Regulation and function of human neural circular RNAs

项目摘要 环状RNA（Circular RNA，circRNA）是一类新型的共价闭合RNA， 前体mRNA的"剪接"。越来越多的证据表明，circRNA在控制 健康的大脑发育及其在神经和神经精神疾病中的异常。 许多circRNA在人类大脑中是独特的和高度丰富的，这被认为是人类大脑的基础。 人类大脑的复杂功能和各种脑部疾病的脆弱性。机械地说， circRNA可以通过海绵状microRNA或RNA结合蛋白发挥作用，这些蛋白广泛地调节 多种生物学途径。我们目前对调节 人类大脑中的circRNA生物合成仍处于起步阶段。特别是，人类中的circRNA生物学 对神经胶质细胞了解甚少。神经元和神经胶质细胞是否具有不同的circRNA景观 而下游的相互作用组仍然完全未知。circRNA在肿瘤细胞中的生物学功能 控制大脑发育和调节损伤修复是非常难以实现的。这些普遍 知识上的差距限制了目前对许多脑部疾病复杂病因学的理解。我们 长期目标是阐明健康和疾病中circRNA的调节和功能， 这可能有助于开发针对脑部疾病的新疗法。在本申请中，我们 专注于少突胶质细胞（OL）中的circRNA生物学。OL负责中枢神经系统的髓鞘形成， 神经系统和影响在许多疾病，代表多发性硬化症和 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，其可以促进人和啮齿动物OL的分化。我们建立 最先进的技术平台，以确定人类OL中的circRNA景观和相互作用组， 神经元我们假设人类circRNA在控制OL和髓鞘中起重要作用 QKI介导发育信号以增强人OL circRNA生物合成。 在目标1中，我们将确定QKI如何调节OL circRNA生物合成以促进OL分化。 在目标2中，我们将确定人类OL circRNA景观的发育调控，下游 来自多个平台的OL中的circRNA作用途径和机制， 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（iPSC）衍生的少突胶质细胞球（hOLS）的开发 或髓磷脂损伤修复。这些研究的结果将提供 关于人类OL功能和髓鞘修复基本规则的新见解。

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.