(MRC DTP) Using zebrafish to determine the mechanisms of renal disease

Lowe syndrome and Dent-2 disease are renal tubular disorders, yet patients can develop glomerular dysfunction. Conversely, Alport syndrome is primarily a glomerular disease, yet manifestations occur in the renal tubule and interstitium. In these disorders, and in kidney disease more generally, there is a significant amount of ‘cross-talk’ between these two functional units of the kidney. The underlying mechanisms are currently unknown, and effective means to study these processes are lacking. The goal of this project is to generate transgenic zebrafish dual reporter strains to simultaneously monitor both glomerular and tubular function in the same animal, allowing us to uncover the processes linking dysfunction of the glomerulus with that of the renal tubule and vice-versa. The dual reporter strains will be used to investigate the disease mechanisms of Lowe syndrome/Dent-2 and Alport syndrome, and how the glomerular-tubular crosstalk occurs in both conditions. This will be achieved by crossing the reporter strains with existing or newly generated genetic models for Lowe syndrome/Dent-2 and Alport syndrome. Glomerular filtration and tubular reabsorption will be monitored in parallel, and combined with a number of other analyses including histology and high-resolution microscopy to dissect underlying mechanisms. A key aspect of the proposal will be to investigate the role of inflammatory responses and the immune system in disease progression, which will be achieved by crossing the Lowe/Dent-2 and Alport models with existing transgenic reporter lines that mark various immune cell types. This project will address a major gap in our knowledge by providing new insight into the mechanisms underlying progression of renal disease, which is a major health burden on society.

http://www.manchester.ac.uk/research/martin.p.lowe/
http://www.manchester.ac.uk/research/rachel.lennon/
http://www.manchester.ac.uk/research/Adam.Hurlstone/