This PPG is organized to perform basic research which is oriented towards understanding fundamental mechanisms underlying renal stone formation. Project 1 will explore the contributions of cell injury a) to calcium oxalate (CaOx) urolithiasis by studying the reactions of renal tissue culture cells exposed to CaOx crystals and/or oxalate (Ox) ion, and b) to retention of CaOx crystals at the renal papillary tip in a rat model. In both systems, anti-oxidized agents will be employed to test the hypothesis that modifying cell injury will interrupt the crystallization urolithiasis processes. Project 2 will develop a better understanding of the relationship between phosphate and Ox by investigating the concept that calcium phosphate is a nucleator for CaOx. It is proposed that phosphate nidi produced in the rat using a well-defined diet will subsequently act as nucleators for CaOx calculi. The role of bacterial membranes in stone formation will be studied by characterizing non-urease producing bacteria from stone patients; bacterial mineralization will be examined in a rat model in vivo. Project 3 will evaluate the role of several aggregation mechanisms in stone disease. Interparticle bond strength will be determined in model systems by determining the hydrodynamic stress required to displace aggregates in suspension and particles attached to surfaces. Theoretical predictions will evaluate the interparticle strength of each aggregation mechanism. Project 4 will study nucleation and growth of CaOx monohydrate and further expand knowledge of enthalpy and entropy of activation. Temperature dependence of nucleation kinetics will be analyzed and the role of desolvation in nuclei organization will be determined. The hypothesis that transfer of phosphatidylserine from the cytoplasmic face of the outer cell membrane to the exoplasmic face plays a role in crystalluria from cell damage will be tested. The scope of EQUIL software will be extended to create a method for analyzing CaOx supersaturation in human serum. Core A will provide analytical support including chemical analysis of urine for various ions and molecules, and will provide data for determination of relative supersaturation. Electron microscopy will also be centralized in this Core. Core B will provide budget administration for the entire PPG and other services such as preparation of travel documents, editorial review of manuscripts and production of reports.
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