The goal of the Mitogenic Networks Project is the development of high-level statistical and specific physico-chemical models that describe key features of mitogenic signaling networks activated by ErbB receptors and by oncogenic K-ras.
We have made significant progress in developing models of ErbB family mitogenic signaling networks over the past few years. We will extend these efforts to include additional receptor tyrosine kinases while constructing models for EGFR and Ras mutations that are directly associated with poor prognosis in human cancers of the central nervous and respiratory systems. Models will be developed and tested at a variety of scales, including in vitro cell culture systems, murine xenografts, and mouse cancer models. In addition, we will extend our computational models of mitogenic signaling to include transcriptional regulatory networks, to provide a more global, quantitative model of cellular regulation in response to oncogenic mutation. The ultimate goal is to apply these quantitative models to directly test their relevance in predicting responsiveness of human tumors to selected chemotherapeutic agents. We will integrate this mitogenic signaling network program with the other core programs in this Center, to understand how mitogenic signaling networks activated by EGFR and Ras mutants may affect chemotherapeutic sensitivity (DNA Damage Signaling Networks/Therapeutics) and cell invasion and metastasis (Migration Signaling Networks).
Specific Aim 1 - Logic and mechanistic modeling of the ErbB network
Specific Aim 2 - Integrating proteomic and transcriptomic networks
Specific Aim 3 - Network dysregulation by EGFR mutations
Specific Aim 4 - Network dysregulation by K-ras mutations