Identifying novel therapeutics and disease mechanisms for ribosomal-protein mediated human haematopoietic disease: Award of a Wellcome-Beit Prize. (360G-Wellcome-095854_Z_11_A)

My research project uses embryos from zebrafish, a simple vertebrate organism to model two genetically related but clinically distinct conditions, myelodysplasia with loss of 5q and Diamond-Blackfan anaemia. The pathophysiology of these conditions is thought to be related because both result in anaemia associated with ribosomal protein haploinsufficiency. In Aim 1 I use an innovative adaptation of Illumina next generation sequencing technology to identify specific alterations in translational ca pacity in ribosome protein haploinsufficiency. Detailed analysis of this data will prioritise genes/proteins for further study in primary human cells from normal donors (initially) and patient samples. In the second Aim I will screen in vivo for novel compounds that improve the anaemia associated with ribosomal protein deficiencies (myelodysplastic syndrome (RPS14) and Diamond-Blackfan Anaemia (RPS19 and others)). The libraries being applied to the zebrafish embryos will initially be compounds w hich are approved for clinical use. This will facilitate the translation to primary human samples (in this project) and clinical trials (in later projects). The key goal of this study are to provide an unprecedented depth of knowledge about the biological effects of ribosomal protein loss which will inform our understanding of the disease mechanism as well as providing novel therapeutic targets.