# Hox5 gene regulation of lung fibroblasts and distal lung extracellular matrix

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $441,425

## Abstract

ABSTRACT
 Alveologenesis occurs during postnatal development in humans and mice and this process allows
for the growth of gas exchange surface area of the lung. One of the key events during this phase is the
establishment of the elastin-based matrix in the distal airway. The incorporation of elastin into the
existing lung matrix provide the elasticity that allows the distal airways to stretch and recoil effectively
during breathing and mesodermally-derived SMA+ lung fibroblasts are key drivers of this process. Our
previously published work has shown that the Hox5 genes are exclusively expressed in the
mesenchyme of the lung and that loss of all three Hox5 genes leads to early, severe developmental
lung defects and neonatal death. Four-allele, compound Hox5 mutant mice (Hox5 AabbCc) are born in
Mendelian ratios and are phenotypically normal at birth, however, they develop alveolar simplification at
postnatal stages. Consistent with a direct role for Hox5 genes in alveologenesis, the expression levels
of all three Hox5 genes are highest during early postnatal stages when the bulk of alveologenesis
occurs, higher than observed at any embryonic stage and these genes remain expressed through adult
life. Using a newly generated conditional allele for Hoxa5, we show that conditional deletion of Hoxa5
in the lung mesenchyme beginning at birth results in an alveolar simplification phenotype postnatally.
Hox5 mutant animals exhibit abnormal myofibroblast morphology and impaired function. Hox5 mutant
fibroblasts demonstrate defects in cell adhesion and the expression of Integrin 5 and 1 are down-
regulated. The continuing importance of Hox5 function at all stages is highlighted by surprising
preliminary evidence that deletion of Hoxa5 at later stages (after the establishment of the elastin-based
matrix) leads to rapid loss of the integrity of the elastin matrix. In this proposal, we will interrogate the
cellular and molecular mechanisms of Hox5 regulation of lung mesenchyme during alveolar
development, remodeling and homeostasis.

## Key facts

- **NIH application ID:** 9980992
- **Project number:** 5R01HL144086-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Deneen M Wellik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,425
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980992

## Citation

> US National Institutes of Health, RePORTER application 9980992, Hox5 gene regulation of lung fibroblasts and distal lung extracellular matrix (5R01HL144086-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9980992. Licensed CC0.

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