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Mathematical Modeling of G-protein-coupled Receptor Signaling Pathways

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dc.contributor.advisor Green, David F. en_US
dc.contributor.author JIANG, TAO en_US
dc.contributor.other Department of Applied Mathematics and Statistics. en_US
dc.date.accessioned 2017-09-20T16:53:29Z
dc.date.available 2017-09-20T16:53:29Z
dc.date.issued 2014-12-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/77743 en_US
dc.description 140 pg. en_US
dc.description.abstract G-protein-coupled receptor (GPCR) signaling plays an important role in converting extracellular stimuli into cellular responses. Many biological functions are regulated by GPCR signaling, and nearly 40\% of current pharmaceuticals target GPCRs. In this work, mathematical modeling is used to investigate the initial steps of GPCR signaling with two major aims: 1) to understand the causes for non-canonical signaling behaviors; 2) to understand how signaling specificity is reacted to in the individual reactions of the pathway. The classic ternary complex model describing the interaction between a single ligand, receptor and G-protein served as our basic model for the initial investigation. Dose response curves were generated using computer simulations and qualitative differences were observed due to variations in the model parameters. A systematic study on individual parameters demonstrates that the rate for the binding of ligand-receptor complex to G-protein is the key determinant. In the next step, models containing two signaling pathways were built. The two signaling pathways can be considered to interact with each other when interactions between the components of both pathways exist. When nonspecific interactions exist in both the binding of the ligand to the receptor and the binding of the receptor to the G-protein, a biphasic dose response is observed. Specificity for the steady state response and dynamics of the signal were defined and how the strength of interactions and concentration of molecules affect signaling specificity were investigated. Other processes involved in GPCRs signaling were also considered. GPCRs undergo internalization upon ligand activation; they also form homo/hetero-dimers. A double-peaked dynamical response was observed due to the internalization of the receptors, while dimerization of the receptors may produce a double-peaked steady state response. Specificity as previous defined was also calculated and shown to be affected by both internalization and dimerization. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Systematic biology en_US
dc.title Mathematical Modeling of G-protein-coupled Receptor Signaling Pathways en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Rizzo, Robert en_US
dc.contributor.committeemember MacCarthy, Thomas en_US
dc.contributor.committeemember Scarlata, Suzanne. en_US

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