DESCRIPTION: Chronic renal failure (CRF) and end stage renal disease (ESRD) are worldwide public health problems and an enormous economic burden. In the United States alone, today 8-10 million individuals suffer from CRF. Cardiovascular disease (CVD) is the most common cause of chronic morbidity and accounts for more than 50% of the deaths in CRF patients. Endothelial dysfunction contributes significantly to CVD and is universal in CRF patients. However, signaling pathways involved in endothelial dysfunction in these patients remain unknown. The proposed research will focus on the role of intracellular signaling in endothelial dysfunction in patients with CRF. The experiments will entail exploration of Wnt signaling pathway in molecular pathogenesis of endothelial dysfunction. Potentially this can be a novel therapeutic strategy and may have porfound benefits in CRF patients. The specific aims include examining the functions of cultured endothelial cells exposed to uremic serum (serum from patients with ESRD) with modulating Wnt signaling;determining if upregulation of Wnt signaling protects endothelial cells from uremic toxicity in a uremic animal model. This work will be the first detailed functional analysis of the role of signaling pathway in uremia-induced endothelial dysfunction. The applicant is an Instructor in Medicine and is pursing a Ph.D. in the Graduate Program of Molecular Medicine at Boston University School of Medicine in Dr. Herbert T. Cohen's laboratory. He has 6 years experience in basic cellular and molecular biology and 6 months experience in endothelial biology. He is deeply committed to a career centered on basic science in an academic division of Nephrology. Dr. Elazer Edelman, the mentor for PI, is a recognized leader in the field of vascular biology and a Professor in the Department of Medicine at Harvard Medical School. The work will be performed in the thriving research environment of Dr. Edelman's laboratory, home to 90 research scientists and affiliated faculty, located at MIT in the Harvard-MIT Division of Health Sciences and Technology. The combined expertise of the sponsor and collaborators within this thriving environment will provide an outstanding opportunity for the applicant to achieve the goals of the project and to become a successful independent investigator. PUBLIC HEALTH RELEVANCE: These studies may help to delineate a novel role for Wnt signaling in uremia and design further studies to explore both the diagnostic/prognostic and therapeutic benefits of Wnt signaling in CVD in CRF patients.