# Biological Basis of Phenotypes and Clinical Outcomes in Biliary Atresia

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $486,146

## Abstract

PROJECT SUMMARY/ABSTRACT
 This is a competing renewal application studying the biological basis of clinical phenotype and outcome of
biliary atresia, the most common cause of neonatal cholestasis. The disease results from a fibro-inflammatory
obstruction of extrahepatic bile ducts and present in early infancy. Despite nearly uniform progression to end-
stage cirrhosis, the variable response to surgical/medical treatment and rate of progression of disease suggest
the existence of unrecognized biological processes that are driving different phenotypes or stages of disease.
In the previous tenure of the award, we found evidence of increased signaling via IL-8, TNF, and components
of the inflammasome in pathogenesis of bile duct injury, and the simultaneous activation of molecular circuits
dependent on IL-33 to induce tissue repair. We also identified a key role for MMP-7 in bile duct epithelial injury
and as a highly sensitive and specific biomarker for biliary atresia. In preparation for this application, we
applied computer modeling and high analytics to mine the hepatic transcriptome and found a 14-gene
signature that predicts 2-year survival with the native liver and identifies glutathione metabolism as a new
therapeutic target to suppress fibrosis. Using serum proteomics, we also uncovered serum proteins that
segregate with children with advanced fibrosis as determined by portal hypertension. These data form the
foundation for the new studies proposed in three inter-related aims: 1) To discover molecular determinants of
outcome and pathogenesis of biliary atresia, 2) To identify biomarkers of portal hypertension during
progression of liver disease, and 3) To define pathogenic mechanisms of tissue injury in biliary atresia.
Experiments for Aim 1 will use RNAseq data from a large cohort to mine gene groups and molecular pathways
that predict clinical outcome, followed by complementary studies in mouse models of biliary atresia and
neonatal fibrosis in pre-clinical trials to suppress fibrosis by targeting metabolic circuits in the liver. Experiments
for Aim 2 will use data from serum proteomics to investigate how SEMA6B, sFRP3, COMMD7, VCAM1, and BMX
perform as biomarkers of portal hypertension individually or in combination. And experiments in Aim 3 will
derive biliary organoids from the liver of subjects with biliary atresia and test hypothesis related to defects of
cell maturation and to how the activation of fibrogenesis in cholangiocytes is an important mechanisms of bile
duct injury. By applying highly complementary approaches to study tissues from adequately sized cohorts that
have been phenotyped prospectively, our experiments will provide insight into new biomarkers of disease, their
role in pathogenesis, and how new clinical trials can be personalized based on biological end-point.

## Key facts

- **NIH application ID:** 10425310
- **Project number:** 5R01DK083781-13
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** JORGE A. BEZERRA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $486,146
- **Award type:** 5
- **Project period:** 2009-09-01 → 2022-09-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425310

## Citation

> US National Institutes of Health, RePORTER application 10425310, Biological Basis of Phenotypes and Clinical Outcomes in Biliary Atresia (5R01DK083781-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10425310. Licensed CC0.

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