Circadian iron metabolism, implications for health, and response to inflammatory disease.

铁相关疾病是导致全球疾病的主要因素。根据世界卫生组织（世卫组织）的数据，全世界约有42%的6岁以下儿童和40%的孕妇患有贫血症，这是一种红细胞数量和红细胞内铁含量远低于正常水平的疾病。缺铁饮食和传染病，包括疟疾和结核病，在中低收入国家很常见，导致贫血。铁代谢的变化还与高收入国家常见的肝脏和代谢性疾病有关，并且在关节炎等慢性炎症中也很突出。从帮助我们的细胞产生能量到在我们的血液中携带氧气，铁对地球上的生命至关重要。然而，铁在生物过程中如此重要的化学性质，如果不严格控制这种营养物质的水平，也会导致毒性和细胞损伤。复杂的生物体，如人类和老鼠，有能力通过产生hepcidin来调节铁的水平，hepcidin是一种在肝脏内产生的激素，它可以减少消化系统对膳食铁的吸收，也可以减少细胞内储存铁的释放。在传染病期间，免疫反应产生的炎症信号也可以刺激Hepcidin，这被认为是为了限制入侵微生物的生长，因为它们也需要铁来生存。虽然刺激hepcidin有利于阻止微生物感染，但它可以提高以炎症为特征的常见疾病的严重程度，例如关节炎，一种常见的与年龄有关的疾病。在这些情况下，hepcidin受到炎症信号的刺激，导致铁水平降低，即使致病性感染不存在。这通常会导致铁的长期减少，从而导致贫血和其他健康问题。最近，我们的研究表明，小鼠肝脏内hepcidin的产生取决于一天中的时间。这一发现可以解释为什么在一天中的不同时间服用铁会影响铁的吸收。此外，在炎症中，hepcidin的节律发生变化，在一天中的不同时间达到峰值。我们现在对细胞如何记录时间有了很好的了解。有趣的是，一些对维持细胞内日常节律很重要的蛋白质可以被铁控制，进而控制铁的代谢。这表明铁和生物钟有着密切的关系，如果在疾病期间一个改变，另一个很可能也会受到影响。这项研究将确定这在多大程度上是正确的，并可能通过在一天中的特定时间提供治疗来开辟治疗铁失衡的新途径。老鼠是研究这种关系的一个很好的模型，因为它们调节铁和保持时间的方式与人类非常相似，我们将操纵老鼠体内的铁水平，以确定这对肝脏生物钟的影响。疾病期间经常发生铁或生物钟的破坏，炎症已被证明可以改变生物体中的铁水平和昼夜节律。我们将利用关节炎（一种常见的炎症性疾病）的小鼠模型，建立炎症的影响，这是许多疾病的共同特征。这将帮助我们确定炎症是如何破坏铁调节和生物钟的，并可能确定针对炎症条件的潜在药物靶点，这可能有助于改善对昼夜节律和铁通路的双重影响。这将有利于许多炎症性疾病，除了关节炎，一些常见的疾病，影响肝脏，以及肥胖和代谢紊乱。

Iron related disorders are a leading factor contributing to global diseases. According to the World Health Organisation (WHO) approximately 42% of children under the age of 6 years and 40% of pregnant women worldwide are anaemic, a condition in which the number of red blood cells and iron content within these cells are far lower than normal. Iron poor diets and infectious diseases, including malaria and tuberculosis, that are common in low to middle income countries, lead to anaemia. Changes to iron metabolism are also associated with common liver and metabolic diseases often observed in high income countries as well as being prominant in chronic inflammatory conditions such as arthritis. From helping our cells produce energy to carrying oxygen within our blood, iron is essential for life on earth. However, the chemical properties that make iron so important for biological processes can also lead to toxicity and cell damage if levels of this nutrient are not strictly controlled. Complex living organisms, like humans and mice, have the ability to regulate iron levels through the production of hepcidin, a hormone produced within the liver that reduces both the uptake of dietary iron within the digestive system and the release of stored iron reserves within cells. Hepcidin can also be stimulated by inflammatory signals produced by immune responses during an infectious disease, this is thought to occur to limit growth of invading micro-organisms as they also require iron to survive. Although the stimulation of hepcidin is beneficial in stopping a microbe infection it can enhance the severity of common diseases that are characterised by inflammation, such as arthritis, a common age-related illness. In these conditions hepcidin is stimulated by inflammatory signals causing reduced iron levels even though a pathogenic infection is not present. This often causes a long-term reduction in iron which can cause anaemia and other health problems. Recently, our studies have shown that the production of hepcidin within the liver of mice changes dependent on time of day. This finding may explain why taking iron at different times of day affects its absorption. Moreover, in inflammation the rhythm of hepcidin changes, with a peak at a different time of the day.We now have a good understanding of how cells can keep track of time. Interestingly, some proteins that are important in keeping a daily rhythm within cells can be controlled by iron and, in turn, control iron metabolism. This shows that iron and the circadian clock have an intimate relationship and it is likely that if one is changed during disease the other will also be affected. This study will determine to what extent this is true and would potentially open a new therapeutic avenue to treat iron imbalances by delivering treatments at specific times of the day. Mice are an excellent model to study this relationship as they regulate iron and keep time in a very similar manner to humans, and we will manipulate iron levels in mice to determine the effects this has on the circadian clock of the liver. Disruption to either iron or the circadian clock often occurs during disease, and inflammation has been shown to alter both iron levels and circadian rhythms in living organisms. We will establish the effect of inflammation, a common characteristic of many diseases, with use of a mouse model of arthritis, a common inflammatory disease. This will help us determine how inflammation contributes to the disruption of iron regulation and the circadian clock and may identify potential drug targets specific to inflammatory conditions that may help ameliorate dual effects on circadian and iron pathways. This will have benefits for many inflammatory diseases, aside from arthritis, a number of common diseases that affect the liver, as well as obesity and metabolic disorders.