Transposon landscapes and transcriptome diversity in aging neurons

衰老神经元的转座子景观和转录组多样性

基本信息

批准号：
9076923
负责人：
NELSON C LAU
金额：
$ 31.89万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9076923
关键词：
Age Aging Animal Model Animals Area Bioinformatics Biology Brain Cataloging Catalogs Circadian Rhythms Code Data Databases Development Disease Drosophila genus Enzymes Event Exhibits Foundations Gene Expression Genetic Genetic Models Genome Genomics Health Human Individual Link Longevity Mammals Measures Mediating Messenger RNA Modeling Molecular Molecular Profiling Nature Neurobiology Neurons Nucleic Acids Pathway interactions Population Process Proteins RNA RNA Editing RNA Interference RNA Interference Pathway Regulation Resolution Retrotransposon Small RNA Specific qualifier value Testing Transcript Transgenic Organisms Up-Regulation aged aging brain fly gene therapy genome sequencing human disease improved juvenile animal knock-down novel overexpression protein expression public health relevance success tool transcriptome transcriptome sequencing

项目摘要

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.

描述（由申请人提供）：确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的活动。果蝇和人类中，主要的转座子类别是逆转录转座子，主要通过 RNA 中间体动员，因为 RNA 监视途径（例如 RNAi-小 RNA 和 Adar-RNA 编辑途径）是关键机制。与转座子调控有关，我们发现它们在发育过程中也介导神经元多样性，但在衰老过程中可能会下降。为了检验这一假设，我们将在该项目中实现以下目标：目标 1：发现果蝇衰老过程中转座子景观（TL）的变化。目标 2：发现衰老果蝇大脑和神经元中与 TL 变化相关的转录组和 RNA 编辑变化。我们将对调节果蝇活动的大脑和高度纯化的神经元的基因组和转录组进行深入测序，这些数据将使我们能够将 TL 动态与 RNA 库的多样化结合起来。编码 mRNA 的变化，因为我们还将发现新的 RNA 编辑事件、lncRNA 和小 RNA 群体，这些转录组数量变化可能都集中在转座子调控上，因此我们还将检查是否遗传。 RNAi/小RNA和Adar/RNA编辑途径的调节可以帮助神经元管理不断变化的TL并促进衰老动物的寿命和活动。