The overall goal of this project is to develop detailed spatial models of cell signaling networks to understand the origins and dynamics of microdomains of signaling components. We will combine spatially realistic models developed in the program Virtual Cell with experiments to understand the characteristics of microdomains. The proposed project is based on the following central hypothesis: """"""""the dynamics of spatial localization as well as activity of the regulators will contribute to amplitude and location of information flow within the signaling network"""""""". To test this hypothesis we have set up a simple network consisting of camp and MAP-kinase 1, 2 pathways in neuronal cells. Using this network we will determine the role of the location, concentrations and activity state of key upstream stimulatory components of the systems in the development of spatially defined domains of activated MAP-kinase 1,2. Specific questions include the effect of varying levels of beta-adrenergic receptor occupancy on the extent of MAP-kinase activation as well as the spatial domains of active MAP-kinase; the effect of varying GTPase activity rates of Gs in the coupling of beta-adrenergic receptor to adenylyl cyclases 5 and 2, and the consequent characteristics of the spatial domains of activated MAP-kinase 1,2 and the effect of varying levels of activation of protein kinase A on the extent and spatial localization of MAP-kinase activity. We will also define the role of negative regulators of the signaling network, such as phosphodiesterases and protein phosphatases in determining the characteristics of the spatial domains of activated MAP-kinases 1,2 We will study the role of cellular morphology in defining spatial domains by analyzing the relationship between the length of dendrites and distance from the cell body as well as the length to breadth ratios of dendrites in determining the spatial domains of activated MAPkinase. From such analysis we hope to define the key criteria involved in determining the characteristics of microdomains of signaling molecules within the cell.
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