Investigation of the function of Zip14-mediated transient zinc-uptake into the liver during normal infection and sepsis

锌是人体多种功能所必需的微量元素。这一点通过以下观察得到强调：由营养不良或衰老或怀孕引起的锌缺乏会扰乱免疫细胞功能，并加速炎症性疾病（如败血症）的发作和进展。相反，在治疗肝纤维化或肝硬化、病毒性肝炎或酒精性肝病期间，补锌具有有益效果。在急性感染期间，锌被肝脏吸收，导致血清锌短暂下降。最近的研究结果表明，肝脏锌进口商Zip14负责锌转移到肝脏。然而，这一过程的功能意义以及潜在的机制并不完全清楚。通过在小鼠中通过Zip14敲除阻断Zip14介导的锌摄取，我们将阐明锌是否对肝脏代谢至关重要。此外，我们将调查，如果低血清锌浓度是必要的，以建立一个促炎免疫反应或抑制微生物增殖。我们还将研究预先存在的锌缺乏如何有助于脓毒症的发生和发展，重点是负责炎症反应的机制，这是组织破坏的一部分。最后，我们将研究在脓毒症发作后补充锌是否有益。这将包括使用不同剂量、时间点和锌给药重复的不同治疗策略的分析。

Zinc is an essential trace element for numerous body functions. This is underlined by the observation that zinc deficiency, caused by malnutrition or as a consequence of ageing or pregnancy, disturbs immune cell functions as well as it accelerates onset and progression of inflammatory diseases such as sepsis. In contrast, zinc supplementation had beneficial effects during treatment of liver fibrosis or cirrhosis, viral hepatitis or alcoholic liver disease. During acute infection, zinc is taken up by the liver, causing a transient decrease in serum zinc. Recent results indicate that the hepatic zinc importer Zip14 is responsible for this transfer of zinc into the liver. However, the functional significance of this process as well as the underlying mechanisms are not entirely clear. By blocking Zip14-mediated zinc uptake through Zip14 knockout in mice, we will clarify if zinc is vital for the liver metabolism. Moreover, we will investigate, if low serum zinc concentrations are necessary to establish a pro-inflammatory immune response or to inhibit microbial proliferation. We will also investigate how pre-existing zinc deficiency contributes to the onset and development of sepsis, focusing on the mechanisms responsible for the hyper-inflammatory response, which is responsible in part for tissue destruction. Finally, we will examine if zinc supplementation after sepsis onset can be beneficial. This will include analyses of different treatment strategies using various doses, time points and repeats of zinc administration.