Dean Sheppard

Payment for services (e.g., consulting fees, honoraria, paid authorship)

Interventional Targeting of the IRE1alpha-TGFbeta signaling loop in pulmonary fibrosis

PROJECT NARRATIVE Patients with pulmonary fibrosis have evidence of activation of a stress response in the lungs called the unfolded protein response; this response normally plays an important role in protecting cells, such as epithelial cells and fibroblasts, from being overwhelmed by demands to make more proteins, but in the face of excessive demands the unfolded protein response can lead to cellular dysfunction, inappropriately-high protein secretion, and eventually cell death. We have developed a novel class of drugs that inhibits these destructive consequences of the unfolded protein response and found these drugs protect mice in two different models of pulmonary fibrosis. In the current proposal we will determine the mechanisms underlying the contributions of the unfolded protein response to pulmonary fibrosis and how our novel drugs protect lung epithelial cells and fibroblasts; this work should provide insights into key steps in the development of pulmonary fibrosis and should provide a roadmap for developing novel treatments for fibrotic diseases in general.