Idiopathic pulmonary fibrosis (IPF) is a lethal condition involving progressive scarring of the lungs that affects 50 in every 100,000 Americans. Its pathologies include aberrant and chronic deposition of provisional extracellular matrix (ECM) proteins-including fibrin and fibronectin- as well as prominent amounts of post-translational modifications to these proteins in the form of citrullination. Importantly, citrullination affects arginine residues, including those accessible in RGD and PHSRN motifs found in fibrin and fibronectin, and thus such modifications are expected to have an influence on local fibroblast behavior mediated to altered integrin interactions. IPF is also associated with an activated fibroblast phenotype including characteristics such as invasiveness, resistance to apoptosis, and secretion of excessive ECM proteins. The overall hypothesis is that prolonged interaction of fibroblasts with these citrullinated provisional ECM proteins is responsible for altered fibroblast phenotype. This hypothesis will be explored in three specific aims. In the first, fibroblast cell behaviors including cell attachment, spreading, migration, apoptotic resistance, and secretory profile - including that of chemokines, ECM molecules, and degradation enzymes-will be evaluated in the presence of fibrin, fibrinogen, and fibronectin that has or has not been citrullinated. In the second, the mechanism for these altered fibroblasts will be explored by evaluating changes in specific integrins' binding capacities and activation. Finally, in the third aim, the in vivo efficacy of a targeted treatment that inhibits citrullinated will be evaluated in bleomycin-induced Thy1(-/-) model of IPF. This research is significant because it explores a novel mechanism for fibroblast activation in IPF, which may ultimately suggest a new class of early-stage interventional therapy. It therefore possesses great translational potential. It is als significant because it investigates a fundamental cell-ECM interaction that is prevalent in a wide-variety of chronic inflammatory conditions, including rheumatoid arthritis, malignant cancers, and multiple sclerosis, and it thus has the potential to enhance our understanding of both the onset and progressions many different serious human diseases. This proposal serves at the center of the applicant's training plan allowing her to expand her scientific knowledge, technical proficiencies, communication skills, and leadership capabilities as she prepares for a challenging career in biotechnology.
This proposal investigates a fundamental enzyme modification that occurs in high amounts during several different serious health conditions, including malignant cancers, rheumatoid arthritis, multiple sclerosis, and lung disease. The connection between this modification and the aberrant cell behavior characteristic of these various diseases has never been fully explored, and in doing so, our hope is to (1) improve our understanding of what causes and/or exacerbates these conditions and (2) develop novel strategies for therapeutic intervention.
