Role of Lipid Metabolism in Hepatic Ischemia Reperfusion Injury in Steatotic Livers

PROJECT SUMMARY This proposal describes a 3-year plan to prepare Dr. Kim Liss, MD, for independence as a physician scientist, studying the role of lipid metabolism in ischemia reperfusion injury (IRI) in steatotic livers. During her Pediatric Gastroenterology, Hepatology & Nutrition fellowship at Washington University School of Medicine, Dr. Liss undertook research training in Dr. Brian Finck’s laboratory, where she demonstrated that steatosis significantly worsens hepatic IRI in an experimental model. She also found that manipulation of a single lipid synthesis pathway has far-reaching effects on inflammation, cell death, and regeneration in the liver. She extended these findings and found alterations in multiple lipid metabolic pathways and macrophage subpopulations in response to IRI. These findings serve as the basis for her proposal. Washington University School of Medicine is an outstanding environment for Dr. Liss to further her research training, with its longstanding history of NIH-funded research, breadth and depth of resources, and, most importantly, commitment to launching young investigators. There is constant crosstalk between departments and research groups. Dr. Liss’ mentoring committee and collaborators have expertise spanning Pediatrics, Medicine, Surgery, Chemistry, Immunology, and Developmental Biology. Dr. Finck is a well-suited primary mentor because he is a leader in the field of intermediary metabolism and has an established record of training young scientists during their transition to independence. Furthermore, the Finck laboratory is a hub of intellectual energy with its trainees working on a broad range of inter-related projects. Dr. Liss will have abundant opportunities to present her work within Washington University and the wider scientific community. Her mentor team has complementary skills, and her Division and Department are highly supportive of her goals. She will take graduate classes to enhance her knowledge of metabolomics, genomics, and bioinformatics, and develop technical skills with her mentors and collaborators. At award conclusion, she will have acquired the knowledge and skills to become an independent physician scientist with special expertise in hepatic steatosis relevant to liver transplant care. In parallel to pursuing her structured career development plans, Dr. Liss will accomplish her proposed Aims: 1) determine how adipose tissue lipolysis interacts with the liver in the context of hepatic IRI, and 2) define changes to the hepatic lipidome that determine the macrophage landscape in hepatic IRI. Using advanced multi-omics approaches, Dr. Liss strives to develop an integrated understanding of the factors that contribute to IRI and recovery. Her work will fill the void in our understanding of the pathobiologic mechanisms underlying IRI in steatotic livers, a condition that limits organ use, and threatens graft function. The efforts described in this proposal will prompt novel interventions to increase donor organ availability, decrease waitlist mortality, improve patient outcomes, and, in the process, serve as a springboard for Dr. Liss’ research career.