Cells initiate a highly regulated and multifaceted program in response to changes in the availability of oxygen in the cellular environment. At the molecular level, the hypoxic program is mediated, in part, by the action of the HIF1α transcription factor and reactive oxygen species (ROS). While the hypoxic response is vital to normal physiology and development, it is also prevalent in tumorigenesis and other human diseases. In this study, we developed a family of mechanistic mathematical models of the signaling pathways involved in the Eukaryotic hypoxic response. We cataloged the molecular modules mediating different aspects and branches of the hypoxic response and integrated these modules into a single comprehensive model. The integrated hypoxia model, consisting of 548 molecular species interconnected by 920 interactions, was analyzed to determine critical points of network failure and possible sources of synergy between the pathways involved. Model parameters were estimated by comparing simulations with experimental data. We identified a population of models, consistent with data, using a novel multi-objective optimization framework called POET combined with a cross-validation scheme. Model analysis suggested the upstream regulation of the hypoxic signal was the most critical component of the hypoxia program. Furthermore, it also revealed the fragility of the pro-survival and cell growth related interactions. Synergistic effects between VEGF and IL8 signaling were mediated by PI3K and the MAPK cascade via the control of key transcription factors like AP1 and NF-κB. Lastly, knockout studies revealed the critical role of specific interactions regulating the stability of HIF1α and suggested network configurations that amplified or destroyed the hypoxic response. These simulated network configurations represent testable hypothesis that can be validated experimentally and potentially represent new strategies to manipulate the hypoxia program. While the current study was limited to analyzing the hypoxic response, a similar strategy could be used to study other disease state.
This preliminary program is subject to change.
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Modeling the Eukaryotic Hypoxic Response Revealed the Synergistic Role of VEGF and IL8 Signaling
Cells initiate a highly regulated and multifaceted program in response to changes in the availability of oxygen in the cellular environment. At the molecular level, the hypoxic program is mediated, in part, by the action of the HIF1α transcription factor and reactive oxygen species (ROS). While the hypoxic response is vital to normal physiology and development, it is also prevalent in tumorigenesis and other human diseases. In this study, we developed a family of mechanistic mathematical models of the signaling pathways involved in the Eukaryotic hypoxic response. We cataloged the molecular modules mediating different aspects and branches of the hypoxic response and integrated these modules into a single comprehensive model. The integrated hypoxia model, consisting of 548 molecular species interconnected by 920 interactions, was analyzed to determine critical points of network failure and possible sources of synergy between the pathways involved. Model parameters were estimated by comparing simulations with experimental data. We identified a population of models, consistent with data, using a novel multi-objective optimization framework called POET combined with a cross-validation scheme. Model analysis suggested the upstream regulation of the hypoxic signal was the most critical component of the hypoxia program. Furthermore, it also revealed the fragility of the pro-survival and cell growth related interactions. Synergistic effects between VEGF and IL8 signaling were mediated by PI3K and the MAPK cascade via the control of key transcription factors like AP1 and NF-κB. Lastly, knockout studies revealed the critical role of specific interactions regulating the stability of HIF1α and suggested network configurations that amplified or destroyed the hypoxic response. These simulated network configurations represent testable hypothesis that can be validated experimentally and potentially represent new strategies to manipulate the hypoxia program. While the current study was limited to analyzing the hypoxic response, a similar strategy could be used to study other disease state.