Interactions of trace elements in modulating the immune response during acute and chronic inflammation in mice

我们假设特定年龄的微量元素(TE)图谱正在调节氧化还原敏感的转录因子Nrf2的活性。反之亦然，Nrf2被认为通过改变TE转运和结合蛋白的表达来调节全身TE状态，例如在肠道中。为了解决这些问题，我们的目标是在小鼠和老年小鼠中进行喂养实验，喂饲适量或不适量的六种必需TE，包括铜、铁、碘、锰、硒和锌。此外，我们还将建立“青年适应”和“老年适应”的TE饮食，这将模仿人类史诗参与者的年轻人和老年人的TE状态。与人类研究相比，一个巨大的优势是可以获得小鼠组织样本，其中将与研究股的所有实验小组密切合作，研究不同TE饮食的影响。我们将重点关注肝脏和肠道。利用这些组织，我们将把TE谱、TE生物标志物、TE特异性结合蛋白和衰老标志物与Nrf2途径的活性联系起来。我们的目标是鉴定新的依赖Nrf2的基因，这些基因与幼年和老年小鼠的TE动态平衡和肠道TE吸收相关。为了确定Nrf2调控的TE效应部分，我们将对Nrf2基因敲除(KO)小鼠进行平行研究。年轻和老年WT和Nrf2-KO小鼠之间的潜在差异可能为特定年龄的TE图谱提供了解释。

We hypothesize that age-specific trace element (TE) profiles are modulating the activity of the redox-sensitive transcription factor Nrf2. Vice versa, Nrf2 is supposed to regulate the systemic TE status by changing the expression of TE transport and binding proteins, e.g., in the intestine. To address these points we aim to conduct feeding experiments in young and old mice fed with adequate or suboptimal amounts of six essential TE, including Cu, Fe, I, Mn, Se, and Zn. In addition, we will establish "young-adapted" and "old-adapted" TE diets, which will mimic the TE status of young and old human EPIC participants. A great advantage over human studies is the availability of murine tissue samples, in which effects of different TE diets will be studied in close collaboration with all experimental groups of the Research Unit. We will focus on the liver and the intestine. Using these tissues we will correlate TE profiles, TE biomarkers, TE-specific binding proteins, and aging markers with Nrf2 pathway activity. We aim to identify new Nrf2-dependent genes relevant for TE homeostasis and intestinal TE absorption both in young and old mice. To identify the Nrf2-modulated part of TE effects, Nrf2 knockout (KO) mice will be studied in parallel. Potential differences between young and old WT and Nrf2-KO mice may provide an explanation for age-specific TE profiles.