(679f) Structured Singular Value Analysis of the Fas Apoptosis Pathway

A systems level understanding of the genetic protocol controlling apoptosis, programmed cell death, is critical to the development of multi-targeted therapies for complex diseases such as cancers and autoimmune diseases. While several methods exist to evaluate system robustness, structured singular values offer the advantage of measuring the robustness of specific biological performances to multiple, simultaneous parametric perturbations. In this paper, the Fas-induced apoptosis network, whose failure has been cited in several forms of cancer [14], is analyzed for robust stability to parametric uncertainty. Analysis reveals apoptotic signalling is most sensitive to perturbations in degradation rates, while the system is robustly stable to perturbations in complex formation and catalytic reactions. Correlation analysis shows that the robustness of the interaction of caspase 8 with the mitochondria is restricted by the robustness (or allowable variation) of other elements in the apoptotic pathway. The robustness trends discovered via SSV analysis provides another measure for model (in)validation, and the predicted uncertainty bounds have direct experimental implications.