The G protein signal transduction system represents a source of important specific targets for a variety of therapeutic approaches ranging from the control of blood pressure, allergic response, kidney function, hormonal disorders to neurological disease and pain. It has been estimated that 30-40% of the pharmaceutical products sold in the United States target G protein mediated signal transduction system. We are analyzing the interactions in this complex information processing system at the level of purified proteins, the cellular level and the whole animal level. If we can connect the biochemical changes that are the result of specific protein modifications to the effects of those mutations on cellular function and eventually the effects of cellular function on complex physiology or changes in development and differentiation, we will have gone a long way toward an integral understanding of these systems. In the next grant period we intend to pursue these molecular biochemical and genetic approaches. We will analyze transgenic mice that we have constructed together with our collaborators that result in the disruption or deletion of all of the G/alpha subunits in the Gq signaling pathway as well as mice that we have constructed that have the G/alpha13 and G/alpha12 genes disrupted and animals with deletions of the PI-PLC beta2 and PI-PLC beta4 genes. We will try to determine the specific effects of these mutations on cell and tissue function. We will also examine the effects of mutants in tissue culture and delineate the functions of individual G protein pathways. We will study the modifications of the different components of the G proteins that result from the activation of specific signaling pathways and understand how these modifications affect and integrate different signal transducing pathways. Finally, we will continue our studies on the molecular modification of individual G protein components and measure the effect of modification on protein- protein interaction using plasmon resonance and a variety of other techniques to develop a quantitative picture of the elements necessary for the interaction of components in a specific pathway. These studies will provide a deeper insight into the function of two less well studied G protein families, the Gq and the G12 families. We hope eventually to be able to develop models of how specific signal transductions pathways process information and how these pathways interact and we expect that such models will be important in predicting and developing new approaches to ameliorating the effects of disease.
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