# Macrophage Regulation of Immune Pathogenesis of Biliary Atresia

> **NIH NIH K08** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2022 · $162,975

## Abstract

PROJECT SUMMARY:
Candidate and Career Development: Dr. Taylor is a pediatric hepatologist and Assistant Professor of Pediatrics
at Northwestern University. She has maintained a strong interest in basic science and translational research
throughout her early career. Her long-term career goal is to become an independently funded physician-scientist
with a focus on the immunology of pediatric cholestatic liver disease. This K08 proposal will help achieve this
goal through the following specific objectives: 1) develop Dr. Taylor’s scientific and professional skills in
advanced immunology and bioinformatics, and 2) define the pathogenic macrophage (M) subsets in biliary
atresia (BA) to ultimately develop cell subset-specific treatment strategies. Dr. Taylor and her co-mentors, Dr.
Perlman and Dr. Green, have developed a detailed strategy to achieve these objectives through carefully
planned course work, didactics, laboratory techniques, and collaborations at Northwestern. The current proposal
will lay the foundation for future R01-level proposals on M-driven regulation of adaptive immunity in BA.
Research Plan: BA is a cholestatic liver disease of infancy that is the leading cause of pediatric liver
transplantation. BA is thought to arise from an aberrant immune response to an environmental trigger, however,
the exact mechanism of disease progression remains unknown. Evidence points to a central role for M in BA
pathogenesis, however, M are a heterogeneous and plastic cell population, and prior studies have not
distinguished between subsets. We are the first to demonstrate the M heterogeneity in pediatric cholestatic
liver disease through single-cell RNA sequencing and identified 3 distinct cholestatic liver M subsets: lipid
associated M, monocyte-like M, and adaptive M. Among these, adaptive M demonstrated increased
expression of genes involved in lymphocyte activation and greater disease-specific differences between BA and
a non-immune etiology of cholestasis. These findings suggest that adaptive M may be the pathogenic subset
in BA through stimulation of the T cell immune response known to play a role in BA. In the current proposal we
will build upon this Preliminary Data and investigate the hypothesis that adaptive M drive the pathogenicity of
BA through recruitment of inflammatory M and T cells. To evaluate this hypothesis we have formulated the
following two interrelated Specific Aims: 1) determine whether the novel lipid-associated, monocyte-like, and
adaptive M in human BA correlate with transplant-free survival, and 2) determine whether the adaptive M in
human BA are essential for the disease mechanism of murine BA. Through parallel studies in human and murine
BA, as well as comparison to an innovative non-immune murine model of neonatal bile duct ligation, we will
identify the BA-specific M subsets that drive immune injury. Results obtained upon completion of these aims
may identify new therapeutic targets for M immune modul...

## Key facts

- **NIH application ID:** 10320943
- **Project number:** 5K08DK121937-02
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Sarah Ann Taylor
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $162,975
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320943

## Citation

> US National Institutes of Health, RePORTER application 10320943, Macrophage Regulation of Immune Pathogenesis of Biliary Atresia (5K08DK121937-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320943. Licensed CC0.

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