Mechanisms and Regulation of Brain Iron Uptake

脑铁吸收的机制和调节

• 批准号: 10530586
• 负责人: JAMES Robert CONNOR
• 金额: $ 52.77万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530586
• 关键词: Address; Adult; Affect; Age; Alzheimer' s Disease; Animal Model; Astrocytes; Biological; Blood; Blood - brain barrier anatomy; Brain; Carrier Proteins; Cell Culture Techniques; Cell model; Cells; Cerebrospinal Fluid; Clinical; Cognitive; Data; Development; Endothelial Cells; Extracellular Fluid; Ferritin; Genotype; H ferritin; Health; Human; In Vitro; Injections; Intervention; Intravenous; Investigation; Iron; Knowledge; Metabolic; Modeling; Mus; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Neurologic Process; Neurotransmitters; Oral; Organ; Oxidative Stress; Oxygen; Parkinson Disease; Physiological; Production; Proteins; Public Health; Publishing; Regulation; Restless Legs Syndrome; Role; Side; Signal Transduction; Surface; System; Testing; Therapeutic; Transferrin; Translations; Work; brain endothelial cell; clinically relevant; cognitive performance; experimental study; hearing impairment; improved; in vivo; in vivo Model; indexing; induced pluripotent stem cell; iron deficiency; iron supplementation; myelination; nervous system disorder; novel; oxygen transport; pre-clinical; receptor; response; sex; stem; stem cell differentiation; transcytosis; uptake

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.

项目摘要 铁向大脑的递送对于多种神经过程，例如髓鞘，神经递质至关重要 合成及其适用于所有器官，用于利用氧气来产生能量。以前，我们 引入并确定了以下概念：脑铁吸收受到调节的调节 血脑屏障（BBB），这与BBB内皮细胞服务的广泛概念相反 作为传递转铁蛋白的简单导管。我们还确定了h-铁蛋白，从经典上看 细胞内铁储存蛋白，作为大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和足够数量获得铁的问题。 长期神经系统在临床上表现出及时发育过程中及时铁的重要性 发育铁缺乏的认知影响。法规对充分管理的重要性 在成人大脑中输送的铁量在临床上表现在神经系统疾病中，例如不安 腿综合征（铁太小）和神经退行性疾病（铁太多）。尽管有盛行的意见 BBB是一个简单的导管，没有明显的调节脑铁吸收的机制，我们 确定年龄，基因型，性别和全身铁状态是与改变有关的生理因素 脑铁的获取。我们发现的直接翻译相关性将与全身治疗有关 铁缺乏症，通常用静脉注射或口服铁进行积极治疗 补充。这些策略导致了有关关注的关注的大量公共卫生辩论 治疗可能会覆盖脑摄取机制并增加脑铁的积累，从而导致氧化 压力和神经退行性疾病。因此，在此解决的最重要的知识差距 应用是如何调节脑铁的方式。该提议的科学前提是 转铁蛋白和h-铁蛋白用作铁载体，并被不同的 受体，但这两种蛋白质及其铁货物的释放是由信号协调的 从大脑中的脑脊液和细胞外液中。当前建议的主要目标 将使用血脑屏障的人类内皮细胞培养模型（AIM 1）和临床上解决 相关的动物模型（目标2），以询问脑铁的基本机制和 调节，以及确定脑铁的临床上的铁状态指标。来自 拟议的研究是：1）如何调节脑铁的摄取，这与是否可以治疗有关 预计会起作用，2）H-铁蛋白是否代表一种用来充实脑铁的新型铁输送系统， 3）哪些条件会影响铁的吸收，从而促进策略。