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，随后红细胞的溶解释放出有毒水平的血红素，然后在大脑中释放出危险的过量游离铁。血红素（HPX）不仅与血液中过量的血红素结合，而且可能发出一种遗传反应，以适应性地调节大脑中细胞内铁稳态途径，以适应出血性应激。我们正在评估HPX如何控制铁调节蛋白（IRP1和IRP2）依赖的铁蛋白（Ftn，用于铁的安全储存）和转铁蛋白受体（TfR，用于铁的摄取）的转录后表达，以优化铁稳态途径，更好地保护大脑神经元。至关重要的是，我们将确定HPX如何修改IRP调节网络，以自适应地控制铁转运蛋白的神经元翻译（用于铁出口）及其翻译