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

项目总结： 尽管从人类基因组中产生的大多数转录本都不编码蛋白质，但大量的 大多数非编码RNA仍然完全被理解。一类新的受欢迎的非编码RNA 是环状RNA(CircRNA)。在果蝇和小鼠中，CircRNA倾向于从 已知的神经功能基因及其表达在神经组织中丰富。这表明他们可能会 在神经系统中起作用。最近的研究发现，数千个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探索。在果蝇身上，我们发现 苍蝇头部在正常老化过程中积累了数百个CircRNA。果蝇是一种强大的系统 研究衰老和神经系统的衰老相关疾病。 我们假设这种在大脑中逐渐积累的CircRNA有助于与年龄相关的 神经功能衰退。初步数据显示，衰老过程中CircRNA的积累是可以调节的 受环境压力的影响，包括温度和卡路里摄入量--所有这些条件都可以调节寿命 在果蝇身上。在目标1中，我们建议描述生物衰老过程中CircRNAs的全球调控 使用rna-seq分析的脑神经元。在目标2中，丰富的功能元素随着年龄的积累和 将研究X16调控的CircRNAs。最后，在目标3中，X16抑制ank2 CircRNA的功能 将通过评估寿命、神经肌肉连接形态和耐热性进行研究。 初步数据显示，在衰老过程中，CircRNA在其他生物中积累，包括小鼠， 这使得这种积累很可能也发生在人类的大脑中。对CircRNA机制的洞察 因此，从果蝇身上收集的衰老过程中的积累很可能适用于理解 人类的大脑。鉴于美国人口中与年龄相关的神经退行性疾病对健康的影响， 了解这类在衰老过程中可能具有功能的新型RNA的基础生物学很重要 大脑。

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.