In this MPI RO1 application, we show that high endoplasmic reticulum (ER) stress and dysregulated unfolded protein response (UPR) signaling in lungs precedes development of fibrosis in murine models of pulmonary fibrosis (PF)?similar changes have been reported in lungs of human patients with idiopathic pulmonary fibrosis (IPF). We find that the pathognomonic features of these changes are due to hyperactive signaling by IRE1?, an ER transmembrane protein containing bifunctional kinase/endoribonuclease (RNase) catalytic activities. We have found that novel, small molecule UPR kinase inhibitors of IRE1?, called KIRAs (an acronym for kinase-inhibiting RNase attenuators) reduce IRE1?'s destructive UPR signaling and show potent anti- fibrotic effects in ER-stressed lungs of mice. Thus, even as IRE1? emerges as a potential therapeutic target for treating human patients suffering from IPF, the underlying mechanistic basis for the cytoprotective, anti-fibrotic, efficacy of the KIRA compounds needs to be understood. Through this application, we propose to understand the basis of the KIRA-mediated salutary effects on reducing lung epithelial injury, dysregulation, and death, and also on reducing collagen overproduction by activated fibroblasts. The project is enabled by the complementary skill sets of two labs (Papa and Sheppard) that together have found the UPR is wired through a signaling loop that leads to classical TGF-?-induced, pro-fibrotic signaling in lungs. Thus, the mechanistic understanding to be gained from the successful completion of the proposed studies promises to reveal new nodes and targets for rational disease modification in idiopathic pulmonary fibrosis, a currently incurable disease.
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.