The major objective of this research program is to provide the applicant with new and intensive training in cell and molecular biology. To achieve this goal the applicant will train in the rich scientific environment of the University of Florida, under the close sponsorship of Dr. Harry Nick, in the Department of Biochemistry and Molecular Biology and the expert guidance of Dr. C. Craig Tisher, Chief, Division of Nephrology. The long-term goals of this proposal are to elucidate the cellular and molecular pathogenesis of renal injury, particularly those mechanisms that underlie the progression of renal disease. Renal tubular epithelial cells are exposed to an array of macromolecules including lipoproteins (LDL) that leak into the urinary space, consequent to proteinuria and disordered lipid metabolism, which occur in the nephrotic syndrome (primary and secondary). Oxidation of LDL (LDLox) is pathogenic in atherosclerosis and glomerulosclerosis. Preliminary studies demonstrate that oxidative processes are involved in LDLox-mediated renal tubular cytotoxicity and are associated with marked cellular expression of heme oxygenase, a redox sensitive gene, which is an adaptive response in cells exposed to, a wide variety of oxidant stress. The molecular mechanisms controlling the induction of heme oxygenase in a cell model of LDLox- mediated renal tubular injury will he examined, The proposed experiments will be the basis for training the applicant in molecular biology techniques such as nuclear run-on transcription assays, recombinant DNA, PCR, promoter deletion analysis, transfection studies and to study DNA-protein interactions by in vivo genomic footprinting. The observations in this cell model will be applicable to renal diseases such as diabetic nephropathy and nephrotic syndrome due to other causes. These studies would attempt to establish a pathogenic link between proteinuria and tubulointerstitial disease through the potential harmful effects of LDLox and may aid in developing new therapeutic interventions for modifying the progression of renal disease. Using this comprehensive training in later, independent research, the applicant will further investigate gene regulation in other animal models of renal injury as well. This phase of the applicant's scientific development will be greatly fostered by the ongoing sponsorship and guidance of Dr. Harry Nick and Dr. C. Craig Tisher.
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