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The Alliance has recently completed a comprehensive survey of double ligand perturbations on macrophage-like cells. A primary finding of the double ligand screen is that the vast majority of ligands interact in "simple ways"; they are predictable by the assumption of signal additivity. However, some interactions are "complex" in that the signal response is not additive. The aim of the modeling effort is to understand the mechanistic nature of these and other complex responses. We are achieving this aim by developing a detailed kinetic model that synthesizes a proposed hypothesis of signal transduction with the perturbation data collected by the alliance. To this end, the Alliance is using the model with us to develop experiments, technology, and data that exercise the validity of the model predictions. To start, we have been iteratively building molecular-level models of the GPCR signal transduction pathways starting with the richest data sets on RAW cell Calcium response to C5a and UDP.

To the end of supporting the objectives of the AfCS, the modeling effort has three general purposes:

  • To specify a formal hypothesis of the biological mechanisms in the G protein coupled receptor system.
  • To evaluate the consistency of our hypothesis with the data we have observed experimentally.
  • To assist in the design of experiments to probe the validity of our hypothesis.

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