# Mapping Disease Pathways for Biliary Atresia

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $504,232

## Abstract

This project will map disease pathways for biliary atresia (BA), which has failed all therapy and requires liver
transplantation (LTx), using genetic susceptibility as a common basis. BA causes liver failure at birth and
accounts for up to half of all pediatric LTx, worldwide, but has an uncertain etiology. BA leads to scarred and
atretic bile ducts, which fail to drain the liver. Some children also have anomalous left-right patterning of
extrahepatic organs. Preliminary genome-wide association study (GWAS) of single nucleotide polymorphisms
(SNPs) in BA cases, and other evidence from human BA and experimental models lead us to propose the
following specific aims: Aim 1. We will confirm whether BA associates with SNPs in manosidase-1-α-2
(MAN1A2), and in genes which signal via hedgehog, epidermal and transforming growth factors and genes for
ciliogenesis. These pathways are abnormal in liver from BA cases, zebrafish with knockdown of man1a2, and
Man1a2 -/- (knockout) mice. We will identify novel potentially causal variants with targeted sequencing of
significant SNP loci. Aim 2. We will confirm whether knockdown of man1a2 and other candidates induces biliary
dysgenesis and cardiac and hepatic heterotaxy in zebrafish, impaired ciliogenesis in the ex vivo mouse airway
epithelia model of ciliogenesis, and dysregulation of the abovementioned developmental pathways in the liver
transcriptome. Aim 3. We will construct putative pathways for BA with those significant SNP loci and
dysregulated genes which show interactions in an integrated systems analysis of data from Aims 1 and 2. These
loci will also implicate aberrant inflammatory and stress responses. We will corroborate pathways with combined
perturbations of a developmental gene with an inflammatory and a stress response gene in zebrafish and ex
vivo ciliogenesis models. We expect that aberrant developmental, inflammatory and stress response signaling
contributes to hepatic and extrahepatic BA. We will genotype the largest homogeneous cohort of 800 Caucasian
BA cases with LTx from three of the world's largest pediatric LTx centers: the Children's Hospital of Pittsburgh,
King's College Hospital, London, UK, Birmingham Children's Hospital, UK. We will perform whole genome
transcriptome (RNA) sequencing of liver samples from 80 of these cases. We will use experimental and
bioinformatics resources of the Universities of Pittsburgh and California, San Diego, and the Center for Applied
Genomics, Philadelphia. At the end of our project, we will have expanded our knowledge about pathogenesis of
BA and related birth defects and identified candidate strategies to prevent or overcome delayed biliary
morphogenesis. The international collaboration of leaders in hepatology (Kelly, Dhawan, Squires), transplant
surgery (Sharif, Sindhi), genomics (Weeks, Hakonarson, Higgs), pathology (Ranganathan) and systems
biology/bioinformatics (Subramanian, Higgs) is well suited to this task.

## Key facts

- **NIH application ID:** 9904315
- **Project number:** 5R01DK109365-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** RAKESH K. SINDHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $504,232
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904315

## Citation

> US National Institutes of Health, RePORTER application 9904315, Mapping Disease Pathways for Biliary Atresia (5R01DK109365-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9904315. Licensed CC0.

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