Hypoxia Signaling and Spontaneous Pulmonary Fibrosis in a Novel Mouse Model

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DESCRIPTION (provided by applicant): Idiopathic PF (IPF) is a lethal, incurable disease killing 40,000 Americans every year. As the aged population has grown, the prevalence of IPF has jumped from 20 to 30 cases/100,000 individuals. Despite this enormous public health burden, the molecular basis of the origins and progressive nature of IPF remains elusive. Continuation of this knowledge gap has stymied the development of targeted therapies for IPF. Thus, the long-term goal is to define molecules, mechanisms and cell types in the lung that contribute to the initiation and progression of IPF that will aid in the development of targeted therapies for IPF. While mechanistic insights are being generated from current animal models of injury-induced fibrosis, these models remain inherently limited as the fibrosis resolves over time, precluding the identification of molecular drivers participating in the progression of PF. Therefore, the objective of the present project is to fill this significant gap by developing, characterizing and refining a mouse model of PF exhibiting progressive nature of the disease, recapitulating some of the clinico-pathological features of IPF. Repeated injury to the respiratory epithelial cells (RECs) causes cellular stress, triggering aberrant epithelial repair associated with molecular alterations that render RECs profibrotic. These RECs secrete fibrogenic signals, activating resident fibroblasts/mesenchymal cells, contributing to fibrosis. One such epithelial stress factor is chronic hypoxic response to the epithelial cells, which is known to alter structure and function of RECs in vitro. In addition, based on our in vivo data presented here, we will test the central hypothesis that aberrant hypoxic responses originating in the lung epithelium render RECs profibrotic, contributing to PF in vivo. We will delineate molecules/mechanisms initiating PF utilizing a mouse model of spontaneous and progressive PF that slowly develops over 3 months due to chronic hypoxia signaling elicited by deletion of Vhl gene in the conducting and alveolar airway epithelial cells (AECs) in vivo. This model correlates well with slow progressive features of fibrosis seen in IPF patients in the clinic. We show that hypoxic response in the RECs in vivo triggers activation of Wnt/ß-catenin, TGF-ß and CXCR4/SDF-1 signaling, consistent with their role in PF and findings in IPF patients. Aim#1 will define earliest molecular events initiating PF and molecules activating Wnt/ß-catenin and TGF-pathways in the RECs using systems biology approaches. Aim #2 will ascertain the regulation of CXCR4/SDF-1 genes in human RECs and examine the paracrine roles of profibrotic RECs in activating fibrogenic phenotype of primary human parenchymal fibroblasts. The outcome of the project will be significant, revealing molecules/mechanisms defining early molecular events driving PF. The molecules and signaling networks identified in the profibrotic epithelia would have high prognostic, diagnostic and therapeutic utility. The characterized mouse model holds immense potential for pre-clinical studies in building clinical rationale for emerging targeted therapies of IPF.