RNA Therapeutics and Abeta Precursor Protein Translation

RNA 治疗和 Abeta 前体蛋白翻译

• 批准号: 6773195
• 负责人: JACK T ROGERS
• 金额: $ 29.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6773195
• 关键词: Alzheimer' s disease; RNA binding protein; amyloid proteins; biotherapeutic agent; ferritin; gel mobility shift assay; genetic translation; immunoprecipitation; interleukin 1; messenger RNA; neoplastic cell; neurons; phosphorylation; tissue /cell culture; transfection; western blottings

DESCRIPTION (provided by applicant): The Alzheimer's Amyloid Precursor Protein (APP), like ferritin, is a ubiquitously expressed metaloprotein that is regulated at the level of message translatation. We showed that the primary inflammatory cytokine, Interleukin-1 (IL-1), up-regulated APP synthesis by up to 15-fold in the complete absence of changes to steady-state levels of APP mRNA. IL-1 and iron levels significantly regulate APP-mRNA translation (and ABeta peptide levels) correlated with changed interaction between Iron Regulatory Protein (IRPs) and APP 5'UTR sequences (IRE-Type II sequences). Iron influx is known to release ferritin mRNAs from translational repression by removal of IRP from 5' untranslated region specific RNA stemloops that are related to APP 5'UTR sequences. Understanding regulation conferred by the APP 5'UTR will enable us to better identify medicinal compounds that reduce APP translation and Abeta-peptide levels. RNA-directed strategies have recently been developed for the use of small molecules to suppress viral infections, including a strategy to target the internal ribosome entry site Hepatitis-C virus. The iron chlelator desferrioxamine (Df) (Mw 650) and the novel anticholinesterase, phenserine (Ps) (Mw 480) suppress APP 5'UTR driven translation of APP to reduce amyloid output, exemplifying the use of this sequence as a therapeutic target for Alzheimer's disease. We will: 1. Define the location and functional action of cis-acting IL-1- and iron-responsive RNA enhancers in APP mRNA and examine functional interactions between 5'UTR and 3'UTR sequences. 2. Determine how the unique folding of RNA encoded by the APP 5'UTR offers a therapeutic target for small molecules exemplified by desferrioxamine and the anticholinesterase, phenserine. 3. Test the hypothesis that altering the binding of Iron-regulatory proteins (IRP-1 and IRP-2) to RNA structures in APP 5"UTR mediates IL-1 signals to increase APP translation. Small molecules could well act by this pathway to decrease APP synthesis and concomitant ABeta-peptide output.

描述（由申请人提供）：阿尔茨海默病淀粉样前体蛋白（APP）与铁蛋白一样，是一种普遍表达的金属蛋白，在信息翻译水平上受到调节。我们发现，在 APP mRNA 稳态水平完全没有变化的情况下，主要炎症细胞因子白介素-1 (IL-1) 将 APP 合成上调高达 15 倍。 IL-1 和铁水平显着调节 APP-mRNA 翻译（和 Aβ 肽水平），与铁调节蛋白 (IRP) 和 APP 5'UTR 序列（IRE-II 型序列）之间相互作用的变化相关。已知铁流入可通过去除与 APP 5'UTR 序列相关的 5' 非翻译区特异性 RNA 茎环中的 IRP，从而将铁蛋白 mRNA 从翻译抑制中释放出来。 了解 APP 5'UTR 赋予的调节将使我们能够更好地识别降低 APP 翻译和 Abeta 肽水平的药物化合物。最近开发了RNA导向策略，用于使用小分子抑制病毒感染，包括针对丙型肝炎病毒内部核糖体进入位点的策略。铁螯合剂去铁胺 (Df) (Mw 650) 和新型抗胆碱酯酶苯酚 (Ps) (Mw 480) 可抑制 APP 5'UTR 驱动的 APP 翻译，从而减少淀粉样蛋白的输出，举例说明了该序列作为阿尔茨海默病的治疗靶点。我们将： 1. 定义 APP mRNA 中顺式作用 IL-1 和铁反应性 RNA 增强子的位置和功能作用，并检查 5'UTR 和 3'UTR 序列之间的功能相互作用。 2. 确定 APP 5'UTR 编码的 RNA 的独特折叠如何为去铁胺和抗胆碱酯酶、苯酚等小分子提供治疗靶点。 3. 检验以下假设：改变铁调节蛋白（IRP-1 和 IRP-2）与 APP 5"UTR 中 RNA 结构的结合可介导 IL-1 信号以增加 APP 翻译。小分子可以很好地通过此途径发挥作用，减少 APP 合成和伴随的 Aβ 肽输出。