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

微量营养素硒(Se)对最佳健康至关重要。英国人口的硒水平只是边缘水平，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许多重大疾病的风险。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的相互作用的影响也没有明确的定义。在这个项目中，我们将采用一种系统的方法来描述硒对肠道上皮细胞的影响以及一种特定的基因变异的影响。该项目还将为这种营养素-基因相互作用的分析提供一个原则证明。该工作计划将数学建模与体外分子技术、细胞系实验和转基因小鼠合作，以评估编码硒蛋白谷胱甘肽过氧化物酶的基因中的一个关键变异对硒摄入量的功能影响。将对硒蛋白和相关的生化途径进行测量，实验数据将用于完善硒蛋白代谢及其下游影响的数学模型。在这个项目中产生的系统模型将允许预测硒的供应如何调节生化途径和细胞功能。该模型在生理环境中的验证将为该模型未来在人体研究中的测试奠定基础。这一计划的主要成果将是确定新的硒状态功能生物标记物，用于以后的人类研究，并提高在不同生理水平上模拟与遗传因素有关的营养代谢的能力。

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.