, Molecular regulation of cholestasis in cholangiocytes (5R01DK112797-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10151603. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*