# Molecular control of a novel transitional cell state in alveolar regeneration

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $497,340

## Abstract

SUMMARY
Alveolar injury and ineffective repair have been hypothesized to underlie the pathogenesis of chronic obstructive
pulmonary disease and pulmonary fibrosis. While genome-wide association studies and clinical specimens have
suggested a role for chronic stress, inflammation and DNA damage signaling, the underlying mechanisms and
the cell states in which the above pathways are dysregulated during alveolar regeneration remain elusive.
In our recent studies, using organoids, single cell transcriptomics and in vivo lung injury models, we uncovered
a previously uncharacterized, transient, pre-AEC1 transitional cell state (PATS), traversing between AEC2 and
AEC1 in alveolar regeneration. Interestingly, pathway analysis for genes expressed in PATS showed a significant
enrichment for targets of transcription factors TP53 and SOX4, and DNA damage repair pathway. We also found
that this cell state is vulnerable to stretch mediated DNA damage during differentiation of cuboidal AEC2 into
extremely flat and thin AEC1. Conditional ablation of Tp53 and Sox4 in AEC2s revealed a dramatic decrease in
the number of AEC1, and a significant increase in the number of PATS. These data suggest an essential role
for transcription factors TP53 and SOX4 in regulating AEC2 to AEC1 differentiation via pre-AEC1 transitional
state and the DNA damage repair during alveolar regeneration. Based on our preliminary data, we hypothesize
that the AEC2 progenitors go through a novel and molecularly distinct pre-AEC1 transitional state to
differentiate into AEC1. We also hypothesize that TP53 and SOX4 -mediated mechanisms are essential
for the cell cycle arrest, cell adhesion, cell stretching, and DNA damage repair pathway during
differentiation of AEC2 to AEC1.
The major objectives of this proposal are to molecularly and functionally characterize the newly identified pre-
AEC1 transitional state and to study the mechanisms governing this cell state in alveolar regeneration. In Aim1,
we will study the molecular identity, the temporal dynamics and the plasticity of a novel pre-AEC1 transitional
state in alveolar regeneration. In Aim2, we will test the hypothesis that TP53 and SOX4 mediated mechanisms
control cell cycle regulation, cell adhesion, and DNA damage repair pathways in pre-AEC1 transitional state
during AEC2 differentiation into AEC1. We will use organoid models, in vivo genetic and pharmacological loss-
of-function models, and molecular assays to study these specific aims. This work has taken on added
importance, as recent genome-wide association studies revealed mutations in the components of the DNA
damage repair signaling as one of the major drivers for emphysema and pulmonary fibrosis. Therefore, our
finding that stretch associated DNA damage in the pre-AEC1 transitional state makes it potentially vulnerable to
lung diseases. Thus, the outcomes from the proposed studies will have broader significance and will lay the
foundation for future studies involving human alve...

## Key facts

- **NIH application ID:** 10444905
- **Project number:** 5R01HL153375-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Purushothama Rao Tata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $497,340
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444905

## Citation

> US National Institutes of Health, RePORTER application 10444905, Molecular control of a novel transitional cell state in alveolar regeneration (5R01HL153375-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10444905. Licensed CC0.

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