Urinary tract stone disease (urolithiasis) is a common clinical disorder that frequently leads to hospitalization. The objective of this proposal is to advance the understanding of the pathogenesis of urolithiasis by determining the physical mechanisms through which important inhibitors that include small urinary molecules, such as magnesium and citrate that are currently used in the treatment of urinary tract stone disease and urinary macromolecules, such as osteopontin control the nucleation, growth, aggregation, and phase transformations of calcium oxalate (CaOx) precipitates. This objective will be accomplished by investigations focusing on 1). the mechanisms of modulation of CaOx nucleation and growth by small urinary molecules and urinary macromolecules, 2). the mechanisms by which urinary modulators affect the sequence of events during phase transformations of CaOx crystals and 3). the surface interactions and events underlying urinary protein modulation of CaOx aggregation. The proposed research will use in situ atomic force microscopy to follow the evolution of CaOx crystal surfaces and quantify the impact of growth modulators on the thermodynamic and kinetic factors controlling the dynamics of atomic steps on those surfaces. This work will lead to new insights that integrates an understanding of the specific stereochemical interactions on the crystal surface with the quantitative impact on kinetics and morphology. The atomic force microscopy measurements will be correlated with concurrently performed constant composition measurements of growth kinetics and contact angle measurements of interfacial energies. The knowledge derived from our studies will assist in the design of inhibitory molecules that are potentially useful in therapy of stone disease.