Mathematical modeling of species-specific diacylglycerol dynamics in the raw 264.7 macrophage following P2Y6 receptor activation by uridine 5’-diphosphate

Abstract

In this dissertation, we develop and analyze a mathematical model of the G-protein signaling pathway in RAW 264.7 macrophages downstream P2Y6 activation by the ubiquitous signaling nucleotide uridine 5'-diphosphate. Our model is based on time-course measurements of P2Y6 surface receptors, inositol trisphosphate, cytosolic calcium, with a particular focus on observations from an experimental method we developed for the simultaneous quantification of multiple species of diacylglycerol.

We prove existence, uniqueness, positivity, and boundedness of solutions for a simplified version of the model, as well as global asymptotic stability of a unique steady state solution. Parameter estimation is performed using SIMULINK to minimize a cost function between model outputs and multiple emperical observations. Sensitivity analysis of model parameters using standardized regression coefficients provides insight into which parameters are most responsible for model output uncertainty.

Our modeling efforts provide valuable insight into this signaling pathway, as they suggest the activation of a known metabolic pathway of diacylglycerol to explain behavior which cannot be reproduced under the current known pathway interactions.