Idiopathic pulmonary fibrosis (IPF) is a devastating disorder. Two hallmarks of IPF are (1) profound deposition of collagen 1 (Col 1), and (2) fibroblast activation and proliferation. Although IPF subjects have increased collagen 1 synthesis with attendant matrix deposition that profoundly contributes to disease pathogenesis, the molecular mechanisms by which factors serve as feedback inhibitors of the Col 1 gene remain unclear. Here we discovered in preliminary studies that in human lung fibroblasts from IPF subjects there is a deficiency of a crucial anti-fibrotic protein and fibroblast growth suppressor, E2F8, which is eliminated by an orphan E3 ligase Skp1-Cullin-F-box (SCF) protein, Fbxo15. We found that E2F8 functions as a unique transcriptional silencer of the Col 1 gene. These preliminary observations led to our hypothesis that in humans with IPF, E2F8, an essential repressor of collagen 1 extracellular matrix deposition, is depleted through its selective degradation by the E3 ligase, SCFFbxo15. Therefore, in this application we will first elucidate how SCF-Fbxo15 mediates E2F8 protein degradation to impair fibroblast collagen 1 synthesis. We will specifically elucidate whether Fbxo15 binds and post-translationally modifies E2F8 in a site-specific manner to trigger its degradation. Last we will determine whether Fbxo15 and E2F8 are required to biologically modulate experimental pulmonary fibrosis. These studies will provide a new pathobiologic model of lung fibrosis focusing on two novel molecular inputs (E2F8 and Fbxo15) linked to fibroblast behavior in subjects with IPF.
Idiopathic pulmonary fibrosis (IPF) is a devastating cause of death in the US and evidence suggests that patients die from overwhelming lung scarring, or fibrosis. The fibrosis may be due to loss of a protein called E2F8 in cells. We will find out how E2F8 reduces lung fibrosis and identify how E2F8 is depleted by FBX015 in IPF. This discovery fulfills an unmet need in IPF mechanisms.
