# Targeting pathologic macrophage activation through inhibition of MyD88 to attenuate laryngotracheal stenosis

> **NIH NIH K23** · JOHNS HOPKINS UNIVERSITY · 2024 · $70,000

## Abstract

Project Summary:
 The research strategy of the parent K23 award will not be changed with this administrative supplement.
If awarded, this supplement will be used to support the aims of the parent K23 award through acquisition of a
research specialist to manage daily lab operations. I would reduce my time devoted to research productivity by
50% to help with the needs of my son and soon to be born, daughter. I will continue the career development
plan outlined during this time. After 9 months, I will start a 3-month transition back to full research productivity.
 Laryngotracheal Stenosis (LTS) is the pathologic narrowing of the larynx, subglottis, and trachea
secondary to injury from prolonged intubation. This leads to dyspnea, dysphonia, and can rapidly progress to
airway compromise. Management of LTS is primarily surgical as medical therapies for LTS are limited due to
poor understanding of LTS pathogenesis. Improved understanding of the mechanisms promoting LTS are
needed to improve treatment. Previous investigation has revealed that an intact immune response is critical to
the development of LTS. Characterization of the immune response in LTS has demonstrated increased
populations of CD4+ T-cells and macrophages. Preliminary studies in a murine LTS model reveal that
depletion of the macrophage population attenuates LTS fibrosis, implicating their pathologic role. However, the
local immune mediators and cell signaling pathways promoting pathologic macrophages in LTS are unknown.
 Macrophage activation is regulated through stimulation of Toll-like receptors (TLRs). TLRs are highly
conserved receptors recognizing Pathogen or Damage Associated Molecular Patterns (PAMPs/DAMPs) and
lead to downstream activation of regulatory proteins controlling phenotype. Using single cell RNA sequencing
the PI has demonstrated increased expression of the TLR4-MyD88 signaling pathway in LTS macrophages.
Furthermore, we have identified increased expression of the DAMP S100A8/A9 in LTS tissue. S100A8/A9 is a
known activator of TLR4-MyD88 signaling, and worsens fibrosis in our murine LTS model. These findings
indicate that TLR4-MyD88 signaling pathways in macrophages may be critical to LTS pathogenesis. However,
the relationship between S100A8/A9, TLR4-MyD88 signaling, and pathologic macrophages has not been
explored in LTS or other fibrotic diseases, and may represent a critical signaling axis driving pathologic fibrosis.
 For this study, we will elucidate the signaling networks promoting pathologic macrophages in LTS. In Aim 1
we will assess S100A8/A9 on macrophage phenotype in a murine LTS model, establish that S100A8/A9s
profibrotic effect is mediated by macrophages, and identify key sources of pathologic S100A8/A9. In Aim 2, we
will demonstrate the critical role of TLR4-MyD88 signaling in promoting pathologic macrophages in LTS. Finally,
in Aim 3 we will assess S100A8/A9 as a candidate biomarker for the development of LTS in patients who have
had prolonged intubat...

## Key facts

- **NIH application ID:** 11105126
- **Project number:** 3K23DC020988-02S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Kevin Motz
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $70,000
- **Award type:** 3
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11105126

## Citation

> US National Institutes of Health, RePORTER application 11105126, Targeting pathologic macrophage activation through inhibition of MyD88 to attenuate laryngotracheal stenosis (3K23DC020988-02S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11105126. Licensed CC0.

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