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

TE 稳态失调和 TE 诱导的神经毒性对秀丽隐杆线虫炎症的影响

• 批准号: 349847476
• 负责人: Professorin Dr. Julia Bornhorst
• 金额: --
• 依托单位: Arbeitsgruppe Lebensmittelchemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/349847476?language=en
• 关键词: Consequences; TE; dyshomeostasis; induced; neurotoxicity

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.

由于微量元素（TE）在多种酶促反应中起着不可或缺的作用，其体内平衡失衡被认为是多种疾病的危险因素。TE具有调节已知在衰老过程中被改变的代谢途径的能力，例如炎症和氧化过程。此外，在炎症条件下，单个TE的内稳态以不同的方式调节，这一点已经得到了证实，但这方面的知识仍然很少，对衰老生物体的相应后果也知之甚少。这些知识的空白将通过使用实验模型秀丽隐杆线虫（秀丽隐杆线虫）来解决。线虫免疫系统是一种祖先免疫系统，研究线虫免疫对探索TE在先天免疫信号传导中的作用具有指导意义。该模型的复杂性降低，加上其遗传易变性，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，我们将了解在炎症背景下TE状态的变化是否加速或异常衰老和神经元衰老。因此，年龄特异性以及炎症特异性TE组合将被长期喂给衰老的蠕虫。喂养条件将在某种程度上进行调整，以产生与线虫和小鼠研究中观察到的年龄特异性和炎症特异性TE谱相当的全身TE谱。由于先天免疫和其他信号系统之间的系统性相互作用，如应激反应和参与长寿调节的机制，将在TE暴露的蠕虫中评估不同的终点，包括寿命，年龄相关变化，氧化应激和神经退行性变。由于炎症已被证明在神经退行性疾病的发病机制中发挥作用，神经退行性疾病的蠕虫模型将被用于表征神经炎症是否导致异常TE内稳态。这些蠕虫将进一步用于确定基于药物的疾病治疗对TE稳态的影响，因为有证据表明氨基糖苷对硒（Se）代谢的相互作用。确定影响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与年龄相关的疾病病因，并可能指出维持各自病理稳态所需的TE的最佳摄入量。