Project Summary/Abstract Candidate and environment: Takashi Hato, MD is Assistant Professor of Medicine in the Division of Nephrology at Indiana University School of Medicine. The applicant's long-term goal is to become a physician scientist with a focus on the discovery of targeted therapies for acute kidney injury. The primary goal of his K08 proposal is to provide insight into the role of purine metabolism in sepsis-induced acute kidney injury. The applicant plans on extending the work in his future studies with the ultimate goal to harness this metabolic pathway to control energy and second messenger system for renal protection. Dr. Pierre Dagher, Professor of Medicine, is an accomplished physician scientist specializing in acute kidney injury. Dr. Dagher has been the applicant's primary mentor since his nephrology fellowship training and will serve as the primary mentor during the course of this award. Research: Sepsis remains the leading cause of death in hospitalized patients. The survival rate further deteriorates when sepsis is complicated by acute kidney injury. There is a critical need to identify novel therapeutic approaches to treat sepsis and its grave sequelae. For this proposal, Dr. Hato and his team have performed unbiased metabolomics and transcriptomics analyses and found that purine metabolism is severely deranged in the septic kidneys. Sepsis resulted in significant depletion of purine nucleosides, most notably guanosine. Their preliminary work also revealed that exogenous guanosine supplementation could modulate multiple genes involved in the purine metabolism pathway and limit kidney injury. The beneficial role of guanosine in sepsis is largely unknown. It is therefore the primary goal of this application to investigate the mechanisms of guanosine-mediated renal protection. They hypothesize that the protective effects of guanosine are medicated by positive reprograming of renal purine metabolism at the gene level. A combination of tools will be used including intravital microscopy, in vivo siRNA technology, microdissection and isotope tracing to investigate the mechanisms of guanosine action at the cellular and molecular levels without compromising in vivo significance.