Mechanisms and Regulation of Brain Iron Uptake

描述（由申请人提供）：通常，但错误的是，假设我们了解铁如何进入大脑。现有范式的问题在于，它认为形成血脑屏障的内皮细胞只是作为与转铁蛋白结合的铁通过的管道。这种范式在多个方面存在明显缺陷，但最值得注意的是，它未能解释内皮细胞的铁需求或调节脑铁摄取的机制。这个建议的概念框架是，BBB的内皮细胞，远不是作为一个简单的管道，是调节脑铁代谢的焦点。我们提出了在体内和细胞培养的方法来研究脑铁摄取的动态。我们假设，血脑屏障内皮细胞存储铁，可以释放到大脑中的细胞外液中发现的外部因素的反应，从而首次证明了铁进入大脑的运动的调节系统。因此，在完成所提出的研究后，我们将建立一个重要的和范式转变的概念，即内皮细胞控制铁进入大脑，以响应其细胞外环境。此外，该提议将对脑铁转运的现有范例做出以下具体的新贡献：（i）增加铁转运的新机制（ii）证明通过膜结合铁输出蛋白ferroportin从内皮细胞释放非转铁蛋白结合的铁（iii）揭示从内皮细胞释放铁的调节（iv）揭示内皮细胞储存铁，其可以响应于CSF或细胞外液中的蛋白质水平而释放（v）揭示了内皮细胞中转铁蛋白受体的调节响应于细胞内铁库，表明形成BBB的内皮细胞的铁含量是转铁蛋白介导的脑铁摄取被调节的位点。此外，拟议的研究将扩大我们对微血管中铁管理蛋白谱动态的了解，这将为人类微血管研究提供信息，例如我们最近在不宁腿综合征患者微血管中的发现，或尽管血液学参数已解决，但与铁缺乏相关的CSF蛋白谱的长期变化。因此，本文提出的研究是必不可少的，以告知我们的功能意义的改变轮廓状态的微血管和CSF中的神经系统疾病。最重要的是，这些研究旨在了解脑铁摄取的调节以及释放和运输系统的适应性。内皮细胞中存在对脑源性信号作出反应的适应性系统是脑铁转运的一个全新概念，并将影响发育性铁缺乏症和涉及脑铁稳态受损的成人神经系统疾病的治疗概念。 公共卫生相关性：这项研究的长期目标是了解大脑铁获取的动态，并将这些知识应用于可能导致神经系统疾病的适应不良。许多常见的神经系统疾病，如阿尔茨海默病，帕金森病和不宁腿综合征涉及脑铁稳态的丧失。此外，缺铁及其相关的长期认知和运动障碍是世界上最普遍的营养障碍。因此，了解铁进入大脑的机制以及这些机制是如何调节的，将使我们能够解决重大的全球健康问题。

DESCRIPTION (provided by applicant): It is commonly, but wrongly, assumed that we understand how iron gets into the brain. The problem with the existing paradigm is that it holds that the endothelial cells forming the blood-brain barrier serve simply as a conduit through which iron bound to transferrin passes. This paradigm is significantly flawed in multiple points but most notably it fails to account for the iron requirements of the endothelial cells or for a mechanism for regulating brain iron uptake. The conceptual framework for this proposal is that the endothelial cells of the BBB, far from serving as a simple conduit, are the focal point for the regulation for cerebral iron metabolism. We propose both in vivo and cell culture approaches to investigate the dynamics of brain iron uptake. We postulate that BBB endothelial cells store iron that can be released into the brain in response to external factors that are found in the extracellular fluid; thus for the first time demonstrating a regulatory system for movement of iron into the brain. Thus, upon completion of the proposed studies we will establish the significant and paradigm shifting concept that the endothelial cells control access of iron to the brain in response to their extracellular environment. In addition, this proposal will make the following specific new contributions to the existing paradigm for brain iron transport (i) add a novel mechanism for iron transport (ii) demonstrate non-transferrin-bound iron release from endothelial cells via ferroportin, a membrane-bound iron export protein (iii) reveal regulation of iron release from endothelial cells (iv) reveal endothelial cells store iron, which can be released in response to levels of proteins in the CSF or extracellular fluid (v) reveal that regulation of transferrin receptors in endothelial cells are responsive to the intracellular iron pool indicating that the iron content of the endothelial cells forming the BBB is the site at which transferrin mediated brain iron uptake is regulated. Moreover, the proposed studies will expand our knowledge of the dynamics of the iron management protein profiles in the microvasculature which will inform studies on human microvasculature such as our recent findings in the microvasculature of individuals with Restless Legs syndrome or the long-term changes in CSF protein profiles associated with iron deficiency despite the resolution of hematologic parameters. Thus, the studies proposed herein are essential to inform us about the functional significance of the altered profile status in the microvasculature and CSF in neurological disease. Most importantly, the studies are designed to understand the regulation of brain iron uptake and the adaptability of the systems for release and transport. The existence of an adaptive system in endothelial cells that responds to brain-derived signals is a completely novel concept for brain iron transport and will impact treatment concepts for developmental iron deficiency and adult neurological disorders involving impaired brain iron homeostasis. PUBLIC HEALTH RELEVANCE: The long-term goal of this line of research is to understand the dynamics of brain iron acquisition and to apply this knowledge to the maladaptions that may contribute to neurological disease. Many common neurological disorders such as Alzheimer's Disease, Parkinson's Disease and Restless Legs Syndrome involve loss of brain iron homeostasis. Moreover, iron deficiency and its associated long term cognitive and motor impairments is the most prevalent nutritional disorder in the world. Therefore understanding the mechanisms by which iron gets into the brain and how those mechanisms are regulated will position us to address significant global health issues.