Discovery and Function of Higher-Order RNA Structure

总结 RNA是所有细胞中信息交换的中心管道。RNA分子对此进行编码 它们的一级序列和RNA折叠时形成的复杂结构中的信息 自身。迄今为止，我们MIRA支持的工作的一个一致主题是，生物功能介导的 在真细菌和真核生物中普遍存在。的广泛和 RNA结构的根本重要性是清楚的，但仍然存在深刻的知识差距：我们 通常对大多数人的大部分区域的RNA结构只有初步的了解。 信使和非编码RNA。我们需要超越建模RNA结构， 检测细胞中的跨空间结构通信和相互作用。我们的实验室采用了一种近乎独特的 方法，同时注重实验的简单性和直接性，并广泛 模型系统中的验证。基本上，在每一个我们应用严格和 研究RNA结构-功能相互关系的定量技术， 生物调节机制已经出现。我们还表明，RNA元件具有较高的- 有序结构更可能包含高信息含量的裂缝和口袋， 分子，广泛地通知RNA靶向药物发现的蓬勃发展领域。这项工作旨在 通过追求三个首要机会来维持长期影响。第一，项目重点 发展决定性的，简洁的，广泛实施的技术， 评估RNA的高级结构。第二，本项目将这些直接和实验性地应用于 简明的方法，以广泛的重要性的挑战，从确定结构的必要性， 病原性病毒的复制，以了解RNA构象系综如何控制 转录基因调控和前体mRNA剪接。第三，了解RNA的倾向， 形成更高级的结构--通常是裂缝和口袋--开辟了针对这些的可能性。 小分子的图案，我们将利用这个机会，长期目标是发明简单， 创造RNA靶向疗法的简单策略。

SUMMARY RNA functions as the central conduit of information exchange in all cells. RNA molecules encode this information in both their primary sequences and in complex structures that form when RNA folds back on itself. A consistent theme from our MIRA-supported work to date is that biological function mediated by RNA structure is ubiquitous in both eubacterial and eukaryotic organisms. The broad and fundamental importance of RNA structure is clear, but there remains a profound knowledge gap: We generally have only rudimentary understanding of RNA structure across vast regions of most messenger and non-coding RNAs. We need to move beyond modeling RNA structure to directly detecting through-space structural communication and interactions in cells. Our lab takes a near-unique approach, simultaneously focusing on experimental simplicity and directness and on extensive validation in model systems. In essentially every instance where we have applied rigorous and quantitative technologies to study RNA structure-function interrelationships, new insights regarding biological regulatory mechanisms have emerged. We have also shown that RNA elements with higher- order structures are more likely to contain high-information-content clefts and pockets that bind small molecules, broadly informing a vigorous field of RNA-targeted drug discovery. This work is designed to have sustained long-term impact by pursuing three overarching opportunities. First, the project focuses on development of decisive, concise, and broadly implementable technologies for discovering and assessing higher-order structure in RNA. Second, this project applies these direct and experimentally concise methods to challenges of broad importance, from identification of structures essential for replication of pathogenic viruses to understanding how RNA conformational ensembles govern transcriptional gene regulation and pre-mRNA splicing. Third, understanding the propensity of RNA to form higher-order structures – and often clefts and pockets – opens up the possibility of targeting these motifs with small molecules, an opportunity we will exploit with the long-term goal of inventing facile and straightforward strategies for creating RNA-targeted therapeutics.