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

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.