# Role of p73 in COPD Pathogenesis

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

PROJECT SUMMARY
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and
has no cure. While the association between chronic tobacco smoke exposure and COPD has been known for
decades, the reasons for ongoing lung damage in COPD after smoking cessation remain undefined. We and
others have shown that epithelial remodeling with loss of multiciliated cells (MCCs) is widespread in the
airways of COPD patients and abnormal epithelial differentiation in individual small airways is strongly
associated with loss of the secretory IgA (SIgA) barrier, chronic inflammation, and fibrotic remodeling of the
airway wall. Further, we showed that loss of SIgA in the airways is sufficient to induce a COPD-like phenotype
in mice, suggesting altered mucosal immunity plays a causal role in COPD pathogenesis. In this proposal, we
will focus on the underlying cause of impaired mucosal immunobarrier function which we believe to abnormal
epithelial differentiation. Our preliminary data demonstrate that the differentiation factor p73, recently shown to
be required for the MCC development, is required for MCC-specific expression of a transport protein required
for SIgA transcytosis (polymeric immunoglobulin receptor or pIgR). We found that cigarette smoke suppresses
p73 expression in vitro and in vivo, providing a mechanistic link between cigarette smoke exposure, abnormal
epithelial differentiation, and impaired mucosal immunobarrier function. In this proposal, we will test the
hypothesis that cigarette smoke suppresses p73, resulting in loss of MCCs, reduced pIgR expression and SIgA
transcytosis, and impaired immunobarrier function. In Aim 1, we will investigate the impact of targeted deletion
of p73 or pIgR in FoxJ1-expressing multiciliated cells on airway epithelial differentiation and immune defense.
In Aim 2 we will identify p73-dependent transcription factors that regulate pIgR in murine tracheal epithelial
cells and validate our findings in primary human bronchial epithelial cells. In Aim 3 we will define the
relationships between cigarette smoke, p73 expression, and epithelial differentiation in vivo. Together, these
studies will determine how defects in normal epithelial differentiation result in alterations in mucosal immunity
and evaluate whether p73 represents a mechanistic link between chronic inflammation and MCC loss.

## Key facts

- **NIH application ID:** 10438520
- **Project number:** 5IK2BX003841-04
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Bradley Winston Richmond
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438520

## Citation

> US National Institutes of Health, RePORTER application 10438520, Role of p73 in COPD Pathogenesis (5IK2BX003841-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10438520. Licensed CC0.

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