# Macrophage Cell Subset Specific Biomarkers for Disease Prognosis in Biliary Atresia

> **NIH NIH U01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $167,700

## Abstract

PROJECT SUMMARY:
Biliary atresia (BA) is a cholestatic liver disease of infancy that is the leading cause of pediatric liver
transplantation. While evidence supports a role for an aberrant immune response in the pathogenesis of BA, the
exact mechanism of disease remains unknown. This gap in scientific knowledge limits identification of immune
biomarkers at diagnosis to stratify patient prognosis. While macrophages (M) have previously been implicated
in both human and murine BA, M are heterogeneous by nature and the pathogenic subsets required for ongoing
hepatic injury have not been identified. Overcoming this gap in scientific knowledge will identify the BA-specific
pathogenic M subsets and lead to novel cell-subset specific biomarkers predictive of patient prognosis.
We have been the first to identify 3 novel hepatic M subsets in pediatric cholestatic liver disease at the time of
liver transplant that are distinct from non-diseased M by leveraging the ability of single cell RNA-sequencing
(scRNA-seq). We have defined these M subsets as lipid-associated M (high expression of genes involved in
lipid metabolism), monocyte-like M (expression of genes also identified in monocytes), and adaptive M
(enrichment for genes involved in lymphocyte activation). Furthermore, monocyte-like and adaptive M subsets
positively correlate with the poor prognostic signature at diagnosis established by Luo et al suggesting these
subsets may drive fibrosis and activation of CD8-positive T cells implicated in disease outcome. We thereby
hypothesize that serum cytokine networks drive M polarization towards pathogenic monocyte-like and
adaptive M subsets; increased numbers of these M subsets by histology at diagnosis will be
associated with poor outcome.
To investigative this hypothesis we will: 1) determine if the numbers of lipid-associated, monocyte-like, and
adaptive M at diagnosis in human BA correlate with outcome as defined by clearance of jaundice by 3 months
post-Kasai Portoenterostomy (KPE), and 2) define M-specific cytokine networks in serum that correlate with
prognosis and histologic findings. This innovative research plan applies findings from previous scRNA-seq
analysis to human samples available from ChiLDReN to identify M-subset specific histologic and serum
biomarkers for prognosis at the time of diagnosis. Findings from the study will advance the care of patients with
BA and allow for improved prognostic counseling at the time of KPE.

## Key facts

- **NIH application ID:** 10210749
- **Project number:** 3U01DK062436-19S1
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Estella M. Alonso
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $167,700
- **Award type:** 3
- **Project period:** 2002-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210749

## Citation

> US National Institutes of Health, RePORTER application 10210749, Macrophage Cell Subset Specific Biomarkers for Disease Prognosis in Biliary Atresia (3U01DK062436-19S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210749. Licensed CC0.

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