Title: ``An Integrated Approach to Modeling the TCR-Activated MAPK Pathway''
Speaker: Dr. Ann Rundell, Department of Biomedical Engineering, Purdue University
Place: Stanley Coulter (SC) 239; Tuesday, 4:30pm


Quantifying the T-cell signaling pathway through mathematical models will impact the understanding and potential treatment design for several immunologically-related and malignant diseases. Currently most T-cell signaling pathways have been mapped out in terms of their dominant interactions and key participating elements; however, the quantification of these pathways and their regulation mechanisms remain to be identified. Engagement of plasma membrane-bound T cell receptors (TCRs) by antigen leads to T-cell activation through various signaling pathways including the Ras-MAP kinase pathway. A mathematical model of the T-cell MAPK signaling pathway has been constructed to assist in the quantification and delineation this pathway. The model, a deterministic system of nonlinear differential equation, is continuously refined using an integrated approach that combines in silico analysis with in vitro experimentation. The time-dependent responses of observable signaling intermediates are measured using biochemical techniques and compared to model simulations. Currently a number of regulatory mechanisms are being explored to improve the fit between the experimental and simulated results. Initially a large discrepancy was found between the predicted steady-state and observed damped responses. Based on model analysis, hypotheses of possible inhibitory feedback from the MAP kinase, Erk, to Lck was proposed and confirmed experimentally using a MEK inhibitor. This work demonstrates how model analysis and simulation provide a systematic means to design experiments for distinguishing between hypotheses and refinement of the quantitative model.