Post Transcriptional Control of hemorrhagic iron damage.

出血性铁损伤的转录后控制。

• 批准号: 8383920
• 负责人: JACK T ROGERS
• 金额: $ 25.02万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383920
• 关键词: 5' Untranslated Regions; Address; Affect; Affinity; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Astrocytes; Binding; Blood; Blood Cells; Brain; Brain hemorrhage; Ceruloplasmin; Cytolysis; Cytoprotection; Elements; Erythrocytes; Event; Experimental Models; Ferritin; Gene Expression; Genes; Genetic; Goals; Heme; Heme Iron; Hemopexin; Hemorrhage; Homeostasis; Human; Injection of therapeutic agent; Iron; Iron-Regulatory Proteins; Knock-out; Knockout Mice; Mediating; Messenger RNA; Neurons; Oxidative Stress; Pathway interactions; Post-Transcriptional Regulation; Publishing; Reaction; Research; Role; Signal Transduction; Site; Stress; Testing; Transferrin Receptor; Translations; Wild Type Mouse; brain cell; collagenase; in vivo; insight; iron metabolism; metal transporting protein 1; mutant; novel; protein expression; response; secretase; stem; uptake

DESCRIPTION (provided by applicant): After hemorrhagic stroke, subsequent lysis of red blood cells releases toxic levels of heme and then a dangerous excess of free iron in the brain. Hemopexin (HPX) not only binds to excess heme in the blood, but may signal a genetic response to adaptively modulate intracellular iron homeostatic pathways in the brain to adapt to hemorrhagic stresses. We are assessing how HPX controls Iron-regulatory Protein (IRP1 and IRP2) dependent post-transcriptional expression of ferritin (Ftn, for safe iron storage), and transferrin receptor (TfR for iron uptake) in order to optimize iron homeostasis pathways to better protect brain neurons. Critically, we will determine how HPX modifies the IRP regulatory network to adaptively control neuronal translation of ferroportin (for iron export) and that of its binding partner, the amyloid precursor protein (APP). Our lab showed that APP(s) provides significant and novel protective ferroxidase action that also facilitates ferroportin dependent efflux of excess iron from vulnerable neurons. Upon iron influx, IRP1 and IRP2 dissociate from IREs thus releasing Ftn and APP from a translational block for safe storage of iron. Thus our goal is to determine how hemopexin favorably resets this IRE-mediated IRP1/IRP2 control of APP and ferritin gene expression and thereby promotes safe neuronal iron export and storage. Both ferritin and APP confer cytoprotection as active ferroxidases converting Fe2+ to its storage form of Fe3+. To start this reaction excess iron binds REXXE domain in secreted APP(s) and then oxidizes and safely transports/stores it in ferritin. Here, we will test the sufficiency of ths pathway to protect neurons against heme-aggravated damage. We will set up the experimental model of collagenase injection to experimentally induce hemorrhage. It will then be possible to address how hemopexin induces these neuroprotective responses against excess iron from heme by modulating the activity of the REXXE domain in APP and via the iron- responsive elements (IRE) stem loops in the 5'untranslated regions of APP and ferritin mRNAs. ' PUBLIC HEALTH RELEVANCE: This research will provide fundamental information about how iron homeostasis in human brain cells is affected by the hemopexin, which is the known protective scavenger of toxic heme as released after hemorrhagic stroke. We will seek direct evidence that hemopexin can generate signals via iron regulatory proteins to APP and ferritin to better protect to neurons from iron excess. We believe that the novel ferroxidase activity imparted by secreted APP and cellular ferritin mediates this protection to neurons at an accelerated rate when hemopexin is present.

描述（由申请人提供）：出血性中风后，随后的红细胞裂解会释放出毒性水平的血红素水平，然后在大脑中散发出危险的自由铁。血红素（HPX）不仅与血液中过量血红素结合，而且可能表明对适应性调节大脑中细胞内的铁稳态途径的遗传反应，以适应出血应激。 我们正在评估HPX如何控制铁蛋白（FTN，用于安全铁储存）和转铁蛋白受体（用于铁的摄取的TFR）的依赖性后的铁调节蛋白（IRP1和IRP2），以优化铁稳态途径，以更好地保护脑神经元。至关重要的是，我们将确定HPX如何修改IRP调节网络以适应性地控制铁蛋白的神经元翻译（用于铁的出口）及其其的神经元翻译 结合伴侣，淀粉样蛋白前体蛋白（APP）。我们的实验室表明，应用程序提供了重要的新型保护性铁氧化酶作用，从而促进了弱势神经元中过量铁的依赖铁皮素的外排。铁涌入后，IRP1和IRP2从IRES中解散，从而从翻译块中释放出FTN和APP以安全地存储铁。因此，我们的目标是确定血压素如何有利地重置对APP和铁蛋白基因表达的IRP1/IRP2控制，从而促进安全的神经元铁的出口和储存。 铁蛋白和APP将细胞保护作为活性铁氧化酶转化为Fe2+的活性铁氧化酶。为了开始这种反应，多余的铁在分泌的应用中结合了rexxe结构域，然后氧化并安全地将其运输/存储在铁蛋白中。在这里，我们将测试THS途径的充分性，以保护神经元免受血红素造成的伤害。我们将建立胶原酶注射的实验模型，以实验诱导出血。然后，可以通过调节APP中REXXE结构域的活性以及通过APP和铁蛋白mRNA的5'untranslated区域中的铁反应元素（IRE）茎环调节，可以解决血红素如何通过调节APP中REXXE结构域的活性（IRE）的茎环，从而解决对血红素过量铁的这些神经保护反应。 ' 公共卫生相关性：这项研究将提供有关人脑细胞中的铁稳态如何受到血压素影响的基本信息，呼吸毒素是出血性中风后释放的已知的毒性血红素的保护性清除。我们将寻求直接的证据，表明血压素可以通过铁调节蛋白产生信号，以便更好地保护神经元免受铁的过量保护。我们认为，当存在性血红素时，由分泌的应用和细胞铁蛋白赋予的新型铁氧化酶活性以加速的速率介导了这种保护。