Systems biology approach to defining impact of a genetic variant of GPx4 and selenium intake

微量元素硒（Se）对最佳健康至关重要。英国人口的硒水平很低，不仅可能增加病毒感染的风险，还可能增加包括前列腺癌和结肠癌在内的一些主要疾病的风险。然而，硒摄入量影响肠道健康的机制尚不清楚，硒摄入量与遗传因素之间相互作用的影响也未明确。在这个项目中，我们将采用系统的方法来描述硒对肠上皮的影响和特定遗传变异的影响。该项目还将为这种营养-基因相互作用的分析提供原理证明。该项目将把数学建模与体外分子技术、细胞系实验和转基因小鼠研究结合起来，评估硒蛋白谷胱甘肽过氧化物酶编码基因中一个关键变异对硒摄入量的功能影响。测量硒蛋白和相关的生化途径，实验数据将用于完善硒蛋白代谢及其下游效应的数学模型。在这个程序中产生的系统模型将允许预测硒供应如何调节生化途径和细胞功能。在生理背景下验证该模型将为未来在人体研究中测试该模型奠定基础。该项目的主要成果将鉴定出新的硒状态的功能性生物标志物，用于后期的人体研究，并提高在不同生理水平上与遗传因素相关的营养代谢模型的能力。

The micronutrient selenium (Se) is critically important for optimal health. The Se status of the UK population is only marginal and may increase risk not only of viral infections but also of a number of major diseases including prostate and colon cancer. However, the mechanisms by which Se intake affects gut health are poorly understood and the impact of interactions between Se intake and genetic factors not defined. In this project we will adopt a systems approach to describe the effects of Se on the intestinal epithelium and the impact of a specific genetic variant. The project will also provide a proof of principle of for such analysis of nutrient-gene interactions. The programme of work will combine mathematical modelling with in vitro molecular techniques, experiments in cell lines and work with transgenic mice to assess the functional effects of a key variant in the gene that codes for the selenoprotein glutathione peroxidase in response to Se intake. Measurements will be made of selenoproteins and related biochemical pathways and the experimental data will be used to refine a mathematical model of selenoprotein metabolism and its downstream effects. The systems model generated in this programme will allow prediction of the how Se supply modulates biochemical pathways and cell function. Validation of the model in a physiological context will lay the basis for future testing of the model in human studies. The major outcomes from this programme will identification of novel functional biomarkers of Se status for use in later human studies and an increased ability to model nutrient metabolism at different physiological levels in relation to genetic factors.