PROJECT ABSTRACT The candidate, Dr. Tracey Simon, is an accomplished clinical research fellow at the Massachusetts General Hospital, with training in gastroenterology and hepatology. Her long-term career goal is to become an independent physician-investigator, with a patient-oriented clinical research program devoted to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). To achieve this, she has developed a detailed and integrated career development plan, designed to provide focused training to achieve her short-term career goals: 1) to gain experience in pharmacoepidemiology and large database research; 2) to acquire skills in the analysis of metabololipidomics data, for biomarker development; 3) to build proficiency in the conduct of clinical trials; 4) to obtain the necessary skills, experience and preliminary data to produce a successful R01 application. Experimental and clinical data show that unresolved inflammation is a key hallmark of NASH, the aggressive and inflammatory form of NAFLD. As proof of this principle, anti-inflammatory drugs like aspirin have been shown in vivo to resolve NASH and attenuate fibrosis. This benefit was previously attributed to the inhibition of pro- inflammatory eicosanoid lipid synthesis. However, it was recently discovered that aspirin also stimulates the production of novel anti-inflammatory eicosanoid lipid mediators, called specialized proresolving mediators (SPMs). Based on preclinical studies and the candidate’s preliminary data, we hypothesize that NASH reflects a state of relative SPM deficiency, and that aspirin may resolve NASH and improve hepatic outcomes through pathways governed by SPMs. In Aim 1, we will use nationwide Swedish registers to define the impact of aspirin use on risk for incident HCC and liver-related death, in patients with biopsy-proven NAFLD. In Aim 2, we will use banked serum and liver pathology data from two independent cohorts, to measure a validated panel of ~65 targeted SPMs, using a state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS-MS) platform, and we will define and validate a diagnostic SPM signature for NASH. In Aim 3, we will conduct a pilot randomized controlled trial to assess the preliminary efficacy of low-dose aspirin on NASH regression. Dr. Simon is supported by a multidisciplinary mentorship team of renowned scientists and advisors in Hepatology, pharmacoepidemiology, eicosanoid biology, biomarker discovery and NAFLD clinical trials, to guide her path to scientific independence. She will train in the outstanding scientific environment of the MGH Fatty Liver Clinic, the Harvard School of Public Health and the Karolinska Institute. Completing this project will provide her with preliminary data towards a future biomarker-guided aspirin interventional trial, for patients with NASH. With this foundation, Dr. Simon will launch her independent clinical research career, using advanced lipidomics and pharmacoepidemiologic tools to improve strategies for early detection, risk stratification and treatment of NASH.

PROJECT NARRATIVE In the coming decade, the number of Americans with nonalcoholic steatohepatitis (NASH) is expected to exceed 25 million, and NASH cirrhosis is a leading cause of morbidity and mortality in this rapidly growing population. Despite this epidemic, there are currently no accurate, non-invasive diagnostic biomarkers or effective therapies for NASH. Studying the relationships between aspirin use, proresolving eicosanoid lipid mediators and the natural history of NASH could identify urgently-needed biomarkers and novel therapies to improve the early detection, treatment and prevention of NASH.