Project Summary / Abstract The goal of this proposal is to define a five-year plan to prepare Nicholas P. Semenkovich, M.D., Ph.D., to become an independent physician-scientist studying applications of cell-free DNA as a novel biomarker in sepsis. He obtained his M.D. and Ph.D. degrees at Washington University in St. Louis, where he studied intestinal and immune epigenetic changes induced by the gut microbiome. After clinical training in Internal Medicine at the Brigham and Women’s Hospital, Dr. Semenkovich pursued subspeciality training in Endocrinology and Metabolism, and joined the lab of Dr. Aadel Chaudhuri to focus on the applications of cell-free DNA to understudied diseases. There he has developed and applied key new techniques and deep learning algorithms for analyzing cell-free DNA using epigenetics, which serve as the basis for the aims in the proposal. Key guidance for this project will be provided by Dr. Semenkovich’s mentor, Dr. Chaudhuri. Dr. Chaudhuri is a physician-scientist and an internationally recognized expert in cell-free DNA. He has a passion for and dedication to training physician-scientists as they prepare for independent careers. In addition. Dr. Semenkovich has assembled an advisory committee of faculty with expertise in sepsis, critical care, and immunology, who will provide crucial scientific and career guidance. Washington University in St. Louis is an ideal place to receive this training, with outstanding resources and expertise readily available. The primary research goal of this proposal is to develop and advance cell-free DNA as a novel biomarker with predictive and prognostic roles in sepsis. Dr. Chaudhuri’s lab has previously characterized how cell-free DNA can be leveraged in a range of malignancies. Dr. Semenkovich’s proof-of-concept work has provided the first clear evidence that cell-free DNA can be used to predict complications and early end-organ damage in sepsis. He is developing machine learning methods to identify septic patients at risk of complications and will test those hypotheses in silico, in vitro, and in vivo. These efforts promise to fundamentally change our understanding and management of sepsis and enable potential clinical trials and immunomodulatory interventions to treat sepsis. This K08 award will provide the necessary resources and skills that Dr. Semenkovich will require to become a successful independent investigator.