# Ancillary SOURCE Study: Characterization of Small Airway Basal Cell Biology in Early COPD

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $787,290

## Abstract

Abstract. This is an ancillary study to SOURCE (SPIROMICS Study of Early COPD Progression, NHLBI
HL144718), an observational study of the early manifestations of chronic obstructive pulmonary disease
(COPD). Based on the knowledge that the small airway epithelium (SAE) is the earliest site of the
pathology of COPD, the focus of this ancillary proposal is to characterize the disordered SAE
differentiation in SOURCE participants and correlate this biologic dysfunction with the abnormal
early COPD small airway clinical phenotypes characterized in SOURCE. We will capitalize on the
availability of resources from SOURCE for use in our study, including: detailed clinical phenotyping of
small airway structure and function, with serum, lavage fluid, SAE cytopreps, SAE RNA, and SAE basal
stem/progenitor cells obtained by bronchoscopy from n=80 individuals with early COPD ages 30-55, and
n=20 normal controls. As an additional control, we will provide parallel clinical data and biologic samples
from our BioBank n=10 healthy smokers. Based on our observations that in early COPD, SAE basal
stem/progenitor cells have a decreased capacity to form a normal differentiated SAE, preliminary data
demonstrating that BMP4 and SPDEF are upregulated in the SAE in early COPD smokers and that BMP4
induces squamous metaplasia and SPDEF induces goblet cell hyperplasia, the proposed studies will
characterize the role of BMP4 and SPDEF in the pathogenesis of the disordered small airway
differentiation in early COPD. We hypothesize that early COPD is characterized, in part, by SAE
upregulation of BMP4 and SPDEF which, in turn, contribute to the clinical abnormalities of the
small airways that characterize early COPD. The results will help determine if BMP4 and SPDEF and/or
their driver genes and/or downstream signaling pathways are potential targets for future therapeutic
intervention to reverse/prevent the small airway abnormalities that characterize early COPD. We propose
3 specific aims. Aim 1: To characterize the disordered SAE in early COPD and evaluate the hypothesis
that SAE basal cells (BC) from individuals with early COPD have a reduced capacity to differentiate into a
normal SAE as assessed in vitro using air-liquid interface cultures. Aim 2: To examine the hypothesis that
the disordered SAE BC differentiation in early COPD is caused, in part, by SAE overexpression of BMP4
and SPDEF, resulting in activation of their respective receptor downstream signaling pathways and
consequent abnormal SAE differentiation of squamous metaplasia and goblet cell hyperplasia. Aim 3: To
test the hypothesis that diminished small airway epithelial BC differentiation and BMP4- and SPDEF-
mediated biologic parameters correlate with the clinical parameters of small airway structure and function
in the same SOURCE participants with early COPD.

## Key facts

- **NIH application ID:** 10851831
- **Project number:** 5R01HL166983-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** RONALD G CRYSTAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $787,290
- **Award type:** 5
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851831

## Citation

> US National Institutes of Health, RePORTER application 10851831, Ancillary SOURCE Study: Characterization of Small Airway Basal Cell Biology in Early COPD (5R01HL166983-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851831. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*