Mechanisms and Regulation of Brain Iron Uptake

项目总结 向大脑输送铁对多种神经过程是必不可少的，如髓鞘形成、神经递质 合成，和所有器官一样，用于利用氧气生产能量。此前，我们 引入并确立了脑铁摄取是在血管内皮细胞水平上调节的概念。 血脑屏障(BBB)，这与人们普遍认为的血脑屏障内皮细胞服务的概念相反 作为传递转铁蛋白的简单管道。我们还鉴定了H-铁蛋白，经典地认为是一种 细胞内铁储存蛋白，作为一种重要的大脑铁输送蛋白。这两个新概念 开始解决大脑如何及时和充足地获取铁的问题。 在发育过程中及时提供铁的重要性在临床上表现在长期的神经系统上。 以及发育性缺铁对认知的影响。监管对充分管理环境的重要性 在成人大脑中输送的铁的数量在临床上表现为神经紊乱，如躁动不安 腿部综合症(铁过少)和神经退行性疾病(铁过多)。尽管普遍存在这样的观点 血脑屏障是一种简单的管道，没有调节大脑铁摄取的明显机制，我们 将年龄、基因、性别和全身铁状态确定为与改变相关的生理因素 脑铁质的获得。我们发现的直接翻译相关性将与系统性红斑狼疮的治疗有关。 一种缺铁症，通常通过静脉注射铁或口服铁来治疗 补充。这些战略引发了相当大的公共卫生辩论，人们担心这些 治疗可以推翻大脑摄取机制，增加大脑铁积累，导致氧化 压力和神经退行性疾病。因此，本报告中解决的最显著的知识差距 应用是大脑铁获得的调节方式。这项提议的科学前提是 转铁蛋白和H-铁蛋白作为铁载体，通过不同的途径被血脑屏障内皮细胞摄取 但这两种蛋白质的释放和它们的铁载体进入大脑是由信号协调的 大脑中的脑脊液和细胞外液。当前提案的主要目标是 将使用血脑屏障的人类内皮细胞培养模型(目标1)来解决，并在临床上 相关动物模型(目标2)，以询问脑铁获得和 本研究的目的是为了更好地控制和控制铁的摄入，以及确定临床铁状态指标对脑铁获取的影响。可交付成果来自 建议的研究是：1)大脑铁摄取是如何调节的，这与治疗是否可以 预期是否有效，2)H-铁蛋白是否代表了一种用于补充脑铁的新的铁输送系统， 以及3)什么条件会影响铁的摄取，从而影响再补充策略。

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.