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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，主要的炎症细胞因子，白细胞介素-1 (IL-1)，在APP mRNA的稳态水平完全没有变化的情况下，将APP的合成上调了15倍。IL-1和铁水平显著调节APP- mrna翻译（以及β肽水平），这与铁调节蛋白（IRPs）与APP 5'UTR序列（IRE-Type II序列）相互作用的改变有关。已知铁内流通过去除与APP 5‘ utr序列相关的5’非翻译区特异性RNA茎环中的IRP，将铁蛋白mrna从翻译抑制中释放出来。