PROJECT SUMMARY/ABSTRACT:
Kidney disease is a major contributor of death in the U.S. Chronic inflammation is common among
individuals with chronic kidney disease. A diet high in salt or low in potassium is associated with
increased inflammation and kidney injury. The renal handling of salt and potassium within distal
segments of the nephron is linked to the circadian clock. Recently, distal segment cells have been
linked to initiating tubulointerstitial inflammation. The research goal is to determine the
mechanistic links between BMAL1 and activation of the immune system within distal segment
cells of the kidney. Preliminary data identifies BMAL1 as a driver of inflammation in the kidney in
response to a low K+/high salt diet, leading to kidney injury. Studies will use novel conditional
knockout mouse models to reduce expression and re-express BMAL1 specifically in distal
segment cells. The first aim will test the hypothesis that mice with decreased BMAL1 expression
within distal segments display lower immune mediated kidney damage in response to low
potassium with high salt diet. The second aim will test the hypothesis that BMAL1 within distal
segments stimulates pro-inflammatory cytokine production in mice fed a low K+/high salt diet. To
test these hypotheses, experiments to determine the localization and extent of renal injury,
cytokine/chemokine production, immune cell recruitment and activation in response to a low
K+/high salt diet are planned. These studies will establish a novel line of investigation aimed at
understanding the link between the clock gene BMAL1 and activation of the immune system in
the kidney. The long term goal of this work is to The training plan was carefully designed to build
upon career development skills of the project leader focused around research advancement,
education, and service to the scientific community. The experiments and career development will
take place at the University of Florida, a top ten public research university that provides an
outstanding environment for conducting biomedical research. Together, data from this award will
provide a foundation for identifying new targets to treat renal inflammation/injury in order to
improve the quality of life in individuals with kidney disease. The mentored training plan will
provide the project leader with necessary technical and professional skills training needed to
become an independent investigator.