# Microfibril-associated glycoproteins attenuating pulmonary fibrosis

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2024 · $156,182

## Abstract

Project Summary/Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited treatment options and unclear
pathogenesis. Extracellular matrix (ECM) deposition by proliferating fibroblast populations drives the
progressive airflow limitation and hypoxia characteristic of IPF, mediated by the cytokine transforming growth
factor beta (TGFB). Direct inhibition of TGFB leads to intolerable side effects, and there is increased interest in
therapies that instead modulate its regulation. Microfibril-associated glycoproteins 1 and 2 (Magp1 and Magp2,
or Magps) are fibroblast-produced proteins which are secreted to ECM, anchor to microfibrils, and bind TGFB
to limit its signaling under basal conditions, but have no known role in fibrosis. Magp knockout (KO) mice
exhibit increased TGFB signaling in various tissues and have immune cell alterations due to bone marrow
TGFB effects. In a single cell RNASeq screen, the genes encoding these proteins were markedly upregulated
in fibroblasts in fibrotic lungs, and combined KO of Magp1 and 2 led to more severe fibrosis after bleomycin
injury in mice. This suggests that Magps act as inhibitors of fibrotic signaling and follow up studies in Magp1
and 2 individual KO mice show that deficiency of both proteins is required to produce a pro-fibrotic phenotype.
Which fibroblasts populations produce Magps and how they limit fibrosis is unknown. We hypothesize that
Magp expression is an adaptive response to lung injury and limits fibrosis by sequestering TGFB in ECM and
will explore this central hypothesis through three specific aims: 1) Evaluate anti-fibrotic contributions of
Magp1 and 2 in pulmonary fibrosis. 2) Evaluate Magp effects on TGFB signaling and immune
responses in lung fibrosis. 3) Characterize Magp-producing fibroblast populations. Using combinations
of KO and inducible/tissue-specific KO mice, we will determine the individual relationships of these proteins to
fibrosis and whether they exhibit redundant antifibrotic functions in vivo. We will analyze alterations in TGFB
signaling and immune cell infiltration in lung as possible underlying mechanisms of Magp protection from
pulmonary fibrosis. Finally, we will employ our recently developed single nucleus RNASeq approach along with
single nucleus assay for transposase-accessible chromatin (snATAC)-Seq to characterize the fibroblast
populations that express Magp1 and 2 and evaluate how lung-wide transcriptomes and epigenomes change in
the absence of Magps during fibrosis. This proposal will provide Dr. Koenitzer with the mentored training in
single cell sequencing and bioinformatics, fibroblast and ECM biology, and lung histology/imaging needed to
achieve his goal of independence as a physician-scientist. Under the oversight of an expert scientific advisory
committee, He will realize career milestones, complete formal coursework, and develop lasting collaborations.
Findings from this work will have implications beyond IPF in other inter...

## Key facts

- **NIH application ID:** 10810704
- **Project number:** 5K08HL159418-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jeffrey Koenitzer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $156,182
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810704

## Citation

> US National Institutes of Health, RePORTER application 10810704, Microfibril-associated glycoproteins attenuating pulmonary fibrosis (5K08HL159418-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10810704. Licensed CC0.

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