# Molecular targets in cholestasis caused by bile salt export pump deficiency

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $342,706

## Abstract

PROJECT SUMMARY/ABSTRACT
In humans, mutations in the ABCB11 gene impair bile salt export pump (BSEP) function and cause
progressive familial intrahepatic cholestasis type II (PFIC2), which is a fast-progressing and often-fatal liver
disease in infancy. Liver transplantation remains as the only curable treatment for many PFIC2 patients.
The main challenge for developing alternative therapy is that there is no known mechanism allowing
restoration of bile excretion in the absence of BSEP. Our long-term goal is to discover molecular targets to
treat cholestatic liver diseases. The overall objective for this application is to identify mechanisms that can
be activated to restore bile excretion in the context of BSEP deficiency. Based on the preliminary data
generated using the abcb11b mutant zebrafish, the central hypothesis is that alternative transporters can be
prompted to excrete bile acids in BSEP-deficient hepatocytes. The rationale for the proposed research is
that, finding the alternative bile salt transporter and delineating the molecular mechanisms triggering its bile
excretion function will facilitate the designing of targeted therapies to treat cholestasis caused by BSEP
deficiency. Identifying novel strategies to modulate bile secretion will also benefit the patients with other
cholestatic liver diseases. The central hypothesis will be tested by the experiments proposed in three
complementary specific aims: 1) Determine the alternative transporter that can be prompted to excrete bile
acids in BSEP-deficient hepatocytes; 2) Define the cellular and molecular mechanisms that can be activated
to restore bile excretion in BSEP-deficient hepatocytes; and 3) Identify genetic modifiers that restore bile
excretion in BSEP-deficient hepatocytes. The first aim will test the hypothesis that recovering the
localization of another ABC transporter MDR1 to the bile canaliculus allows it to assume bile excretion
function in BSEP-deficient hepatocytes. The second aim will investigate whether augmentation of
autophagy represents a novel mechanism to restore bile excretion in hepatocytes with BSEP deficiency.
The third aim will utilize an unbiased whole-genome sequencing approach to identify genetic modifiers of
BSEP-deficiency phenotype severity. The research proposed in this application is highly innovative,
because it uses the zebrafish model that offers unique advantages for studying bile excretion, and abcb11b
mutant zebrafish is the first animal model in which loss of BSEP results in severe perturbation of bile
excretion as seen in patients with PFIC2. The proposed research is significant, because it is expected to
reveal strategies to restore bile excretion in BSEP-deficient hepatocytes and uncover new therapeutic
targets for treating cholestatic liver diseases.

## Key facts

- **NIH application ID:** 9983706
- **Project number:** 5R01DK117266-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Chunyue Yin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,706
- **Award type:** 5
- **Project period:** 2018-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983706

## Citation

> US National Institutes of Health, RePORTER application 9983706, Molecular targets in cholestasis caused by bile salt export pump deficiency (5R01DK117266-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983706. Licensed CC0.

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