# Mapping the genetic and cellular regulatory landscape of lung epithelial regeneration

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2020 · $37,495

## Abstract

Abstract
Typically, lung alveolar tissue is quiescent with minimal cellular turnover, however, epithelial alveolar type 2
cells (AT2) maintain a facultative regenerative capacity. A subset of AT2 cells termed alveolar epithelial
progenitors (AEPs) are Wnt responsive, express the Wnt target gene Axin2, and contribute to robust alveolar
regeneration. Given that chronic lower respiratory disease including COPD, chronic bronchitis, emphysema
and asthma, is now the third leading cause of death in the United states, the ability of the lung to repair after
injury is paramount to survival. The mammalian lung exhibits a broad range of reparative capabilities and
understanding the degree to which different tissues of the lung can repair is necessary for the rational design
of regenerative therapies. The individual components of the complex lung tissue must work together to
maintain both adequate gas exchange and barrier function. Importantly, stimulation of endogenous
regeneration would be less invasive and more economical than current treatment options for organ failure.
The extent to which the facultative stem cells of the lung alveolus are pre-defined during development and
maintained during adulthood is ambiguous. If subsets of AT2 cells such as AEPs are maintained with unique
regenerative properties, then these cells should be defined by distinct gene regulatory states. Ostensibly, given
the facultative nature of AEPs, these gene regulatory states should be developmentally defined and
maintained throughout maturation.
Integrating available RNA-seq, ATAC-seq and whole lung scRNA-seq data, I identified a putative set of
transcription factors specific to AEPs including the grainyhead/CP2 family transcription factor Tfcp2l1. The
Tfcp2l1 gene was previously shown to be Wnt responsive and thus could mark the AEP sublineage in a
fashion similar to Axin2. Importantly, Tfcp2l1 is known to repress lineage commitment in mouse ES cells
suggesting it could play a functional role in maintaining the multipotent state of AEPs. Thus, this proposal aims
to understand the role of a specific transcription factor in lung development and regeneration. By
understanding genetic control of AT2/AEP facultative stem cell state rationally designed methods to manipulate
or improve regenerative ability of these cells can be developed.

## Key facts

- **NIH application ID:** 9911717
- **Project number:** 1F32HL151114-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** John Preston Leach
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,495
- **Award type:** 1
- **Project period:** 2020-06-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911717

## Citation

> US National Institutes of Health, RePORTER application 9911717, Mapping the genetic and cellular regulatory landscape of lung epithelial regeneration (1F32HL151114-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9911717. Licensed CC0.

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