Chronic obstructive pulmonary disease (COPD) ranks as the third leading cause of death in the U.S., lacking effective pharmacological treatment. Recent progress suggested that defective lung repair/regeneration likely contribute to emphysema development. During repair/regeneration process, tissue progenitor cells require optimal amount of energy supplies to fulfill cell proliferation and differentiation demands, which has been well documented in stem cells in other organs such as intestine stem cells, neuro-progenitors and hematopoietic stem cells. However, the metabolic control of stemness in lung epithelial progenitor cells remains elusive. FAM13A (family with sequence similarity 13, member A) has been consistently associated with susceptibility to COPD in genome-wide association studies (GWAS). Our published work has demonstrated that FAM13A is mainly expressed in alveolar type II epithelial cells, regarded as lung stem cells. However, whether and how Fam13a regulates alveolar repair/regeneration, especially through modulating metabolism in lung epithelial progenitors remain incompletely understood. In last funding cycle, we have published that Fam13a promotes the degradation of beta-catenin and inhibits cell growth. However, depletion of beta-catenin failed to completely revert phenotype seen in Fam13-/- mice, suggesting additional pathways regulated by FAM13A may play a role in the lung repair/regeneration process. Our unpublished data suggested that Fam13a not only responds to Akt-mediated growth factor signaling but also represses the energy master regulator AMPK (c-AMP activated kinase) in cell lines and primary murine lung epithelial cells, suggesting an undiscovered metabolic control by Fam13a in lung epithelial progenitors. We, therefore, hypothesize that FAM13A may act as a key metabolic switch for cell growth through coupling energy homeostasis with cell growth demands in alveolar epithelial cells during lung regeneration. In this proposal, we are going to test this hypothesis through integrative approaches including in vitro biochemical assays, in vivo lineage tracing, smoke-induced emphysema mouse models, CRISPR-based genome editing and ex vivo organoid co-culture models. Successful completion of this project will shed mechanistic insights into molecular mechanism by which FAM13A transduces growth factor signals to metabolic controls on stemness of lung epithelial progenitors through interacting its upstream regulator Akt and downstream effector AMPK thereby possibly offering novel anti-COPD therapeutics.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD), a major public health burden, can result from defective lung repair/renewal. The primary goal of this project is to define the molecular mechanisms by which FAM13A, a well-replicated gene associated with COPD in genome-wide association studies (GWAS) and enriched in lung epithelial progenitors, responds to extracellular growth factor cues and transduces the signal to intrinsic metabolic controls on the repair capacity of lung epithelial progenitors. This novel concept may shed fresh insights into the biological mechanisms on COPD and pinpoint to new treatment targeting metabolic controls on lung epithelial progenitors.

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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Lu, Jining
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Brigham and Women's Hospital
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