The long term objective of this proposal is to understand the molecular mechanisms of adaptive regulation of the enzymatic signal transduction, using photo-transduction in retinal rods of vertebrates as a model system. While the backbone enzymatic cascade of photo-transduction is known, the molecular circuits responsible for the light adaptation phenomena are complex and poorly understood. The difficulty with experimental dissection of such complex regulatory circuits is common to all cellular signaling systems. Rod photo-transduction offers the advantage of experimental tractability which has resulted in the abundance of accurate electro-physiological data. The proposal seeks support for an interdisciplinary collaboration (physicists/biology) with funding for the theoretical modeling and analysis of complex experimental data.
The specific aims of the proposal are: 1) to develop a novel method of quantitative estimation of signaling pathway parameters on the basis of measured impulse response, 2) to investigate quantitatively the mechanisms of adaptation in photo-transduction (by identifying the systematic variations of impulse response parameters under different conditions in wild type and mutant cells) and to distill a comprehensive model of the process; 3) to investigate the molecular mechanisms responsible for the observed high fidelity of single photon response and to study the possible role of spatial localization of G-protein signaling in this phenomenon; 4) to extend the approach to other (G-protein coupled) signal transduction systems. The proposed parametrization of impulse response (based on Fourier space pole/zero representation) will at least double the amount of quantitative information obtained from measurements. Data analysis will be complemented by the analysis of kinetic models, including the analysis of fluctuations and of spatial localization effects. Non-linearity and multiplicity of time scales in adaptation phenomena will be investigated. Progress in the analysis and understanding of complex signal transduction pathways would have an impact on the development of pharmacological interventions for numerous clinical syndromes linked to pathologies in enzymatic signaling.
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