# Molecular mechanisms of pulmonary disease in Birt-Hogg-Dube syndrome

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2020 · $650,300

## Abstract

Project Summary/Abstract
Bert-Hogg-Dubé (BHD) syndrome is caused by germline mutations in the folliculin (FLCN) gene. Cystic lung
disease with pneumothorax is a major clinical manifestation of BHD, with cysts reported as early as 34 weeks’
gestation and pneumothorax as early as age 14. The mechanisms underlying cystic lung disease in BHD are
poorly understood, representing a critical knowledge gap. We deleted Flcn specifically in mouse lung
mesenchyme, and discovered striking phenotypes of early postnatal alveolar enlargement and adult pulmonary
cysts that resemble the lung pathology in BHD patients. FLCN localizes to the lysosome, where it is a key
activator of mTORC1, suggesting that abnormal mTORC1 signaling is a potential mechanism for Flcn’s impact
in the lung. We have also discovered that Tcf21, a mesenchymal transcription factor, is a novel candidate of
Flcn physical interacting protein, and that Tcf21 is downregulated in Flcn-deficient cells and tissues. Therefore,
we hypothesize that mesenchymal inactivation of Flcn leads to age-dependent defects in alveolar development
and homeostasis via two parallel effectors: mTORC1 and Tcf21. This hypothesis will be tested in two Aims.
Aim 1: To determine how loss of Flcn in lung mesenchyme impacts alveolar development and homeostasis in
vivo. We will test the working hypothesis that mesenchymal Flcn is required for alveolar growth and
maintenance in an age-dependent manner. Our approaches will include temporal-spatial Flcn deletion in lung
mesenchymal cells. The BHD-like lung lesions in mice will be characterized at pathologic, cellular, and
molecular levels, including quantitative and qualitative analyses of lung mesenchymal progenitor cells.
Aim 2: To determine the mechanisms through which Flcn-deficiency in lung mesenchymal cells leads to
defective alveolar development and homeostasis, in vitro and in vivo. (A) To determine how Flcn regulates
mesenchymal mTORC1 activity and how mTORC1 impacts alveolar development and maintenance. We will
test the working hypotheses that Flcn-deficient lung mesenchymal cells have dysregulation of mTORC1 activity
and that downregulation of mTORC1 activity in lung mesenchyme will phenocopy the alveolar defects in our
mice with Flcn inactivation in lung mesenchyme. (B) To determine how the Flcn-TCF21 interaction impacts
alveolar growth and maintenance. We will test the working hypotheses that Flcn directly interacts with Tcf21 to
regulate Tcf21-dependent targets in lung mesenchyme, and that the absence of Flcn impairs the stability and
localization of Tcf21, and affects alveolar development and homeostasis.
Our long-term goal is to elucidate the pathogenic mechanisms of lung disease in BHD. We expect that this will
lead to paradigm-shifting discoveries implicating the lung mesenchyme in the pathogenesis of cystic lung
disease and providing the foundation for novel preventative and therapeutic strategies.

## Key facts

- **NIH application ID:** 9850285
- **Project number:** 5R01HL141352-03
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** WEI SHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $650,300
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850285

## Citation

> US National Institutes of Health, RePORTER application 9850285, Molecular mechanisms of pulmonary disease in Birt-Hogg-Dube syndrome (5R01HL141352-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850285. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*