Transposon landscapes and transcriptome diversity in aging neurons

 描述（由申请人提供）：指定神经元多样性和衰退的分子基础在很大程度上仍然是一个谜。一个新兴的想法是，在衰老和疾病期间转座子的动员可以破坏单个神经元的正常转录组谱并改变动物活动。在果蝇和人类中，主要的转座子类别是主要通过RNA中间体移动的反转录转座子。由于RNA监视途径，如RNAi-小RNA和Adar-RNA编辑途径，是涉及转座子调节的关键机制，我们假设它们也介导发育过程中的神经元多样性，但可能在衰老过程中下降。 为了验证这一假设，我们将在本项目中实现以下目标：目标1：发现果蝇衰老大脑和神经元中不断变化的转座子景观（TL）。目的2：发现老年果蝇大脑和神经元中的转录组和RNA编辑变化，这些变化可能与TL的变化有关。目的3：评估具有调节的RNA监视途径的脑中的TL和转录组。我们将对来自大脑和高度纯化的调节果蝇活动的神经元的基因组和转录组进行深度测序。这些数据将使我们能够将TL动态沿着RNA库的多样化。重要的是，我们将超越编码mRNA的简单定量变化，因为我们还将发现新的RNA编辑事件，lncRNA和小RNA群体。这些转录组改变可能都集中在转座子调控上，因此我们还将研究RNAi/小RNA和阿达尔/RNA编辑途径的遗传调节是否可以帮助神经元管理不断变化的TL，并促进衰老动物的长寿和活动。

 DESCRIPTION (provided by applicant): The molecular underpinnings for specifying neuronal diversity and decline largely remain a mystery. One emerging idea is that the mobilization of transposons during aging and disease can disrupt the normal transcriptome profiles of individual neurons and alter animal activity. In both Drosophila and humans, the dominant transposon classes are retrotransposons which primarily mobilize via an RNA intermediate. Since RNA surveillance pathways, such as the RNAi-small RNA and Adar-RNA editing pathways, are key mechanisms implicated in transposon regulation, we hypothesize they also mediate neuronal diversity during development, but may decline during aging. To test this hypothesis, we will achieve the following aims in this project: Aim 1: Discover changing Transposon Landscapes (TLs) in Drosophila aging brains and neurons. Aim 2: Discover transcriptome and RNA editing changes in aged Drosophila brains and neurons that can be linked to changing TLs. Aim 3: Assess TLs and transcriptomes in brains with modulated RNA surveillance pathways. We will deeply sequence the genomes and transcriptomes from brains and highly purified neurons that regulate Drosophila activity. These data will allow us to integrate TL dynamics along with the diversification of RNA repertoires. Importantly, we will go beyond simple quantitative changes of coding mRNAs, because we will also discover novel RNA- editing events, lncRNAs, and small RNA populations. These transcriptome alterations may all converge on transposon regulation, so we will also examine if genetic modulation of RNAi/small RNA and Adar/RNA editing pathways can help neurons manage changing TLs and promote greater longevity and activity in aging animals.