# CFTR modulates innate immune response in biliary epithelium: Role in the pathogenesis and treatment of Cystic-Fibrosis-related liver disease.

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $551,192

## Abstract

SUMMARY
 Cystic Fibrosis (CF) is a common and clinically severe genetic disease, caused by mutations in CFTR, a
membrane protein that mediates chloride and fluid secretion in a number of secretory epithelia, including the
biliary tree. Cystic Fibrosis liver disease (CFLD) is a chronic cholangiopathy that can eventually evolve into
sclerosing cholangitis and focal biliary cirrhosis. The pathogenesis of this condition is not well understood and
treatment is limited to the administration of choleretic bile acids, or in selected cases, liver transplantation.
 CFLD has been classically considered a consequence of the impaired bile secretion caused by the
defective CFTR channel function. However, while biliary secretion is universally reduced in CF, the
spontaneous development of CFLD is less frequent, suggesting that genetic and/or acquired factors are at
play. Our previous studies suggested that reduced tolerance of the biliary innate immune system to endotoxins
plays a major pathogenetic role in CFLD. We showed that cholangiocytes isolated from Cftr-KO mice have
higher NF-κB activity and secrete a larger amount of inflammatory cytokines, when exposed to the TLR4-ligand
LPS. We have also demonstrated that in CF-defective cholangiocytes, TLR4 is activated by the unrestrained
function of Src family kinases (SFK), a consequence of defective CFTR. This mechanism is present also in
cholangiocytes derived from human iPSC homozygous for the ΔF508 mutation. In addition, novel exciting
preliminary data show that the gut microbiota in CFTR-KO mice is already different from WT littermates at birth
and it is skewed towards the prevalence of a more pro-inflammatory flora.
 In this application we will test the hypothesis that CFLD may result from the combination of a genetic
mutation affecting biliary epithelial innate immunity along with changes in microbiota composition and
increased intestinal permeability. In particular, (1) we will use iPSC technology to dissect the impact of
functionally different CFTR mutations on the mechanisms leading to a pro-inflammatory phenotype in human
cholangiocytes and (2) we will study whether changes in the gut microbiota play a causal role in the
development of liver disease in mouse models of CF.
 Our study will discover novel aspects of secretory epithelia physiology and innate immunity and clarity if
changes in the gut microbiota play a possible causal role in CFLD. These studies represent a paradigm-shift in
the understanding of the pathogenesis of CFLD and imply that treatment for CFLD should also control
inflammation and the impact of the intestinal microbiota. The outcome of this project will lay the foundation for
novel intervention strategies that will have an impact on the management of CFLD and other cholangiopathies.
!

## Key facts

- **NIH application ID:** 10223271
- **Project number:** 5R01DK096096-09
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mario Strazzabosco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $551,192
- **Award type:** 5
- **Project period:** 2013-05-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223271

## Citation

> US National Institutes of Health, RePORTER application 10223271, CFTR modulates innate immune response in biliary epithelium: Role in the pathogenesis and treatment of Cystic-Fibrosis-related liver disease. (5R01DK096096-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10223271. Licensed CC0.

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