The goal of this proposal is to determine the molecular mechanisms by which obesity-related lipid excess can affect the development of pulmonary fibrosis. Obesity affects over a third of Americans and is one of the leading preventable causes of morbidity and mortality. Its role in the development of diabetes, cardiovascular disease and multiple other diseases has been well-studied, yet little is known about the impact on idiopathic pulmonary fibrosis (IPF). IPF is the most common idiopathic interstitial lung disease and has a poor prognosis with a median survival of 5 years. Several risk factors for the development of IPF have been identified, yet its etiology remains uncertain and no therapy has been found effective. Importantly, the prevalence of IPF, like that of obesity, is rising. There is a need to understand how obesity influences the development and progression of IPF in order to identify potentially important modifiable risk factors and therapeutic targets ad ultimately improve outcomes for this devastating disease. The proposed project will address this need by specifically exploring mechanisms by which lipid excess can modulate experimental pulmonary fibrosis. A mouse model has been developed which demonstrates that high fat diet leads to increased susceptibility to bleomycin-induced pulmonary fibrosis and mortality. Using this model and other cell-based assays, this project aims to establish a molecular basis for these findings. It will investigate the effect of lipid excess on three specific mechanisms that ar known to play critical roles in the development of lung fibrosis: TGF-1 signaling, NLRP3 inflammasome activation and mitochondrial oxidative stress. By determining if and how lipid excess modulates these key effectors of pulmonary fibrosis, this work will uncover potential targets for therapy and offer insight into how obesity, a highly prevalent condition, could modify the course of IPF. As such, the project has the potential to significantly impact the management of IPF. The NRSA will provide two years of support for the candidate, Dr. Sarah Chu, while she conducts the proposed research. This project will comprise the core of her research fellowship and provide the training necessary for her development as a physician scientist in the field of pulmonary disease. Completion of the proposed aims is expected to lead to further discoveries pertaining to the role of metabolic abnormalities in the development of IPF. She will undertake this project within the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital, under the close mentorship of her sponsor, Dr. Ivan Rosas and co-sponsor, Dr. Elizabeth Henske, and with the expertise of other highly accomplished members of her scientific advisory committee. She will have access to the comprehensive intellectual and physical resources available within her division and the Harvard biomedical community, thus being poised to obtain the research training required to successfully complete this project and nurture her career in academic medicine.