This K99/R00 application from Kaice A LaFavers, PhD, is designed to acquire the knowledge and training necessary to transition to an independent faculty position leading a research program focused on kidney-organ cross talk in the setting of sepsis and severe infection. Sepsis is a dysregulated host response to infection and is a major contributor to morbidity and mortality worldwide. When acute kidney injury (AKI) occurs in the setting of sepsis, mortality doubles to approximately 1 in 2 patients. We have recent evidence that the kidney-derived Tamm Horsfall Protein (THP) is protective against sepsis mortality. THP is secreted from the kidney primarily into the urine, where it is the most abundant protein component. However, a small portion of THP produced in the kidney is secreted into the kidney interstitium, where it enters the circulation. Increased levels of serum THP have recently been associated with decreased mortality and protection against chronic kidney disease in human cohorts. Circulating THP has also emerged as an immune regulator, with genetic depletion of THP leading to decreased number and function of mononuclear phagocytes in the kidney. In both human and animal models of AKI, THP is acutely depleted shortly following injury. In the current proposal, the overall hypothesis is that the kidney protects other organs during sepsis by releasing THP in the circulation, where it enhances macrophage function and signaling. This hypothesis will be tested by two specific aims. One aim will establish that circulating THP released by the kidney is a key protective molecule in sepsis using a genetic knockout model of THP depletion in murine sepsis. This aim will also determine the potential of treating septic mice with exogenous THP to improve sepsis outcomes. The second aim will define the effect of THP on enhancing macrophage function by assessing in vivo phagocytosis, macrophage activation and signaling, and macrophage- derived IL-15-dependent signaling in sepsis. Under the mentorship of Dr. Tarek Ashkar, Dr. LaFavers extends her current research on THP biology and proposes additional training. This additional training will be in the areas of technical skill development, including bioinformatics, advanced imaging analytics, protein purification, mouse model development and breeding, along with professional career development in science communication, lab management, grant/manuscript writing and mentoring. The completion of this proposal will provide Dr. LaFavers with the expertise and training for her first R01 submission and the establishment of an independent career.