Following the success of our previous Translational Research Grant, in this extension request we are proposing to use inhibitors of fibronectin (FN) fibrillogenesis that we have developed to test their activity in vivo. Specifically, we will test their ability to inhibit fibrosis in the bleomycin-induced lung fibrosis model, the murine model for idiopathic pulmonary fibrosis (IPF).
We previously found that oxidation of FN by members of the LYSYL OXIDASE (LOX) family of enzymes is an essential step for FN fibrillogenesis, a process which underlies extracellular matrix assembly and fibrosis development. Based on these findings, in the previous grant, we developed a novel strategy for blocking FN fibrillogenesis using specific domains from FN that serve as baits for LOX enzymes and act as competitive inhibitors. These can be administered directly as peptides or fused to an antibody Fc-domain to increase their stability. Our data demonstrate that these peptides or Fc-fused peptides inhibit FN fibrillogenesis, affecting cell adhesion, growth, and migration, as well as myofibroblast activation.
We now wish to extend these findings towards in-vivo experiments using these inhibitors. The proposed studies will provide proof-of-concept for our strategy to inhibit/halt IPF, serving as a basis for future studies in patients towards development of a new drug. Notably, as one or more members of the LOX family and FN are involved in essentially all forms of fibrotic diseases, these studies will pave the way for additional treatments of such diseases which are associated with ~45% of deaths in the Western world.