HL-131. Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the U.S. It is also strongly influenced by cigarette smoking (CS) and genetic predisposition. A novel gene, FAM13A (family with sequence similarity 13, member A, with unknown function) has been consistently associated with susceptibility to COPD in case-control studies and with lung function in general population samples in genome-wide association studies (GWAS). Very recently, the COPD risk allele at the FAM13A locus was shown to be associated with increased expression of FAM13A in human lung samples. However, how this novel gene functions in vivo under CS-induced injury remains unknown. This substantial gap in our knowledge has greatly impeded translation of these genetic discoveries into a better understanding of COPD pathobiology and the huge potential of personalized medicine. Using a series of in vitro and in vivo approaches, we demonstrate that Fam13a-deficient mice (Fam13a-/-) showed attenuated emphysema induced by either CS or elastase. We also make the first connection between the novel GWAS gene FAM13A and the canonical Wnt pathway, essential for lung development as well as lung repair/regeneration in a variety of pulmonary diseases. In vitro, Fam13a facilitates assembly of protein phosphatase 2A(PP2A) with -catenin and promotes the phosphorylation and degradation of -catenin. Herein, we propose to extend our studies to a deep and comprehensive dissection of the regulation of the Wnt pathway by Fam13a and how their cross-talk mediates lung repair during CS-induced injury.
In Aim 1, we will utilize a sensitive and specific GFP reporter mouse line for Wnt pathway activation to characterize the temporal and spatial regulation of Fam13a on the activity of the Wnt pathway during CS- exposure.
In Aim 2, we will fully characterize how Fam13a modulates lung regeneration through inhibiting the Wnt pathway in the CS-induced injury model.
In Aim 2. 1,we will generate a double-deficient (Fam13a and - catenin) mouse line specifically in SP-C(surfactant protein C)-positive cells, facultative progenitor cells for lung reair after injury and then expose these mice to CS to determine whether activation of the Wnt pathway led to resistance to CS-induced airspace enlargement in Fam13a-/- mice. Roles of SP-C-positive cells in lung regeneration after CS-induced injury will be further explored in Aim 2.2. We will trace-label SPC-positive cells with GFP after tamoxifen induction in the presence or absence of Fam13a in vivo, then expose mice to acute and chronic CS to determine the role of the Fam13-Wnt axis in lung regeneration mediated by SPC-positive cells.
In Aim 3, we will apply human primary alveolar and airway epithelial cells from COPD subjects with known genotypes at the FAM13A locus to determine whether differential cell proliferation and differentiation correlate with varying beta-catenin levels associated with FAM13A genotypes. Upon completion of this project, we will have a much deeper understanding of the role of Fam13a--catenin/Wnt pathway during CS-induced injury and the mechanisms underlying human COPD.
Understanding the function of candidate genes identified from genetic studies and dissecting the roles of developmentally critical pathways in chronic pulmonary diseases are two major priorities in pulmonary research. The primary objectives of this proposal are to delineate the biological functions of FAM13A, a novel gene consistently identified in genome-wide association studies (GWAS) in human COPD by genetically modified murine models and fully characterize the molecular mechanisms by which Fam13a regulates the activity of the Wnt pathway, thereby modulating lung regeneration/repair during CS-induced injury. The deep understanding we gain of this novel GWAS gene may yield new insights into the biological mechanisms leading to COPD and suggest new approaches to treatment.
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