DPFS Resource request (University of Sheffield) A High-content high-throughput Screening Facility in an Academic Setting

Thanks to the recent multi-national efforts to sequence the entire genomes of species as diverse as worms and humans, we now know that humans and lower organisms share remarkably similar sets of genes. This finding has transformed our understanding of human biology, through the realisation that many of the cellular and biochemical processes controlled by these genes in simple organisms also operate in ourselves. Most of our knowledge about the control of cells and organ systems has come from the study of a few so-called ?model organisms?, especially the fruit fly Drosophila melanogaster, and the tropical fish Danio rerio (commonly known as the zebrafish). Studies of such organisms have the potential to revolutionise our understanding, diagnosis and treatment of human disease, a premise that underpins the activities of the MRC Centre for Developmental and Biomedical Genetics. A key aim of the Centre is to encourage the rapid translation of our basic research findings into clinical application. This proposal will facilitate such translation by providing the means to screen for small molecules that can modulate pathogenic processes in model organisms. Such small molecules will provide powerful tools for probing the molecular basis of these processes and in some cases will provide leads for the developments of new drugs for their treatment.

The MRC Centre for Developmental and Biomedical Genetics (CDBG) brings together basic and clinician scientists using non-mammalian model organisms to understand the genetic basis of human disease, knowledge that will be essential for the development of novel therapies. In recent years, several groups within the CDBG have established disease models that provide a basis for high content screens. The primary objective of this proposal is to establish a facility for, high-throughput screening of small molecule libraries using these high content biological assays with the dual aim of identifying novel reagents for continued research and the establishment of systems to speed the identification and validation of lead compounds for drug discovery. In contrast to conventional drug screening programs where efforts are focused on a relatively small number of disease-relevant target pathways and proteins, the whole organismal nature of our models provides the potential for identification and validation of reagents affecting multiple pathways in the pathogenic process. A second application of the facility will take advantage of more conventional tissue culture based assays that are currently being devised for use in RNAi screens. The shared Screening Facility will have the flexibility to accommodate many different types of assay. Individual researchers will carry out the vast majority of work for their own screening projects (see CDBG component outline applications), but the Facility will provide the capacity for integrated management and automation of assay protocols and for access to business and pharmaceutical pipelines. Further, the Facility will enable and underpin future translational needs that lie at the heart of the University?s strategic vision: as functional genomic/proteomic datasets of patient-based materials accumulate in the Academic Medical Centre, these will integrate with the information from high throughput screens from cell-based and animal model systems in the CDBG. The Facility will therefore support a bidirectional flow of information, integrating mutually informative data from basic and clinical platforms.