This F30 application is for support of Morgan Locy's MD/PhD training. Interstitial lung disease (ILD) is a chronic, progressive lung disorder that results in loss of functional alveolar-capillary units leading to impaired gas exchange and respiratory failure. The number of individuals with interstitial lung disease (ILD) in the United States is estimated at 500,000 with increasing incidence and prevalence. About 40% of diagnoses of ILD are idiopathic pulmonary fibrosis (IPF) with this population having particularly high mortality and morbidity with a five-year mortality rate of 50-70%. IPF is a disease of aging with features of aberrant wound healing. Oxidative stress has been implicated in IPF pathogenesis, and ?signatures? of chronic oxidative damage observed in lung tissue from IPF patients. Our lab has shown that NADPH oxidase 4 (NOX4), a hydrogen peroxide (H2O2) producing enzyme, is upregulated in the lung of IPF patients; the pro-fibrotic cytokine, transforming growth factor-?1 (TGF-?1), upregulates NOX4-dependent H2O2 production. We recently reported that o,o'-dityrosine levels, a covalent tyrosine modification catalyzed by H2O2 and a heme peroxidase (hPx), are increased in proteins within the circulating plasma of ILD patients. This increase in plasma levels of this oxidative biomarker was also replicated in a murine model of lung injury and fibrosis. The identity of the hPx or the enzymatic source of H2O2 in the context of ILD and experimental lung fibrosis is not known. Mechanisms of the formation of protein-associated o,o'-dityrosine and how it contributes to disease pathogenesis is also unknown. I have observed that the ECM protein, fibronectin (FN), undergoes o,o'-dityrosine cross-linking. FN is known to play a central role in physiologic and pathologic wound healing. Further understanding the modulation of FN by o,o'-dityrosine cross-linking could provide novel insights into normal wound healing and the dysregulation that occurs in pathologic states of aberrant wound healing. The central hypothesis for these studies is that the hPx, myeloperoxidase (MPO), and NOX4-dependent H2O2 generate o,o'-dityrosine in an in vivo lung injury model; additionally, FN o,o'-dityrosine cross-linking alters its function/stability in in vitro cell models. The long-term goal of this research is to understand the mediators of o,o'-dityrosine formation and its effect on physiologic and pathologic wound healing in the lung. This understanding will guide strategies for the development of novel therapeutics in the setting of aberrant wound healing seen in ILD. This proposal will provide a solid training platform for Morgan Locy (PI) under the mentorship of Dr. Victor Thannickal (sponsor) that will foster his career development as an astute and creative physician-scientist.
Interstitial lung disease (ILD) is a chronic, progressive lung disorder with increasing incidence and prevalence that leads to impaired gas exchange and respiratory failure. Oxidative stress has been implicated in ILD pathogenesis, and we recently reported that the oxidative tyrosine modification, o,o'-dityrosine, is increased in proteins within the circulating plasma of ILD patients. This proposal will determine the enzymatic sources that catalyze o,o'-dityrosine formation and the effects o,o'-dityrosine cross-linking has on protein function and stability.
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