# VEGF/KDR Signaling in Airway Epithelial Regeneration and Disease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $491,769

## Abstract

ABSTRACT
Mucous metaplasia is commonly associated with morbidity and mortality in multiple lung diseases including
fibrosis, COPD and asthma. However, the cellular and molecular mechanisms leading to mucous metaplasia in
these diseases remain largely unknown. Recent lineage tracing data suggest that club cells are the cell of origin
for metaplastic mucous epithelium. However, the club cell is a heterogenous population, and it remains unknown
which club cell subpopulation(s) contribute to mucous metaplasia. Moreover, the molecular mechanisms leading
to mucous cell differentiation are largely undetermined. We aim to address these outstanding issues in this
proposal. Our single-cell RNA sequencing analysis identified three club cell subpopulations, two of which are
characterized by the expression of VEGF receptor 2 (also known as Flk1 or Kdr). Significantly, deletion of Kdr
leads to mucous metaplasia of the intrapulmonary airway epithelium at the early postnatal stage. Furthermore,
transiently increased Kdr is required for blocking mucous metaplasia during airway regeneration following
naphthalene challenge. Loss of epithelial Kdr or a hypomorphic mutation for the ligand Vegfa leads to abundant
mucous cells expressing Sox9 which has been shown to regulate mucous cell differentiation in the intestine.
Importantly, mucous metaplasia is also associated with reduced Kdr expression accompanied by increased
SOX9 protein levels in ovalbumin (OVA)-induced asthmatic lungs. We therefore hypothesize that Vegf/Kdr
signaling is a gatekeeper blocking mucous differentiation of club cell subpopulations during airway
regeneration, and that suppressed Kdr promotes mucous metaplasia via Sox9 during asthma
pathogenesis. We formulate three specific aims to test the hypothesis. Aim 1: To test the hypothesis that
epithelial Kdr blocks club cell differentiation into mucous cells via Erk signaling. Aim 2: To test the hypothesis
that Vegfa/Kdr signaling blocks mucous metaplasia of club cell subpopulations. Aim 3: To test the hypothesis
that Vegfa/Kdr signaling blocks mucous metaplasia via inhibition of Sox9. Findings from these studies will
provide critical insights into the cellular and molecular mechanisms that govern normal mucous cell differentiation
and how the mechanism goes awry, leading to mucous metaplasia. Our study will also provide potential
therapeutic targets for this common pathological entity.

## Key facts

- **NIH application ID:** 10122090
- **Project number:** 1R01HL152293-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jianwen Que
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,769
- **Award type:** 1
- **Project period:** 2021-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122090

## Citation

> US National Institutes of Health, RePORTER application 10122090, VEGF/KDR Signaling in Airway Epithelial Regeneration and Disease (1R01HL152293-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10122090. Licensed CC0.

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