DiMeN Doctoral Training Partnership: Drug re-purposing and lead compound discovery for cystic kidney disease

Primary cilia are microtubule-based organelles that are thought to control the response of mammalian cells to key developmental signals. Mutations in genes important for the structure and function of primary cilia cause inherited developmental conditions and cystic kidney disease that make a major contribution to childhood morbidity and mortality. In the UK about 4000 patients annually require renal replacement therapy (dialysis and transplantation) as a result of kidney failure because of cystic kidney disease. However, there are no preventative treatments currently available due to a lack of understanding of molecular causes of these conditions.

We have recently completed cell-based screens of FDA-approved drugs and clinical development compounds for effects on cilia formation and function. These have identified several drugs and clinical development compounds that we now wish to take forward for further testing. For the latter, more extensive libraries of derivative compounds are available either locally (supervisor: Dr. Richard Foster, Medical Chemistry & Chemical Biology, University of Leeds) or through collaboration with an industrial partner (the Pfizer Rare Diseases Consortium). Compounds will be assessed by assays of in vitro cytotoxicity, efficacy, specificity and rescue of ciliary function. The top hits will then be more extensively validated using three-dimensional renal cultures, human patient-derived cells and organogenesis assays. The elucidation of preliminary structure-activity relationships (SARs) should lead to the identification of follow-up lead compounds for more extensive validation and refinement of SARs. This will include the optimisation of hit compounds, testing for cell permeability and the identification of the specific protein target. We will also test in vivo efficacy in zebrafish embryo models of ciliopathy disease. The overall objective of the project is to enable the future rational design of therapeutics to prevent ciliopathy disease progression and for possible treatment of cystic kidney disease.

You must demonstrate a strong background in either molecular cell biology or medicinal chemistry with a first degree in a relevant biomedical subject, and have the ability and ambition to develop a successful multidisciplinary research project.

Training in the following techniques:
High-throughput screening and high content imaging
Cell culture of mammalian cell-lines and patient-derived primary cells (fibroblasts, urine-derived renal epithelial cells)
General molecular biology techniques (PCR, plasmid construct preparation for mammalian cell transfection and expression Sequencing, western blotting etc.)
Live cell imaging of fluorescently-tagged proteins
Immunofluorescence confocal microscopy
Affinity chromatography and protein identification
Image analysis and bioinformatics techniques, including analysis of structure-activity relationships