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Mechanism and Function of Circular RNA Accumulation in the Aging Nervous System

衰老神经系统中环状RNA积累的机制和功能

基本信息

批准号：
9232903
负责人：
Pedro Miura
金额：
$ 41.75万
依托单位：
UNIVERSITY OF NEVADA RENO
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：
2016-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232903
关键词：
3&apos Splice Site ANK2 gene Age Aging Aging-Related Process Back Biological Aging Biology Brain Cells Data Defect Drosophila genus Drosophila melanogaster Elements Energy Intake Exhibits Exons Genes Genomics Glean Head Health Heat Stress Disorders Human Human Genome Impairment Investigation Longevity Maintenance Measurement Messenger RNA MicroRNAs Morbidity - disease rate Morphology Mus Nervous System Physiology Nervous system structure Neurodegenerative Disorders Neuromuscular Junction Neurons Neurophysiology - biologic function Organism Pathway interactions Phosphotransferases Play Population Porifera Process Production Property Protein Isoforms Proteins RNA RNA Splicing Regulation Reporter Research Personnel Resistance Role Site-Directed Mutagenesis Stress Students Synapses System Temperature Testing Tissues Transcript Untranslated RNA Work age related aging brain base brain health circular RNA fly genome-wide in vivo insight knock-down mortality nervous system disorder normal aging novel overexpression prevent protective effect relating to nervous system research study transcriptome sequencing

项目摘要

Project Summary: Although most of the transcripts produced from the human genome do not encode for proteins, the vast majority of non-coding RNAs remains completely understood. A newly appreciated class of non-coding RNAs are circular RNAs (circRNAs). In both Drosophila melanogaster and mice, circRNAs tend to emanate from genes with known neural functions and their expression is enriched in neural tissue. This suggests they might have functions in the nervous system. Recent work has found thousands of circRNAs to be expressed in mice and Drosophila; however, their functional relevance has only started to be explored. In Drosophila, we found that hundreds of circRNAs accumulate during normal aging in the fly head. Drosophila is a powerful system to study aging and age-related disorders of the nervous system. We hypothesize that this progressive accumulation of circRNAs in the brain contributes to age-related decline in neural function. Preliminary data shows that circRNA accumulation during aging can be modulated by environmental stresses, including temperature and caloric intake- all conditions that can modulate lifespan in Drosophila. In Aim 1 we propose to characterize the regulation of circRNAs globally during biological aging in brain neurons using RNA-seq analysis. In Aim 2, the functional elements enriched in age-accumulated and X16 regulated circRNAs will be investigated. Finally, in Aim 3, the function of X16 suppression of ank2 circRNA will be investigated by assessing lifespan, neuromuscular junction morphology and heat stress resistance. Preliminary data shows that circRNAs accumulated during aging in other organisms, including mice, making it likely that this accumulation also occurs in the human brain. Insights into the mechanism of circRNA accumulation during aging gleaned from Drosophila will thus likely be applicable to understanding circRNAs in the human brain. Given the health impact of age-related neurodegenerative disease in the US population it is important to understand the fundamental biology of this novel class of RNAs with likely functions in the aging brain.

项目概要：尽管人类基因组产生的大部分转录本并不编码蛋白质，但大量的转录本并不编码蛋白质。大多数非编码 RNA 仍被完全了解。一类新近受到重视的非编码 RNA 是环状RNA（circRNA）。在果蝇和小鼠中，circRNA 往往源自具有已知神经功能的基因，其表达在神经组织中丰富。这表明他们可能在神经系统中具有功能。最近的工作发现数千种 circRNA 在小鼠体内表达和果蝇；然而，它们的功能相关性才刚刚开始被探索。在果蝇中，我们发现果蝇头部正常衰老过程中会积累数百个 circRNA。果蝇是一个强大的系统研究衰老和与年龄相关的神经系统疾病。我们假设，大脑中 circRNA 的逐渐积累会导致与年龄相关的疾病。神经功能下降。初步数据表明衰老过程中circRNA的积累可以被调节环境压力，包括温度和热量摄入——所有可以调节寿命的条件在果蝇中。在目标 1 中，我们建议描述生物衰老过程中全局 circRNA 的调控特征使用 RNA-seq 分析大脑神经元。在目标2中，功能元素丰富了年龄积累和将研究 X16 调节的 circRNA。最后，目标3中，X16抑制ank2 circRNA的功能将通过评估寿命、神经肌肉接头形态和耐热应激能力进行研究。初步数据表明，circRNA 在其他生物体（包括小鼠）的衰老过程中积累，使得这种积累很可能也发生在人脑中。深入了解circRNA的机制因此，从果蝇中收集到的衰老过程中的积累可能适用于理解人类的大脑。考虑到美国人口中与年龄相关的神经退行性疾病对健康的影响，了解这类新型 RNA 的基础生物学非常重要，这些 RNA 可能在衰老过程中发挥作用脑。