Cystic airspace enlargement and spontaneous pneumothorax are major pathological manifestations Birt-Hogg- Dube (BHD) syndrome. Although the etiology of this disease is not known, lung cysts in BHD are linked to autosomal dominant mutational inactivation of tumor suppressor gene folliculin (FLCN). FLCN, a 64-kDa ubiquitously expressed protein with high homology throughout species that lacks apparent functional domain, through adaptor proteins FNIP1/2, binds the 5'-AMP-activated protein kinase (AMPK). Little, however, is known about a role of folliculin (FLCN) in lung cell survival. Our in vitro and in vivo studies demonstrate that FLCN is required for lung cell survival by acting within 5'-AMP-activated protein kinase (AMPK) - tuberous sclerosis complex 2 (TSC2) - mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. To fill a gap in the current understanding of airspace enlargement, we have restricted the scope of this proposal to one testable, central hypothesis that FLCN is required for lung cell survival. To test our hypothesis, in Aim 1, we will determine whether FLCN is required for lung epithelial cell survival in vivo using new transgenic FLCNf/f:SP-C- Cre mice generated in PI's lab. Targeted conditional inducible deletion of FLCN in SP-C-expressing lung epithelial cells will allow us to identify the specific lung epithelial cell type affected by FLCN loss that promotes alveolar space enlargement.
In Aim 2 we will examine whether FLCN is required for maintenance of epithelial cell morphology and metabolism.
In Aim 3, we will determine FLCN role in regulating activities of Akt and AMPK kinases, and whether pharmacological activation of AMPK will rescue lung epithelial cell survival with targeted inducible deletion of FLCN in FLCNf/f:SP-C-Cre mice. These studies will identify the role of FLCN in lung cell survival, provide insights into the cellular an molecular mechanism of lung epithelial cell-cell contacts, actin cytoskeleton, and metabolism regulated by FLCN. These studies will also establish a mechanistic link between loss of FLCN and cystic airspace enlargement by using our unique novel FLCNf/f:SP- C-Cre transgenic mice and identify potential molecular target(s) for novel therapeutic approaches to treat BHD.

Public Health Relevance

These studies will identify the role of FLCN in lung cell survival, and will provide insights into the cellular and molecular mechanism of lung epithelial cell interactions, actin cytoskeleton, and metabolism regulated by FLCN. Although our immediate specific aims focus on FLCN loss as it relates to BHD syndrome, our long term goals are to provide insights into mechanisms of lung cell survival and cystic airspace enlargement in other pulmonary diseases and to identify potential molecular target(s) for novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL110551-01A1
Application #
8320578
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (04))
Program Officer
Peavy, Hannah H
Project Start
2012-05-01
Project End
2016-02-28
Budget Start
2012-05-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$515,522
Indirect Cost
$174,624
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Parker, Whitney E; Orlova, Ksenia A; Parker, William H et al. (2013) Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med 5:182ra53