Disorders affecting kidney function are a serious health problem with significant human and economic costs to society. An important step toward the goal of reducing the impact of renal disease is to understand how the kidney performs its primary task: transporting water, ions, and small molecules from the blood to the urine in order to maintain homeostasis of the internal environment. The use of invertebrate model systems has been tremendously important in advancing our understanding of these transport processes. These organisms, because of their small size and rapid generation time, are far more conducive to genetic studies than vertebrates. In addition, because many of the proteins responsible for membrane transport have been conserved throughout evolution, experimental results obtained in simpler organisms are often directly translatable to mammals. The study proposed here employs such a model organism, the fruit fly Drosophila melanogaster, taking advantage of the enormous array of available genetic techniques and tools, including the recently completed sequence of its genome. The goal of this project is to generate, isolate, and characterize strains of Drosophila that have altered capacities for maintaining internal homeostasis in the face of osmotic stress. This will be accomplished through a series of genetic screens for altered survival on food containing high concentrations of salt. These screens are expected to produce a large number of fly lines with defects in a variety of physiological functions, ranging from ion transport to the cell signaling pathways that coordinate the proper functioning of the insect excretory system. The flies that result from the work described in this proposal will form the basis for years of subsequent studies that should help to elucidate the molecular mechanisms underlying the regulation of ion transport, not only in Drosophila, but in all animals. By providing the tools necessary for an understanding of the regulation of ion transport and the maintenance of osmotic homeostasis in Drosophila, this project will further our understanding of the modulation of renal function and the ways that failure of such modulation might result in disease states.