Modeling Intracellular Mechanisms of Hypoxic Response

描述(申请人提供)：维持氧平衡对人类生命至关重要。低氧应激与缺血性中风、肿瘤生长和运动疲劳有关。然而，细胞对低氧的反应背后的分子机制--在健康的人类中，更不用说在疾病中了--在很大程度上让研究人员摸不着头脑。1993年发现的低氧诱导因子1(HIF1)是一种可以激活70多个基因的转录因子，它揭示了细胞如何感知氧气水平并对氧气水平做出反应。在这项提案中，将使用计算方法来开发HIF1通路的理论模型。该模型由代表HIF1α降解和HIF1合成的生化动力学方程和传递函数组成，将检验关于低氧下血管适应的基本分子机制的假设。在特定的目标1中，该模型将用于预测HIF1通路在不同程度的低氧条件下对P53和Pro羟基酶浓度的敏感性。在具体目标2中，将描述间歇性和慢性缺氧对HIF1α降解的不同影响。计算结果将通过实验数据进行验证。

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.