An emerging theory of the etiology and pathogenesis of idiopathic pulmonary fibrosis (IPF) is based on the concept of chronic injury, aberrant repair, and apoptosis of type II alveolar epithelial cells (AECII), the specialized lung cells that secrete surfactant. As AECIIs are professional secretory cells containing highly active endoplasmic reticulum (ER) organelles, we hypothesize that myriad upstream insults may generate ER stress as protein folding capacity becomes exhausted. A signaling pathway called the unfolded protein response (UPR) affords adaptation to ER stress, but can paradoxically cause apoptosis if the stress is irremediable. We have learned to prevent key destructive outputs from the UPR with novel small molecule UPR modulators that we have developed. In this tPPG, we propose to use our UPR modulators (and improved versions developed in the Medicinal Chemistry Core) to test an emerging hypothesis that ER stress-induced apoptosis of AECIIs is central to development of IPF through ameliorating the apoptotic process, and potentially modifying progression of this deadly disease. We will evaluate our most potent and specific UPR modulators in 3 murine models of pulmonary fibrosis, one involving induction of DNA damage combined with endoplasmic reticulum (ER) stress by low dose bleomycin and tunicamycin, another by low dose bleomycin in mice expressing a surfactant protein C mutation associated with pulmonary fibrosis in patients, and a third involving induction of ER and lyosomal stress in a genetic model of the Hermansky Pudlak Syndrome. We will also evaluate the effectiveness of each of these inhibitors on murine AECIIs and human AECIIs from normal lungs and patients with IPF obtained from the Human Cell and Tissue Core. We will also utilize stressed AECIIs and BAL and blood samples from the Longitudinal Cohort Core to evaluate the utility of micoRNAs we have found to be modulated by the UPR as mechanistically informative biomarkers of this pathway. Based on this work we expect to identify drugs to test in clinical trials in the second phase of this PPG and a strategy for rapidly monitoring the effectiveness of these compounds in patients.

Public Health Relevance

We are developing drugs to treat an incurable lung disease called idiopathic pulmonary fibrosis. Our drugs are expected to work by preventing the death of special lung cells called AECs. We theorize that preventing the death of AECs in this manner may be therapeutically benficial to patients suffering from idiopathic pulmonary fibrosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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University of California San Francisco
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