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

所有细胞都含有各种由RNA和蛋白质组成的大的、显微镜下可见的复合物-核糖核蛋白（RNP）颗粒。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，可以作为细胞环境变化的高精度传感器。最近在RNP颗粒研究中取得了令人兴奋的突破，将这些结构确定为活细胞的关键组织原理。考虑到RNP颗粒的基本活动，其结构的微小变化导致致命的人类疾病（如神经退行性疾病）也就不足为奇了。因此，通过靶向其成分和调节因子来恢复细胞中的RNP颗粒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（例如那些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（FTD）。这一发现不仅建立了细胞中信号传播的新生物学概念，而且表明RNP颗粒网络的组成部分，包括rna，代表了治疗干预的有希望的点。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-蛋白复合物的具有生物活性的小分子药物的发现可以通过一种称为“表型测定”的特定药物发现方法成功地驱动，并通过RNA结构中的复杂基元获得信息。我的建议旨在提高我们对RNP颗粒网络如何被调节的认识，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来恢复它。这将通过以下方式实现：1)RNP颗粒网络在两种典型神经退行性疾病ALS和FTD的正常细胞生理和病理生理中的结构和功能询问；2)利用小分子药物对上述疾病的新型RNA药物靶点进行鉴定和随访。我将根据我以前在RNP颗粒和神经退行性疾病研究方面的经验领导这个创新项目；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意见；在药物研发中心的战略位置；定制培训和个人发展项目。总的来说，我的研究将为细胞如何利用相互连接的RNP颗粒来生存和繁荣以及如何纠正RNP颗粒的异常代谢以造福人类健康提供新的知识。

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.