Role of Circular RNAs in Innate Immunity

环状 RNA 在先天免疫中的作用

• 批准号: 9299853
• 负责人: Rui Zhou
• 金额: $ 29.25万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-06 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9299853
• 关键词: Affinity Chromatography; Antiviral Agents; Autoimmunity; Bacterial Infections; Biochemical; CCL4 gene; Collection; Computational Biology; Consensus; Databases; Drosophila genus; Event; Exons; Genetic; Genomics; Goals; Head; Host Defense Mechanism; Human; Immune response; Immunity; Invaded; Lead; Literature; Malignant Neoplasms; MicroRNAs; Molecular; Mus; Natural Immunity; Nematoda; Organism; Pathologic; Play; Proteins; Proteomics; RNA; RNA Splicing; RNA-Binding Proteins; Role; Siblings; Signal Pathway; Signal Transduction; Small Interfering RNA; Tail; Technology; Untranslated RNA; circular RNA; deep sequencing; differential expression; fitness; fly; immune activation; insight; knock-down; novel; overexpression; pathogen; protein complex; response

Project Summary The goal of the proposed study is to identify and determine the function of circular RNAs (circRNAs) in innate immunity. Appropriate activation of the immune response is crucial for host fitness. While effective control of invading pathogens depends on rapid and robust induction of immunity signaling pathways, prolonged or aberrant activation, either systemically or locally, can lead to pathological conditions in humans such as autoimmunity and cancer. Thus both the magnitude and duration of innate immunity signaling need to be tightly regulated. Non-coding RNAs (ncRNAs), exemplified by small interfering RNAs (siRNAs) and microRNAs (miRNAs), play a critical role in modulating antiviral innate immunity in a wide variety of organisms. Recent advances in deep- sequencing technology and computational biology have greatly expanded the repertoire of regulatory ncRNAs, with circRNAs as the latest addition. Besides their unique configuration, circRNAs are also distinct from their canonical linear RNA siblings by harboring frequent exon scrambling events. Originally viewed as merely by-products of rare “head-to-tail” splicing events, circRNAs have recently been characterized as an abundant class of RNAs in nematodes, flies, mice and humans. With the exception of only a handful of circRNAs, the function of the vast majority of circRNAs is unknown. We identified a collection of Drosophila circRNAs that are differentially expressed in response to bacterial infection, and our preliminary studies have implicated select circRNAs in modulating innate immunity. We hypothesize that select circRNAs function as modulators of innate immunity signaling, and propose to employ a combination of genomic, computational, genetic, and biochemical approaches to comprehensively discover these enigmatic RNA species, and establish their function in the context of innate immunity signaling. Completion of the proposed study will establish circRNAs as a novel class of regulatory ncRNAs and uncover their function in modulating innate immunity. This will advance our understanding of their evolutionarily conserved mammalian counterparts, and provide insights into the molecular mechanisms underlying innate immunity signaling and ncRNA function.

项目摘要 这项研究的目的是鉴定和确定环状RNA的功能 （circRNA）在先天免疫中的作用。适当激活免疫反应对宿主至关重要 健身虽然对入侵病原体的有效控制取决于快速且强有力的诱导 免疫信号通路，延长或异常激活，无论是全身或局部，可导致 人类的病理状况，如自身免疫和癌症。因此，无论是规模和 先天免疫信号传导的持续时间需要严格调节。非编码RNA（ncRNA）， 例如小干扰RNA（siRNA）和微小RNA（miRNA），在 在多种生物体中调节抗病毒先天免疫。最近的进展深- 测序技术和计算生物学极大地扩展了调控基因的库， ncRNA，circRNA是最新加入的。除了它们独特的构型，circRNA还 与其典型的线性RNA兄弟不同，其具有频繁的外显子扰乱事件。 circRNA最初被认为是罕见的“头-尾”剪接事件的副产物，最近 在线虫、蝇、小鼠和人类中被表征为丰富的RNA类别。与 除了少数circRNA外，绝大多数circRNA的功能尚不清楚。我们 鉴定了一组果蝇circRNA，它们在对细菌的应答中差异表达， 感染，并且我们的初步研究已经涉及选择circRNA调节先天免疫。 我们假设选择circRNA作为先天免疫信号传导的调节剂， 建议采用基因组，计算，遗传和生物化学方法的组合， 全面发现这些神秘的RNA种类，并在生物学背景下建立它们的功能。 先天免疫信号 这项研究的完成将使circRNA成为一类新的调控性ncRNA。 并揭示它们在调节先天免疫中的功能。这将促进我们对他们的理解。 进化上保守的哺乳动物对应物，并提供对分子生物学的见解。 先天免疫信号传导和ncRNA功能的潜在机制。