The influence of purinergic signaling on intracellular calcium signal transduction in podocytes in vivo

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The aim of this proposal is to study changes in podocyte calcium levels in reaction to purinergic and mechanic stimulation in healthy and diseased podocytes to delineate the effect of prior activation of purinergic signaling pathways in disease states. Our studies will provide more detailed insight into podocyte biology and in the long run help to develop new therapeutic strategies. If we are able to block long lasting calcium increases due to podocyte damage, we will be able to reduce podocyte loss and preserve kidney function of our patients. The proposed experiments utilize the newly available technique of in vivo calcium imaging of podocytes and will enable us to visualize calcium signal in podocytes after purinergic stimulation for the first time in physiologic and pathophysiologic states in the intact kidney. For this we will combine our expertise in in vivo imaging with state-of-the-art imaging technology and several new mouse models.The proposal will elucidate three questions :(1) To which extent leads preexisting activation of purinergic signaling pathways induced by disease models of nephrotic syndrom to increased calcium responses after purinergic stimulation and can this be blocked as a therapeutic approach ?(2) What kind of effect has the elimination of single purinergic receptors and calcium channels in podocytes on progression of kidney damage in different glomerular disease modells ?(3) What is the role of mechanical stress in podocyte foot processes in respect to calcium signaling in the microdomain of the foot processes and does this influence podocyte damage in disease models.