# Role of TGFβ/BMP Antagonism in Regeneration of the Alveolar Epithelium After Lung Injury

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $470,579

## Abstract

PROJECT SUMMARY
Significance. Many lung diseases, including the acute respiratory distress syndrome, pulmonary fibrosis, and
emphysema, result from a failure of the alveolar epithelium to regenerate normally after injury. Unfortunately, no
therapies exist to promote lung regeneration, in large part because of our limited understanding of the underlying
molecular mechanisms. Regeneration of the alveolar epithelium is orchestrated principally by alveolar type 2
epithelial cells (AEC2s). Surviving AEC2s proliferate to replace lost cells, after which proliferation halts and
some AEC2s differentiate into AEC1s to restore normal alveolar architecture and gas exchange function.
Historically, investigations of lung regeneration have explored the mechanisms of AEC2 proliferation. The
molecular signals that induce a switch from the proliferation phase to the differentiation phase are poorly
understood.
Hypothesis. Based on our preliminary data, we hypothesize that during regeneration of the alveolar
epithelium after lung injury, TGFβ halts AEC2 proliferation whereas deactivation of TGFβ induces BMP-
dependent AEC2 to AEC1 differentiation.
Research Plan. Aim 1 will test the hypothesis that TGFβ induces the termination of AEC2 cell proliferation during
regeneration after lung injury. Aim 2 will test the hypothesis that TGFβ deactivation drives BMP-dependent
differentiation during regeneration after lung injury. Mechanisms of epithelial-fibroblast crosstalk during alveolar
regeneration will also be examined. Lung injury will be induced in AEC2- and fibroblast-specific gene deficient
mice, and proliferation and differentiation will be quantitated using stringent stereologic techniques. In vivo
studies will be directly linked to mechanistic experiments in rodent and human AEC2s grown in 2-dimentional
and organoid culture.
Conclusion. This work will enhance our understanding of fundamental mechanisms of lung regeneration.
Specifically, we will investigate the molecular mechanisms underlying the termination of proliferation and
initiation of differentiation, coordinated processes that are critical for restoration of normal alveolar structure and
function after injury. These studies may identify novel therapeutic targets to accelerate epithelial regeneration
during the pathogenesis of diverse lung diseases.

## Key facts

- **NIH application ID:** 9971633
- **Project number:** 1R01HL147920-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Rachel Lynne Zemans
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $470,579
- **Award type:** 1
- **Project period:** 2020-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971633

## Citation

> US National Institutes of Health, RePORTER application 9971633, Role of TGFβ/BMP Antagonism in Regeneration of the Alveolar Epithelium After Lung Injury (1R01HL147920-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971633. Licensed CC0.

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