# Mechanical signaling through the nuclear membrane in lung alveolar health

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $774,963

## Abstract

PROJECT SUMMARY
The mammalian respiratory system undergoes cyclical mechanical strain as part of its normal function. Lungs
have evolved to be flexible to adapt to this strain, which involves rhythmic inflation and deflation of the alveoli for
efficient gas exchange. Multiple cell lineages comprise the alveolar niche including alveolar type 1 (AT1) and
alveolar type 2 (AT2) epithelial cells as well as various unique mesenchymal and endothelial cell types. AT1 cells
are required for efficient gas exchange across the endothelial capillary plexus while AT2 cells generate
pulmonary surfactant and act as facultative progenitors that differentiate into AT1 cells. While most studies on
mechanotransduction have focused on the response of mesenchymal lineages, the ability of epithelial cells, in
particular those within the lung alveoli, to respond to and maintain their identity and function in the face of this
continuous and rhythmic biomechanical strain has not been well defined. Using multiple genetic and biophysical
approaches, we present new preliminary data demonstrating that loss of cytoskeletal-extracellular matrix
interactions via genetic, mechanical and chemical perturbations in AT1cells, leads to their rapid reprogramming
into AT2 cells in vivo. Single cell RNA-seq (scRNA-seq) analysis shows that these reprogrammed AT2 cells are
very similar to normal AT2 cells. Loss of AT1 cell fate is accompanied by coordinate changes in lamina-
associated chromatin domain (LAD) organization, causing sequestration or release of AT1 or AT2 specific loci
located in LAD sat the nuclear periphery. This phenomenon inversely correlates to the changes in alveolar
epithelial cell fate. Importantly, we have developed a novel model of unilateral mechanical unloading of the
cyclical strain from breathing movements in the lungs and show that this causes a profound reprogramming of
AT1 into AT2 cells. In agreement with these new Preliminary Data, our laboratories recently demonstrated that
Yap/Taz are found in the nucleus of AT1, but not AT2cells, and are essential for maintaining AT1 cell fate
throughout the lifespan of mice. Loss of Yap/Taz results in a rapid reprogramming of AT1 cells into AT2 cells in
the absence of injury. Since Yap/Taz can function as cytoplasmic mechanotransducers in cells and translocate
to the nucleus upon actin-regulated cell stretch and strain, our combined preliminary and published data suggest
that mechanotransduction plays a specific role in AT1cells to maintain alveolar function in the homeostatic lung.
Thus, our published and preliminary data raise a provocative hypothesis that the lung has evolved specific
epigenetic and transcriptional mechanisms to maintain cellular fate in the face of mechanical strain from normal
respiration and these pathways are altered in the response to injury and disease. This proposal brings together
two complementary laboratories with extensive experience in the study of lung development, epigenetic control
of c...

## Key facts

- **NIH application ID:** 10848443
- **Project number:** 5R01HL168803-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** EDWARD E MORRISEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $774,963
- **Award type:** 5
- **Project period:** 2023-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848443

## Citation

> US National Institutes of Health, RePORTER application 10848443, Mechanical signaling through the nuclear membrane in lung alveolar health (5R01HL168803-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10848443. Licensed CC0.

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