Consequences of TE dyshomeostasis and TE induced neurotoxicity on inflammation in C. elegans

由于微量元素(TE)在几种酶反应中扮演着不可或缺的角色，其体内平衡的失衡被认为是一系列疾病的危险因素。TE具有调节已知在衰老过程中改变的代谢途径的能力，如炎症和氧化过程。此外，众所周知，单个TE的动态平衡在炎症条件下以不同的方式调节，但知识仍然很少，对衰老有机体各自的后果也知之甚少。这些知识差距将通过使用实验模型秀丽线虫(线虫)来解决。线虫免疫系统由祖先免疫系统组成，对线虫免疫的研究有助于探索线虫在天然免疫信号中的作用。这个模型的复杂性降低，加上它的遗传易控性，使得可以详细描述炎症条件下免疫信号级联及其对TE稳态的影响。此外，我们还将深入了解在炎症背景下TE状态的变化是加速还是异常衰老和神经元衰老。因此，年龄特定的TE组合以及炎症特定的TE组合将被长期喂养给老化的蠕虫。饲养条件将以一种方式进行调整，以产生与在线虫和小鼠研究中观察到的特定年龄和炎症特定的TE分布相媲美的系统性TE分布。由于先天性免疫与其他信号系统之间的系统相互作用，如应激反应和参与调节寿命的机制，TE暴露的蠕虫将被评估不同的终点，包括寿命、与年龄相关的变化、氧化应激和神经退化。由于炎症已被证明在神经退行性疾病的发病机制中起作用，因此将使用神经退行性疾病的蠕虫模型来表征神经炎症是否导致异常的TE稳态。这些蠕虫将进一步用于确定药物疾病治疗对TE动态平衡的影响，因为有证据表明氨基糖苷类化合物对硒(Se)代谢的相互作用。识别影响TE代谢的相关生化途径，发现炎症和神经炎症的后果，将有助于更好地了解年龄相关疾病的病因，并可能指示维持相应病理中的动态平衡所需的TE的最佳摄入量。

Since trace elements (TE) occupy indispensable roles in several enzymatic reactions, imbalances of their homeostasis are supposed to be a risk factor for a broad range of diseases. TE have the capacity to modulate metabolic pathways known to be altered during aging, such as inflammatory and oxidative processes. Additionally, it is well-established that the homeostasis of single TE are regulated in a different manner under conditions of inflammation, but knowledge is still rare and the respective consequences for the aging organism are poorly understood. These gaps of knowledge will be addressed by the usage of the experimental model Caenorhabditis elegans (C. elegans). Comprising an ancestral immune system, studies on nematode immunity can be instructive in exploring TE roles in innate immune signaling. The reduced complexity of this model together with its genetic tractability allows a detailed characterization of the immune signaling cascade and consequence for the TE homeostasis in inflammatory conditions. Additionally, we will gain insights whether changes in the TE status hasten or aberrant aging and neuronal aging in the background of inflammation. Thereby age-specific, as well as inflammatory-specific TE combinations will be fed chronically to aging worms. The feeding conditions will be adapted in a way to result in systemic TE profiles which are comparable to the age-specific and inflammatory-specific TE profiles observed in the nematode and mouse studies. Due to the systemic interactions between innate immunity and other signaling systems, such as stress responses and mechanisms involved in the regulation of longevity, different endpoints including lifespan, age-related changes, oxidative stress and neurodegeneration will be assessed in the TE exposed worms. Since inflammation has been shown to play a role in the pathogenesis of neurodegenerative disorders worm models for neurodegenerative diseases will be used in order to characterize whether neuroinflammation results in an aberrant TE homeostasis. The worms will further be used to identify consequences of drug-based disease treatments on TE homeostasis since evidence suggests the interactions of aminoglycosides on the selenium (Se) metabolism. The identification of relevant biochemical pathways affecting TE metabolism and spotting consequences of inflammation and neuroinflammation will help to better understand age-related disease etiologies and might indicate the required optimal intake of the TE to maintain homeostasis in the respective pathology.