Translational regulation in Alzheimer's Disease.

阿尔茨海默病的翻译调控。

基本信息

批准号：
7840405
负责人：
LESLIE A KRUSHEL
金额：
$ 30.28万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-15 至 2010-05-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7840405
关键词：
5&apos Untranslated Regions Acetylcholine Alzheimer&apos s Disease Amyloid beta-Protein Precursor Binding Binding Sites Blood Vessels Brain Cell Death Cellular Stress Cerebrovascular Disorders Cholinesterase Inhibitors Complex Data Dementia Disease Progression Drug Design Elements Etiology Genetic Transcription Goals Individual Internal Ribosome Entry Site Iron Ischemia Learning Link Messenger RNA Molecular Neuraxis Neurotransmitters Pathway interactions Peptides Process Protein Biosynthesis Proteins RNA-Binding Proteins Scanning Senile Plaques Signal Pathway Site Stimulus Structure Symptoms Therapeutic Intervention Toxic effect Translating Translation Initiation Translational Regulation Translations Untranslated Regions Work base hyperphosphorylated tau mouse model neuron loss phenserine research study response tau Proteins

项目摘要

DESCRIPTION (provided by applicant): Two hallmarks of Alzheimer's Disease (AD) are increased expression and aggregation of an insoluble peptide, derived through the cleavage of the amyloid precursor protein (APR) and hyperphosphorylation of the microtubule associated protein tau. Both processes are thought to contribute to cell death and inhibiting expression of both proteins is effective in ameliorating AD symptoms. The major mechanism whereby translation of eukaryotic mRNAs is initiated is through a cap-binding complex. The preinitiation complex, however, can also bind sites on the mRNA, termed internal ribosomal entry sites (IRESes) and initiate translation in a cap-independent manner. IRESes have been most extensively characterized in picornaviral mRNAs and little is known about IRESes in cellular mRNAs. IRES-dependent translation is unaffected or promoted by cellular stress. Interestingly, both vascular insults including ischemia and increased levels of iron in the central nervous system are two stressful stimuli that may predispose individuals or enhance the progression of AD. Indeed, in response to ischemia and iron toxicity, there is a decrease in global protein synthesis, but the synthesis of APR increases. Our working hypothesis is that the APP and tau 5' UTRs contain an IRES and that internal initiation is the primary mechanism utilized for their translation. In addition, we propose that IRES-dependent APP synthesis is upregulated by iron and ischemia. Accordingly our goals are 1) determine if the APP and tau mRNAs are translated through IRESes located in their 5' UTR, 2) identify intracellular signaling pathways, transcriptional elements, and gene products that contribute to basal and ischemia/iron induced IRES activity, 3) identify RNA binding proteins crucial for APP and tau IRES activity, and 4) characterize the interaction between these proteins and the APP and tau IRESes. The proposed experiments will determine the mechanism of protein synthesis contributing to APP and tau protein synthesis in AD. Understanding the molecular basis of this translational mechanism will open new avenues for rationale drug design for the therapeutic intervention of individuals with AD.

描述（由申请人提供）：阿尔茨海默氏病 (AD) 的两个标志是不溶性肽的表达和聚集增加，这种肽是通过淀粉样前体蛋白 (APR) 的裂解和微管相关蛋白 tau 的过度磷酸化而衍生的。这两个过程都被认为会导致细胞死亡，抑制这两种蛋白质的表达可有效改善 AD 症状。启动真核 mRNA 翻译的主要机制是通过帽结合复合物。然而，起始前复合物也可以结合 mRNA 上的位点，称为内部核糖体进入位点 (IRES)，并以不依赖帽的方式启动翻译。 IRES 在小核糖核酸病毒 mRNA 中得到了最广泛的表征，但人们对细胞 mRNA 中的 IRES 知之甚少。 IRES 依赖性翻译不受细胞应激的影响或促进。有趣的是，血管损伤（包括缺血和中枢神经系统铁水平升高）都是两种应激刺激，可能使个体易患 AD 或加速 AD 的进展。事实上，为了应对缺血和铁毒性，整体蛋白质合成减少，但 APR 合成增加。我们的工作假设是 APP 和 tau 5' UTR 包含 IRES，并且内部起始是其翻译的主要机制。此外，我们认为铁和缺血会上调 IRES 依赖性 APP 合成。因此，我们的目标是 1) 确定 APP 和 tau mRNA 是否通过位于其 5' UTR 中的 IRES 进行翻译，2) 识别有助于基础和缺血/铁诱导 IRES 活性的细胞内信号通路、转录元件和基因产物，3 ) 鉴定对 APP 和 tau IRES 活性至关重要的 RNA 结合蛋白，以及 4) 表征这些蛋白质与 APP 和 tau IRES 之间的相互作用。拟议的实验将确定 AD 中 APP 和 tau 蛋白合成的蛋白质合成机制。了解这种转化机制的分子基础将为 AD 患者治疗干预的药物设计原理开辟新途径。