Project 3 - Post-transcriptional regulation of tau in aging and AD

项目 3 - 衰老和 AD 中 tau 蛋白的转录后调控

• 批准号: 8848716
• 负责人: John Fonda Crary
• 金额: $ 16.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8848716
• 关键词: 3' Untranslated Regions; Address; Affect; Aging; Alzheimer' s Disease; Autopsy; Behavior; Binding; Biochemical; Bioinformatics; Biological Markers; Brain region; Cell Culture Techniques; Complement; Consensus; Data; Development; Disease Progression; Down-Regulation; Drosophila genus; Drug Targeting; Event; Gene Expression; Generations; Genetic Programming; Glycogen Synthase Kinase 3; Human; In Vitro; Knowledge; Late Onset Alzheimer Disease; Lateral; Lead; Link; Longevity; Mammalian Cell; Measurement; Measures; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Post-Transcriptional Regulation; Post-Translational Protein Processing; Regulation; Regulator Genes; Reporter; Repression; Research; Role; Staging; Testing; Therapeutic; Toxic effect; Transcript; Transgenic Organisms; Untranslated RNA; Untranslated Regions; Work; base; brain tissue; cognitive function; disease phenotype; entorhinal cortex; gene repression; glycogen synthase kinase 3 beta; hyperphosphorylated tau; in vivo; innovation; miRNA expression profiling; neuron loss; neurotoxicity; novel; overexpression; research study; tau Proteins; tau expression; tau phosphorylation; transcriptome sequencing

PROJECT 3 SUMMARY Understanding the earliest events in Alzheimer disease (AD) has the potential to lead to therapeutic strategies that slow and/or halt disease progression. Addressing AD at its earliest stages is critical as it might be too late to regain cognitive function once neuronal loss has occurred. Development of neurofibrillary tangles (NFT) in the entorhinal cortex (EC) is among the earliest pathological events in AD, but what underlies this regional vul- nerability remains a mystery. NFT are abnormal aggregates of the microtubule-associated protein tau that be- come hyperphosphorylated and aggregated following abnormal kinase activity. Several post-translational modi- fications have been proposed to contribute to tau toxicity, with hyperphosphorylation thought to play a pivotal role. Recently, it has become widely recognized that late-onset AD is associated with abnormalities in mi- croRNAs (miRNAs), small non-coding RNAs that are powerful regulators of gene expression. MiRNAs bind to and silence target mRNAs on the post-transcriptional level. Each miRNA can bind many target transcripts, providing an additional level of regulation that complements canonical transcriptional pathways. While a con- sensus is beginning to emerge that certain miRNAs are consistently altered in AD, the functional significance if these findings remain unclear. The overall objective of this application is to characterize miRNA regulation of the expression of tau and glycogen synthase kinase 3 b (GSK3b), a kinase implicated in tau phosphorylation and leading candidate drug target in AD. This will be accomplished by performing miRNA profiling studies in human autopsy brain tissue and then modeling candidate pathogenic changes with in vitro mammalian neu- ronal cultures and transgenic Drosophila. Our central hypothesis is that down-regulation of miRNAs leads to de-repression of a genetic program that increases expression of genes that drive tau toxicity. To test our hy- pothesis, we propose the following specific aims: 1) to characterize changes in miRNA expression early in AD progression, with a focus on the lateral entorhinal cortex, a region affected early in AD, 2) to characterize miR- NA regulation of the expression of tau and GSK3b, and 3) to demonstrate that miRNAs modulate tau neurotox- icity. This project is significant because it will lead to a better understanding of a genetic program that regulates the expression of genes that we hypothesize contribute the generation of toxic forms of hyperphosphorylated tau and the progression of AD. This proposal is innovative because looking at miRNA regulation has forced a re-assessment of gene expression that will provide a new perspective on the pathogenesis of AD as well as a new framework and new models to investigate mechanisms of tau regulation and toxicity. Together, these ex- periments will help us address the critical need of understanding the earliest events in AD and help pave the way towards new strategies to address AD with miRNA-based biomarkers and therapeutics.

项目3摘要 了解阿尔茨海默氏病（AD）中最早的事件有可能导致治疗策略 缓慢和/或停止疾病的进展。在最早的阶段介绍广告至关重要，因为可能为时已晚 一旦发生神经元丧失，才能恢复认知功能。神经纤维缠结（NFT）的发展 内河皮质（EC）是AD中最早的病理事件之一，但这是该地区脆弱的基础 可怕的性仍然是一个谜。 NFT是微管相关蛋白Tau的异常聚集体 异常激酶活性后，过度磷酸化和聚集。几个翻译后的修改 已经提出了典型的效果，导致tau的毒性，而过度磷酸化则可以发挥作用 角色。最近，它已被广泛认识到，晚发广告与Mi-i的异常有关 瑞典（miRNA），小型非编码RNA，是基因表达的强大调节剂。 miRNA与 并在转录后水平上沉默目标mRNA。每个miRNA可以结合许多目标转录本， 提供补充规范转录途径的额外调节水平。而 Sensus开始出现某些miRNA在AD中持续改变，功能意义，如果 这些发现尚不清楚。该应用的总体目的是表征miRNA调节 Tau和糖原合酶激酶3 B（GSK3B）的表达，一种与Tau磷酸化有关的激酶 和AD中的领先候选药物目标。这将通过在 人体尸检脑组织，然后通过体外哺乳动物neu-建模候选的致病性变化 罗纳尔培养物和转基因果蝇。我们的中心假设是miRNA的下调导致 消除遗传程序的抑制，以增加驱动TAU毒性的基因表达。测试我们的hy- pothesis，我们提出以下特定目的：1）表征AD早期miRNA表达的变化 进展，重点是侧向肾上腺皮质，在AD早期受影响的区域，2）表征mir- NA调节Tau和GSK3B的表达，以及3）证明miRNA调节Tau Neurotox- ICITY。该项目很重要，因为它将使人们对调节的遗传计划有更好的了解 我们假设的基因表达有助于产生过度磷酸化的有毒形式 tau和AD的进展。该提议具有创新性 对基因表达的重新评估将提供有关AD发病机理的新观点 新框架和新模型，以研究TAU调节和毒性机制。在一起，这些 中心将帮助我们解决了解广告中最早事件的关键需求，并帮助铺路 采用基于miRNA的生物标志物和治疗剂来解决广告的新策略的方法。