PROJECT SUMMARY Despite decades of research, the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF) is still not completely understood. As a consequence, IPF causes significant morbidity and mortality and there are no therapies that reverse existing fibrosis. IPF is characterized by accumulation of collagen and fibrotic extracellular matrix in the lung that replace normal tissue and interfere with gas exchange, leading to dyspnea, respiratory failure, and death. A key knowledge gap preventing our development of effective therapeutics is the understanding of how collagen is degraded and turned over. If we were able to promote enhanced turnover and clearance of collagen in fibrotic IPF, this could provide a viable strategy to reverse fibrosis in IPF. This grant proposes to address this knowledge gap by delineating pathways of collagen clearance that we discovered by a recent unbiased CRISPR screening approach. We have found a previously unappreciated mechanism of regulation of collagen clearance: that collagen synthesis is sensed by cells internally and directly regulates clearance of collagen (i.e. cellular uptake and degradation of extracellular collagen). The sensing mechanism is dependent on ER resident protein SEL1L. This mechanism appears to be a homeostatic negative feedback loop to limit accumulation of collagen in tissues. Importantly, we have also found that the induction of collagen turnover by collagen synthesis is impaired in IPF, contributing to the excess and unmitigated buildup of collagen in lung tissue. The research proposed in this grant will fully define the upstream and downstream mechanisms governing this pathway as well as the cause of the impairment in this pathway in IPF. We will use mouse models, human lung organoids, human IPF tissue and cells, and in vitro and in vivo functional experiments. If successful, the proposed research has the potential to open the door to entirely new therapeutic avenues to try to reverse fibrosis in IPF and ameliorate symptoms in patients.