Lowe syndrome and Dent-2 disease are rare genetic disorders that cause defects within the brain, eyes and kidneys. The renal symptoms, which are a major cause of morbidity, manifest as a proximal tubulopathy with the hallmark of proteinuria. Currently there are no treatments for either disorder. We have generated a zebrafish model for Lowe syndrome and Dent-2 disease and shown that it can recapitulate the symptoms of the human patients. We would now like to use the zebrafish model to screen for drugs to rescue the renal manifestations of these disorders. We have generated transgenic reporter strains to monitor renal function in living zebrafish larvae, paving the way for phenotypic screening of renal function. The goals of this PhD project are to: a) optimise the phenotypic screen so that it provides a robust readout of renal function in vivo; and b) perform a high throughput screen to identify drugs that ameliorate or rescue the renal impairment seen in the Lowe/Dent-2 fish. ‘Hit’ compounds identified in the screen will be further characterised to better understand their mode of action and also to determine their efficacy at rescuing the phenotypes of other renal tubulopathies. An additional benefit of the reporter screen is that it can be used to assess nephrotoxicity, a common side effect of many drugs or environmental poisons. Experiments will therefore be performed to assess the utility of the reporter strains in measuring nephrotoxicity, which has the potential to be exploited for a wide range of applications.
This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.
Ebarasi, L., Oddsson, A., Hultenby, K., Betsholtz, C., and Tryggvason, K. (2011). Zebrafish: a model system for the study of vertebrate renal development, function and pathophysiology. Curr. Op. Nephrol. Hypertens. 20, 416-424.
◾ Ramirez, I.B., Pietka, G., Jones, D.R., Divecha, N., Alia, A., Baraban, S.C., Hurlstone, A.F.L., and Lowe, M. (2012). Impaired neural development in a zebrafish model for Lowe syndrome. Hum. Mol. Gen. 21, 1744-1759.
◾ Mehta, Z.B., Pietka, G., and Lowe, M. (2014). The cellular and physiological functions of the Lowe syndrome protein OCRL1. Traffic 15, 471-487.
◾ Oltrabella, F., Pietka, G., Ramirez, I.B., Mironov, A., Starborg, T., Drummond, I.A., Hinchliffe, K.A., and Lowe, M. (2015). The Lowe syndrome protein OCRL1 is required for endocytosis in the zebrafish pronephric tubule. PLoS Genetics 11:e1005058.