# Molecular Analysis of Airway Secretory Cells in Health and Disease > **NIH NIH K99** · UNIVERSITY OF COLORADO DENVER · 2023 · $108,515 ## Abstract Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US and worldwide, and it remains disease incurable in part due to an incomplete understanding of its cellular mechanisms. Small airway (SAD) and emphysema are important pathological phenotypes of COPD. SAD is characterized by excessive mucus production and reduced alveolar attachment in the small airways (<2mm in diameter). SAD may also worsen emphysema, the progressive destruction of alveolar tissue. However, the mechanisms underlying the pathogenesis of small airway mucin overproduction and alveolar destruction are not well understood. Importantly, mucin is produced by an epithelial progenitor, the club cell, which can differentiate into alveolar type II cells for tissue repair. Here, we have discovered that overproduction of a polymeric gel-forming mucin MUC5B may be linked to impaired alveolar regeneration by club cells in a murine COPD model. Therefore, this proposal aims to test the central hypothesis that alveolar maintenance and repair by club cells in health and COPD is dependent on MUC5B expression. Specific Aim 1 will test the hypothesis that MUC5B expression inhibits differentiation of club cells into ATII cells during homeostasis. I will employ organoid assays to test steady state progenitor functions of MUC5B-expressing and non-expressing club cells from healthy mice with tamoxifen-induced lineage tracing of club cells and fluorescent labeling of endogenous MUC5B. Further studies will employ mice with genetic deficiency or transgenic overexpression of Muc5b. Specific Aim 2 will test the hypothesis that overproduction of MUC5B inhibits alveolar repair in a mouse model of COPD. Mice from Aim 1 will be treated with porcine pancreatic elastase (PPE) to test whether excessive MUC5B in club cells impairs alveolar differentiation in vitro and in vivo, and whether conditional depletion of Muc5b ameliorates SAD and emphysema. Finally, Specific Aim 3 will test the hypothesis that disrupting stimulated mucin overproduction prevents SAD and emphysema by restoring progenitor function of club cells. I will investigate the mechanism of how extra- versus intra-cellular excessive MUC5B impairs progenitor functions of club cells, and I will identify novel genes that regulate club cell mucous and progenitor functions and expand on translational studies in human COPD. These studies will fill gaps in our knowledge of heterogeneous functions of club cells in small airways in homeostasis and disease. Aim 1, 2 and part of Aim 3 will be completed during the K99 training phase. Key elements of my training will be learning new fields of mucin biology and bioinformatics that will help me develop my career as a translational COPD researcher. Results of my studies will supply a foundation for strong lines of independent research on pathways regulating epithelial phenotypes in COPD and development of novel therapeutics for SAD and emphysema in the R00 phase. With my outstandi... ## Key facts - **NIH application ID:** 10592181 - **Project number:** 1K99HL161446-01A1 - **Recipient organization:** UNIVERSITY OF COLORADO DENVER - **Principal Investigator:** Yan Hu - **Activity code:** K99 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2023 - **Award amount:** $108,515 - **Award type:** 1 - **Project period:** 2023-04-01 → 2025-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10592181 ## Citation > US National Institutes of Health, RePORTER application 10592181, Molecular Analysis of Airway Secretory Cells in Health and Disease (1K99HL161446-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10592181. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*