Regulation and function of human neural circular RNAs

项目摘要 环状RNAs(CircRNAs)是一类新的共价闭合RNA物种，起源于Back 剪接“前信使核糖核酸。越来越多的证据表明，CircRNA在治理中扮演着重要的角色 神经和神经精神障碍中健康的大脑发育及其异常。 许多CircRNA在人脑中是独一无二的，并且含量非常丰富，被认为是 人脑的复杂功能和各种脑部疾病的脆弱性。从机械上讲， CircRNAs可以通过海绵状的microRNAs或RNA结合蛋白发挥功能，后者广泛地调节 无数的生物途径。我们目前对调控的分子机制的了解 人类大脑中的CircRNA生物发生仍处于初级阶段。特别是，人类的CircRNA生物学 人们对神经胶质细胞知之甚少。神经元和神经胶质细胞是否具有不同的CircRNA景观 下游的相互作用仍然完全未知。CircRNAs的生物学功能 控制大脑发育和调节损伤修复是非常难以捉摸的。这些流行的 知识差距限制了目前对许多脑部疾病复杂病因的理解。我们的 长期目标是阐明在健康和疾病中CircRNAs的调节和功能。 大脑，这可能有助于开发对抗脑部疾病的新疗法。在此应用程序中，我们 重点研究少突胶质细胞(OL)的CircRNA生物学。一氧化氮合酶负责中央的髓鞘形成。 神经系统，在许多疾病中受到影响，以多发性硬化症和 精神分裂症。我们的初步数据显示，RNA结合蛋白QKI促进生物发生 人OL CircRNA，可促进人和啮齿动物OL的分化。我们建立了 最先进的技术平台，用于识别人类OL中的CircRNA景观和互动 神经元。我们假设人类CircRNA在控制OL和髓鞘方面起着重要作用 QKI介导发育信号，促进人OL CircRNA的生物发生。 在目标1中，我们将确定QKI如何调节OL CircRNA的生物发生以促进OL的分化。 在目标2中，我们将确定人类OL CircRNA景观的发育调节，下游 整合了多种平台的CircRNA在OL中作用的途径和机制 分析。在目标3中，我们将探索人类OL CircRNA通路是否可以促进OL谱系 人诱导多能干细胞来源的少突胶质细胞球的研究进展 或在已建立的小鼠模型中修复髓鞘损伤。这些研究的结果将提供 对管理人类OL功能和髓鞘修复的基本规则的新见解。

Project Summary Circular RNAs (circRNAs) are a novel class of covalently closed RNA species derived from “back splicing” of pre-mRNAs. Mounting evidence suggests the essential roles of circRNAs in governing healthy brain development and their abnormalities in neurological and neuropsychiatric disorders. Many circRNAs are unique and highly abundant in the human brain, which are thought to underlie the sophisticated function of human brains and the fragility of various brain diseases. Mechanistically, circRNAs can function through sponging microRNAs or RNA-binding proteins, which broadly regulate numerous biological pathways. Our current knowledge of molecular mechanisms that regulate circRNA biogenesis in the human brain is still in its infancy. In particular, circRNA biology in human glial cells are poorly understood. Whether neurons and glia cells possess distinct circRNA landscapes and downstream interactomes remain entirely unknown. The biological functions of circRNAs in governing brain development and modulating lesion repair are vastly elusive. These prevailing knowledge gaps limit the current understanding of the complex etiology of many brain diseases. Our long-term goals are to elucidate the regulation and function of circRNAs in healthy and diseased brains, which may help to develop novel therapeutics against brain illnesses. In this application, we focus on circRNA biology in oligodendroglia (OL). OLs are responsible for myelination of the central nervous system and affected in numerous diseases, represented by multiple sclerosis and schizophrenia. Our preliminary data revealed that the RNA-binding protein QKI advances biogenesis of a human OL circRNA, which can promote differentiation of human and rodent OLs. We established state-of-the-art technical platforms to identify circRNA landscapes and interactomes in human OL and neurons. We hypothesize that human circRNAs play essential roles in controlling OL and myelin development, and QKI mediates developmental signals to enhance human OL circRNA biogenesis. In Aim 1, we will determine how QKI regulates OL circRNA biogenesis to advance OL differentiation. In Aim 2, we will determine developmental regulation of human OL circRNA landscapes, downstream pathways, and mechanisms of circRNA action in OLs from multiple platforms with integrated analyses. In Aim 3, we will explore whether human OL circRNA pathways can promote OL lineage development in human induced pluripotent stem cell (iPSC)-derived oligodendrocyte spheres (hOLS) or myelin lesion repair in a well-established mouse model. Findings from these studies will provide novel insights on fundamental rules governing human OL function and myelin repair.