Role of Circular RNAs in Innate Immunity and Neuro-development

项目摘要 这项研究的目的是鉴定和确定环状RNA的功能 （circRNA）在先天免疫和神经发育中的作用。适当激活免疫 反应对于宿主适应性至关重要。在有效控制入侵病原体或应对 内源性应激信号依赖于免疫信号传导途径的快速和强有力的诱导， 全身或局部的延长或异常激活可导致病理状况 例如自身免疫、癌症和神经变性。特别是大脑中的慢性炎症 与受损的神经发育和功能有关。因此， 免疫反应需要严格控制非编码RNA（ncRNA）在 在多种生物体中调节抗病毒免疫。深度测序的最新进展 技术和计算生物学极大地扩展了调节性ncRNA的库， 而circRNA是最新加入的。除了它们独特的构型外，circRNA与 他们的典型线性兄弟姐妹窝藏频繁的外显子扰乱事件。最初被视为 仅仅是罕见的“头到尾”反向剪接事件的副产品，circRNA最近被 在真核生物中被表征为丰富的一类RNA。然而，除了只有一个 除了少数circRNA外，绝大多数circRNA的功能尚不清楚。我们发现了一批 果蝇中对细菌感染的应答中差异表达的circRNA，以及我们的 初步研究表明，大脑富集的circRNA Edis与先天免疫和神经系统疾病有关。 发展我们假设Edis调节先天免疫信号和神经发育 和功能，并建议采用基因组，计算，遗传和 生物化学方法来建立Edis的功能并阐明其调节机制 Edis表达的基础。 这项研究的完成将使circRNA成为一类新的调控性ncRNA， 阐明circRNA表达的调控机制，并确定它们在调节 先天免疫和神经发育。这将促进我们对它们进化的理解 保守的哺乳动物对应物，并提供新的见解的机制， 在生理和病理环境中先天免疫和神经发育之间的相互作用。

PROJECT SUMMARY The goal of the proposed study is to identify and determine the function of circular RNAs (circRNAs) in innate immunity and neuro-development. Appropriate activation of the immune response is crucial for host fitness. While effective control of invading pathogens or response to endogenous stress signals depend on rapid and robust induction of immunity signaling pathways, prolonged or aberrant activation, either systemically or locally, can lead to pathological conditions such as autoimmunity, cancer and neurodegeneration. In particular, chronic inflammation in the brain is associated with impaired neuro-development and function. Thus both the magnitude and duration of the immune response need to be tightly regulated. Non-coding RNAs (ncRNAs) play a critical role in modulating antiviral immunity in a wide variety of organisms. Recent advances in deep-sequencing technology and computational biology have greatly expanded the repertoire of regulatory ncRNAs, and circRNAs are the latest addition. Besides their unique configurations, circRNAs are distinct from their canonical linear siblings by harboring frequent exon scrambling events. Originally viewed as merely by-products of rare “head-to-tail” back-splicing events, circRNAs have recently been characterized as an abundant class of RNAs in eukaryotes. However, with the exception of only a handful of circRNAs, the function of the vast majority is unknown. We identified a collection of circRNAs in Drosophila that are differentially expressed in response to bacterial infection, and our preliminary studies have implicated the brain-enriched circRNA Edis in innate immunity and neuro- development. We hypothesize that Edis modulates innate immunity signaling and neuro-development and function, and propose to employ a combination of genomic, computational, genetic, and biochemical approaches to establish the function of Edis and elucidate the regulatory mechanism underlying Edis expression. Completion of the proposed study will establish circRNAs as a new class of regulatory ncRNAs, elucidate the regulatory mechanism of circRNA expression, and determine their function in modulating innate immunity and neuro-development. This will advance our understanding of their evolutionarily conserved mammalian counterparts, and provide new insights into the mechanisms underlying the interplay between innate immunity and neuro-development in physiological and pathological settings.