# Chymotrypsin-like Elastase 1 in Lung Development and Disease

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $529,161

## Abstract

Project Summary
Normal postnatal lung morphogenesis and repair after injury requires the precise coordination of
cellular activities and matrix remodeling for the formation or restoration of normal alveolar
structures and optimal respiratory efficiency. We recently identified a critical role for the protease,
Chymotrypsin-like elastase 1 (Cela1), in the regulation of postnatal lung elastance and its critical
role in the pathogenesis of α1-antitrypsin (AAT) deficiency. This program of research is based
on our novel preliminary findings that Cela1 expression is induced during regenerative
and pathological alveolar remodeling, and that inhibition of Cela1 activity prevents AAT
deficiency related emphysema. This proposal will identify the role of Cela1 in both physiological
and pathologic remodeling in the postnatal lung. Based on data that Cela1 expression is
dysregulated in hyperoxic lung injury, Aim 1 will define cell-specific roles for Cela1 in lung
development using conditional deletion models to identify Cela1-expressing cells and
characterize dynamic changes in expression during development under normal and hyperoxic
conditions. Aim 2 will test whether cell-specific expression of Cela1 changes in pathological lung
matrix remodeling and whether targeting Cela1 can protect against emphysema long-term. Using
lineage tracing and proximity ligation in situ hybridization in an AAT-deficient emphysema model,
we will determine whether Cela1-expressing ATII cells represent a unique epithelial cell subclass
or if all ATII cells can express Cela1 in the appropriate context. In Aim 3, whether AAT
neutralization of Cela1 is required for cellular uptake will be tested, and the cells involved in this
uptake and recycling of AAT-Cela1 complexes will be identified using lineage tracing, proximity
ligation in situ hybridization, confocal microscopy, and flow cytometry. The association among
Cela1 gene expression and regions of elastin remodeling will be identified in human AAT deficient
emphysema specimens. Lastly, site of Cela1-AAT molecular interaction will be defined. From a
scientific and clinical standpoint, this proposal will define a novel critical mechanisms by which
Cela1 mediates matrix remodeling processes to regulate normal alveolarization and regeneration
after injury that will provide a strong rationale to explore Cela1 as a target for development of
future therapies for interstitial lung diseases.

## Key facts

- **NIH application ID:** 9898442
- **Project number:** 5R01HL141229-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Brian Michael Varisco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $529,161
- **Award type:** 5
- **Project period:** 2018-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898442

## Citation

> US National Institutes of Health, RePORTER application 9898442, Chymotrypsin-like Elastase 1 in Lung Development and Disease (5R01HL141229-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898442. Licensed CC0.

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