Modeling Intracellular Mechanisms of Hypoxic Response

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Maintaining oxygen homeostasis is critical for human life. Hypoxic stress has been associated with ischemic stroke, tumor growth and fatigue in exercise. Yet molecular mechanisms underlying cellular response to low oxygen - in healthy humans, let alone in disease - have largely eluded researchers. The 1993 discovery of hypoxia-inducible factor 1 (HIF1), a transcription factor that activates over 70 genes, shed some light onto how cells sense and react to oxygen levels. In this proposal, computational methods will be used to develop a theoretical model of HIF1 pathways. The model, comprised of biochemical kinetic equations and transfer functions that represent HIF1 alpha degradation and HIF1 synthesis, will test hypotheses about the fundamental molecular mechanisms of vascular adaptation in hypoxia. In Specific Aim 1, the model will be used to predict the sensitivity of the HIF1 pathway to p53 and prolyl hydroxylase concentrations in varying degrees of hypoxia. In Specific Aim 2, differential effects of intermittent and chronic hypoxia on HIF1 alpha degradation will be characterized. Computational results will be validated by experimental data.