RNA Therapeutics and Abeta Precursor Protein Translation

RNA 治疗和 Abeta 前体蛋白翻译

基本信息

批准号：
7116896
负责人：
JACK T ROGERS
金额：
$ 28.68万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7116896
关键词：
Alzheimer&apos 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

项目摘要

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）：阿尔茨海默氏蛋白的淀粉样蛋白（APP），例如铁蛋白，是一种普遍表达的金属蛋白，在消息翻译水平下受调节。我们表明，在完全没有对App mRNA的稳态水平的变化的情况下，原发性炎症细胞因子，白介素-1（IL-1），上调的APP合成最多可达15倍。 IL-1和铁水平显着调节APP-MRNA翻译（和ABETA肽水平）与铁调节蛋白（IRP）和APP 5'UTR序列（IRE-Type II序列）之间的相互作用发生了变化相关。已知铁的流入通过与App 5'UTR序列相关的5'未翻译区域特异性RNA茎卢普从5'未翻译区域特异性RNA茎卢斯中删除IRP来释放铁蛋白mRNA。了解该应用程序5'UTR提供的法规将使我们能够更好地识别降低应用程序翻译和ABETA肽水平的药用化合物。最近已经开发了用于使用小分子来抑制病毒感染的策略，包括针对内部核糖体进入部位乙型肝炎病毒的策略。铁氯芯蛋白甲胺（DF）（MW 650）和新型的抗胆碱酯酶Phenserine（PS）（MW 480）抑制App 5'UTR驱动的APP转换以减少淀粉样蛋白输出，以这种序列作为Alzheimer的治疗靶标的使用。我们将：1。定义APP mRNA中顺式作用IL-1-和铁响应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desferrioxamine和抗胆碱酯酶Phenserine示例的小分子提供治疗靶标。 3。检验以下假设：在应用程序5“ UTR中介导IL-1信号以增加APP翻译的App 5”中，铁调节蛋白（IRP-1和IRP-2）与RNA结构的结合。小分子可以通过这种途径来降低App Pynthesisis和Abeta蛋白肽的输出。