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

确定 GPx4 遗传变异和硒摄入量影响的系统生物学方法

• 批准号: BB/H011471/1
• 负责人: John Hesketh
• 金额: $ 103.67万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH011471%2F1
• 关键词: Systems; biology; approach; defining; impact

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.

微量营养素硒（Se）对最佳健康至关重要。英国人口的硒状态只是边缘，不仅可能增加病毒感染的风险，而且可能增加一些主要疾病的风险，包括前列腺癌和结肠癌。然而，硒摄入量影响肠道健康的机制知之甚少，硒摄入量和遗传因素之间的相互作用的影响没有定义。在这个项目中，我们将采用系统的方法来描述硒对肠上皮细胞的影响和特定的遗传变异的影响。该项目还将为营养素-基因相互作用的这种分析提供原理证明。该工作方案将把联合收割机数学模型与体外分子技术、细胞系实验结合起来，并与转基因小鼠合作，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体对硒摄入量的反应的功能影响。测量将硒蛋白和相关的生化途径和实验数据将被用来完善硒蛋白代谢及其下游效应的数学模型。该计划中生成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。该模型在生理环境中的验证将为未来在人体研究中测试该模型奠定基础。该计划的主要成果将确定硒状态的新功能生物标志物，用于以后的人类研究，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。

项目成果

Modeling and gene knockdown to assess the contribution of nonsense-mediated decay, premature termination, and selenocysteine insertion to the selenoprotein hierarchy.

• DOI: 10.1261/rna.055749.115
• 发表时间: 2016-07
• 期刊: RNA (New York, N.Y.)
• 作者: Zupanic A;Meplan C;Huguenin GV;Hesketh JE;Shanley DP
• 通讯作者: Shanley DP

Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21-Mediated Early Senescence Signalling.

• DOI: 10.1371/journal.pcbi.1004246
• 发表时间: 2015-05
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Dolan DW;Zupanic A;Nelson G;Hall P;Miwa S;Kirkwood TB;Shanley DP
• 通讯作者: Shanley DP

Detecting translational regulation by change point analysis of ribosome profiling data sets.

• DOI: 10.1261/rna.045286.114
• 发表时间: 2014-10
• 期刊: RNA (New York, N.Y.)
• 作者: Zupanic A;Meplan C;Grellscheid SN;Mathers JC;Kirkwood TB;Hesketh JE;Shanley DP
• 通讯作者: Shanley DP

Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort

• DOI: 10.1002/ijc.29071
• 发表时间: 2015-03-01
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Hughes, David J.;Fedirko, Veronika;Hesketh, John E.
• 通讯作者: Hesketh, John E.