# Molecular pathways controlling alveolar epithelial remodeling in development and regeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $569,053

## Abstract

ABSTRACT
The formation of the lung alveolus is the culminative event in the development of the respiratory system. The
alveoli perform the hallmark function of the respiratory system: gas exchange between the cardiovascular
system and the external environment. Alveologenesis begins at approximately birth in mice, ends between 2-4
weeks of postnatal life in mice but extends several years after birth in humans. Disruptions in alveologenesis
can lead to severe pediatric diseases such as bronchopulmonary dysplasia (BPD), and in the adult, defective
regeneration or persistent degeneration of alveolar homeostasis can lead to chronic obstructive pulmonary
disease (COPD). The mature lung alveolus contains a myriad of epithelial, endothelial, and mesenchymal cell
lineages, all of which have to communicate properly to form a functional niche that efficiently exchanges
gasses with the external environment. Despite the importance of the lung alveolus, we still have little
information how the multifarious cell lineages within the lung alveolus communicate with each other during
alveolar development or regeneration. During the previous funding period of this grant, we have identified
many novel transcriptional, epigenetic, and signaling pathways that play essential roles in the development,
homeostasis, and regeneration of the lung alveolus. We have also dedicated extensive effort during the first
funding period in defining at a single cell level the full cellular repertoire, molecular pathways, developmental
trajectories, cellular plasticity, and transient cell phenotypes that are present during alveologenesis, to derive a
better understanding of this critical stage of lung development and its response to injury. These preliminary
data have confirmed our previous work showing the importance of pathways such as Tgf-beta, and begun to
define the molecular cues that drive development and maturation of poorly understood cell lineages including
the alveolar type 1 (AT1) cell. Together, our data reveal two novel insights into AT1 cell biology: 1) AT1 cells
play a central role in mediating cellular crosstalk in the developing and mature alveolus and 2) AT1 cells, but
not AT2 cells, exhibit a remarkable level of lineage plasticity in response to neonatal injury and this plasticity is
controlled, in part, by the Hippo pathway. Taken together, our studies highlight the central role AT1 cells play in
alveolar development and homeostasis.

## Key facts

- **NIH application ID:** 10051468
- **Project number:** 2R01HL132999-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** EDWARD E MORRISEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $569,053
- **Award type:** 2
- **Project period:** 2016-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051468

## Citation

> US National Institutes of Health, RePORTER application 10051468, Molecular pathways controlling alveolar epithelial remodeling in development and regeneration (2R01HL132999-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10051468. Licensed CC0.

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