RNA-protein complexes in health and disease and their therapeutic targeting

所有的细胞都含有各种大的、显微镜下可见的由RNA和蛋白质-核糖核蛋白（RNP）颗粒组成的复合物。RNP颗粒内分子浓度的增加使它们成为非常有效的生化“微反应器”。RNP颗粒以非常动态的方式处理细胞功能，并且可以充当细胞环境变化的高度精确的传感器。最近在RNP颗粒研究中取得的令人兴奋的突破将这些结构确定为活细胞的关键组织原则。考虑到RNP颗粒的基本活性，即使其结构的微小变化也会导致致命的人类疾病，如神经退行性疾病，这并不奇怪。因此，通过靶向其成分和调节因子来恢复细胞中RNP颗粒的平衡是一种有吸引力的治疗策略，可以改变许多疾病。我最近的研究表明，在细胞中物理分离的RNP颗粒（例如位于细胞核和细胞质中的颗粒）连接成一个网络。它还表明，整个网络在疾病状态下受到影响，例如致命的和目前无法治愈的神经退行性疾病肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）。这一发现不仅建立了细胞中信号传播的新生物学概念，而且还表明RNP颗粒网络的组成部分，包括RNA，代表了治疗干预的前景。直到最近，用小分子药物靶向RNA一直被认为是有问题的，因为这种分子的结构灵活性。然而，人们越来越认识到，作用于RNA/RNA-蛋白质复合物的生物活性小分子药物的发现可以通过称为“表型测定”的特定药物发现方法成功地驱动，并通过RNA结构中的复杂基序来告知。我的建议旨在提高我们对RNP颗粒网络如何调节，为什么这种调节在疾病状态下崩溃以及如何使用治疗性小分子恢复的知识。这将通过以下方式实现：1）RNP颗粒网络在两种代表性神经退行性疾病ALS和FTD的正常细胞生理学和病理生理学中的作用的结构和功能研究;以及2）使用小分子药物识别和跟踪上述疾病的新型RNA药物靶点。我将领导这个基于我在RNP颗粒和神经退行性疾病研究方面的经验的创新项目;获得合作者网络和卡迪夫神经科学界的技能和工具包;来自药物发现专家的合作研究者的输入;药物发现中心的战略布局;以及定制培训和个人发展计划。总体而言，我的研究将提供新的知识，细胞如何利用相互连接的RNP颗粒生存和繁荣，以及RNP颗粒的异常代谢如何影响细胞的存活和繁荣。为了人类健康的利益可以进行纠正。

All cells contain a variety of large, microscopically visible complexes made of RNA and protein - ribonucleoprotein (RNP) granules. Increased concentration of molecules within RNP granules makes them very efficient biochemical "microreactors". RNP granules transact cellular functions in a very dynamic fashion and can act as highly accurate sensors of changes in the cell environment. Recent exciting breakthroughs in RNP granule research established these structures as the key organising principle of a living cell. Given the fundamental activities carried out by RNP granules, it is unsurprising that even small changes in their structure lead to fatal human diseases such as neurodegenerative disorders. Restoring RNP granule balance in cells by targeting their components and regulatory factors is therefore an attractive therapeutic strategy that can be transformative for many diseases.My recent research suggested that RNP granules that are physically separated in cells (e.g. those localised in the cell nucleus and those in the cytoplasm) are connected into a network. It also suggested that the entire network becomes affected in disease states, such as the fatal and currently incurable neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This finding not only established a new biological concept of signal propagation in cells but also suggested that components of the RNP granule network, including RNAs, represent promising points for therapeutic intervention. Until recently, targeting RNA with small molecule drugs has been seen as problematic, because of the structural flexibility of this molecule. However, it is becoming increasingly appreciated that the discovery of biologically active small molecule drugs acting on RNA/RNA-protein complexes can be successfully driven by a specific drug discovery approach called "phenotypic assay" and informed by complex motifs in the RNA structure. My proposal aims to improve our knowledge of how RNP granule network is regulated, why this regulation collapses in disease states and how it can be restored using therapeutic small molecules. This will be achieved via: 1) structural and functional interrogation of the role for the RNP granule network in the normal cell physiology and pathophysiology of two representative neurodegenerative disorders, ALS and FTD; and 2) identification and follow-up of novel RNA drug targets for the above diseases using small molecule drugs.I will lead this innovative programme building upon my previous experience in RNP granule and neurodegenerative disease research; access to the skills and toolkit of the collaborator network and Cardiff neuroscience community; input from the co-investigator who is a drug discovery expert; strategic placement within a drug discovery centre; and bespoke training and personal development program.Overall, my research will provide new knowledge of how cells exploit interconnected RNP granules to survive and thrive and how abnormal metabolism of RNP granules can be corrected for the benefit of human health.