# Transcriptional Regulation of Lung Alveolar Regeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $570,702

## Abstract

ABSTRACT
The respiratory system is comprised of multiple unique and spatially distinct compartments that respond to
injury and diseases states differently based on their cellular and extracellular composition. The alveolar
compartment or niche is responsible for the majority of gas exchange with the external environment in the
lungs and is an area that is dramatically altered during lung diseases such as chronic obstructive pulmonary
disease (COPD) and idiopathic pulmonary fibrosis (IPF). Within the alveolus, there are at least two major
mature epithelial cell types, alveolar type 1 (AT1) and alveolar type 2 cells (AT2), as well as various
mesenchymal cells including Pdgfra+/Axin2+ mesenchymal alveolar niche cells (MANCs), Axin2+
myofibroblast precursor cells (AMPs), and poorly defined vascular endothelial cell populations. Despite our
increasing knowledge of the cell types that comprise the lung alveolus, we have little information on how they
communicate with each other or how their progenitor-differentiated progeny relationships are ultimately
regulated. To address these questions, we propose to characterize the genetic pathways of the mature adult
lung to better understand the transcriptional and epigenetic mechanisms underlying lung homeostasis and
regeneration. Our preliminary data has identified two new and important transcriptional regulators of alveolar
epithelial homeostasis and regeneration: Tfcp2l1 and Klf5. Our preliminary data suggest that Tfcp2l1 and Klf5
regulate the self-renewal of AEP and AT2 cells and their differentiation into AT1 cells, in opposing manners.
Tfcp2l1 is essential in restricting AT2 differentiation into the AT1 lineage whereas Klf5 is essential for licensing
the ability of AT2 cells to differentiate into AT1 cells after acute injury. Moreover, our preliminary data suggests
that Tfcp2l1 marks the AEP sublineage in a manner similar to how Lgr5 marks the intestinal stem cell.
Together, these data provide critical insight into the molecular and cellular orchestration of alveolar
homeostasis and regeneration through the engagement of cell type specific transcriptional pathways that
regulate self-renewal and differentiation of epithelial cell lineages.

## Key facts

- **NIH application ID:** 10331870
- **Project number:** 5R01HL152194-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** EDWARD E MORRISEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $570,702
- **Award type:** 5
- **Project period:** 2021-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331870

## Citation

> US National Institutes of Health, RePORTER application 10331870, Transcriptional Regulation of Lung Alveolar Regeneration (5R01HL152194-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10331870. Licensed CC0.

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