Determining the Role of Myeloid-derived HB-EGF in Pulmonary Fibrosis

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Project Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no known cure, with patients experiencing a gradual loss of lung function and debilitating pulmonary symptoms that result in respiratory failure within 2-5 years after diagnosis. IPF is characterized by lung injury and inflammation, excessive deposition of extracellular matrix proteins, fibroblast hyperplasia, and scar formation. With prevalence highly associated with age and suboptimal treatment options, IPF is a devastating disease that is a serious global health concern in an aging world population. Preliminary data in the Moore lab suggest that heparin-binding epidermal growth factor-like growth factor (HB-EGF) may be critically important in the development and progression of fibrosis. HB-EGF is an EGF receptor (EGFR) ligand that has essential roles in angiogenesis and wound healing, keratinocyte migration and epithelial-mesenchymal transition. Recent clinical studies show that IPF patients expressing levels of HB-EGF and its receptor above an identified threshold are more likely to experience disease progression (HR=8.772, P=0.0053, 95% CI 1.905-40.385 and HR=2.2, P=0.0251, 95% CI 1.104-4.378 respectively). Furthermore, the functionality of HB-EGF as a key target in prevention of fibrosis progression has been noted via the success of receptor tyrosine kinase (RTK)-EGFR-specific antagonism in animal models. However, clinical trials administering select RTK-EGFR inhibitors can result in toxicity and lethality in some patients, and thus there is a need to better understand this pathway in the development of fibrosis to allow for more targeted therapeutic options. Our lab recently conducted a preliminary study showing that mice lacking myeloid-specific HB-EGF are protected from bleomycin-induced pulmonary fibrosis compared to wild type controls. These data suggest that inhibition of myeloid-derived HB-EGF could serve as a viable therapeutic for IPF patients in the future. This proposal will test the hypothesis that HB-EGF production from myeloid cells induces alveolar epithelial cell (AEC) or fibroblast alterations that promote the development of lung fibrosis. This hypothesis will be tested through three specific aims: (1) Demonstrate the impact of myeloid-specific HB-EGF on parameters of pulmonary fibrosis in mice, (2) Determine if soluble or cell-associated HB-EGF is responsible for profibrotic changes to epithelial cells or fibroblasts, and (3) Determine if HB-EGF primarily signals through EGFR or HER4. To accomplish these specific aims, mouse cell lines and genetically engineered mouse models will be used to perform the appropriate in vitro and in vivo experiments to study cell signaling and cell-cell interactions with and without myeloid-derived HB-EGF. The results from these innovative studies will establish the impacts of myeloid-HB-EGF signaling on relevant AEC and fibroblast activation outcomes with the overall future aim of identifying myeloid-derived HB-EGF as a therapeutic target for patients. This project will also serve as an excellent training vehicle for the applicant to gain core skills in research and critical thinking to help her become a successful and independent scientist.