Bert-Hogg-Dub (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.

Public Health Relevance

This project is focused on the mechanisms underlying cystic lung disease in Birt-Hogg-Dub syndrome. This project will lead to paradigm-shifting discoveries implicating the lung mesenchyme in the pathogenesis of cystic lung disease. Finally, the mouse model generated in this project may represent the first genetically engineered mouse with lung pathology in Birt-Hogg-Dub syndrome, providing a novel platform for preclinical therapeutic investigation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Vuga, Louis J
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Children's Hospital of Los Angeles
Los Angeles
United States
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