Mechanisms and Regulation of Brain Iron Uptake

项目摘要 铁输送到大脑是必不可少的多种神经过程，如髓鞘形成，神经递质 合成，以及所有器官利用氧气产生能量。此前我们 引入并建立了脑铁摄取在内皮细胞水平上调节的概念， 血脑屏障（BBB），这与广泛持有的概念相反，即BBB内皮细胞 作为传递转铁蛋白的简单管道。我们还鉴定了H-铁蛋白，传统上被认为是 细胞内铁储存蛋白，作为脑的重要铁递送蛋白。这两个新概念 开始解决大脑如何及时获得足够数量的铁的问题。 在发育过程中及时提供铁的重要性在临床上表现为长期的神经系统疾病。 和认知能力的影响。监管对充分管理 在成人大脑中递送的铁的量在临床上表现为神经系统疾病， 腿部综合征（铁太少）和神经退行性疾病（铁太多）。尽管普遍认为 血脑屏障是一个简单的管道，没有明显的机制来调节脑铁的摄取，我们 确定年龄、基因型、性别和全身铁状态为与改变的铁相关的生理因素， 脑铁摄取我们的研究结果的直接翻译相关性将涉及到治疗系统性 铁缺乏，通常通过静脉注射铁或口服铁进行积极治疗 补充。这些策略引起了相当大的公共卫生辩论， 治疗可以覆盖脑吸收机制，增加脑铁积累，导致氧化性铁缺乏。 压力和神经退行性疾病。因此，本报告所述最重要的知识差距 应用是如何调节大脑铁的获取。这一建议的科学前提是， 转铁蛋白和H-铁蛋白充当铁载体，并通过不同的免疫调节剂被吸收到BBB的内皮细胞中。 但这两种蛋白质的释放及其铁货物进入大脑是由信号协调的 从脑脊髓液和脑细胞外液中分离出来本提案的主要目标 将使用血脑屏障的人内皮细胞培养模型（Aim 1）和临床 相关的动物模型（目的2），以询问脑铁获取的潜在机制， 调节，以及确定铁状态对脑铁获取的临床指标。可交付成果来自 建议的研究是：1）如何调节脑铁摄取，这与治疗是否可以 预期是否起作用，2）H-铁蛋白是否代表用于补充脑铁的新型铁递送系统， 和3）什么条件影响铁的吸收和因此的补充策略。

PROJECT SUMMARY Iron delivery to the brain is essential for multiple neurological processes such as myelination, neurotransmitter synthesis and, as it is for all organs, for the utilization of oxygen for energy production. Previously, we introduced and established the concept that brain iron uptake is regulated at the level of the endothelial cells of the blood-brain barrier (BBB), which is contrary to the widely held concept that the BBB endothelial cells serve as a simple conduit for the delivery of transferrin. We also identified H-ferritin, classically considered an intracellular iron storage protein, as a significant iron delivery protein for the brain. Both of these new concepts start to address the question of how iron is acquired by the brain in a timely manner and in adequate amounts. The importance of timely iron delivery during development is clinically manifested in the long term neurological and cognitive impact of developmental iron deficiency. The importance of regulation to adequately manage the amounts of iron delivered in the adult brain is clinically manifested in neurological disorders such as Restless Legs Syndrome (too little iron) and neurodegenerative diseases (too much iron). Despite the prevailing opinion that the BBB was a simple conduit with no apparent mechanism for regulation of brain iron uptake, we identified age, genotype, sex, and systemic iron status as physiological factors that are associated with altered brain iron acquisition. The immediate translational relevance of our findings will relate to treatment of systemic iron deficiency which is treated, often aggressively, with intravenous iron injections or oral iron supplementation. These strategies have led to considerable public health debate over concerns that these treatments could override brain uptake mechanisms and increase brain iron accumulation leading to oxidative stress and neurodegenerative diseases. Therefore, the most significant knowledge gap addressed in this application is how brain iron acquisition is regulated. The scientific premise for this proposal is that both transferrin and H-ferritin serve as iron carriers and are taken up into endothelial cells of the BBB by different receptors but the release of these two proteins and their iron cargo into the brain are coordinated by signals from the cerebrospinal fluid and extracellular fluid in the brain. The major objectives for this current proposal will be addressed using a human endothelial cell culture model of the blood-brain-barrier (Aim 1) and clinically relevant animal models (Aim 2) to interrogate the underlying mechanisms for brain iron acquisition and regulation, as well as to identify clinically indices of iron status on brain iron acquisition. The deliverables from the proposed studies are: 1) how brain iron uptake is regulated which is relevant to whether a therapy can be anticipated to work or not, 2) whether H-ferritin represents a novel iron delivery system for repleting brain iron, and 3) what conditions affect iron uptake and thus repletion strategies.