Development of a pre clinical model for kidney disease treatment

Prof Colin A. Johnson (Lead supervisor), Prof. Chris Inglehearn (Co-supervisor), Dr. Sandra Bell (Co-supervisor)

Cystic kidney disease that leads to kidney failure is a major cause of renal replacement therapy (dialysis and transplantation) in patients. Cystic kidney disease comprises a group of inherited conditions, also known as “ciliopathies” that are all caused by mutations in genes that encode proteins of the primary cilium or basal body/centrosome, and are a significant cause of childhood morbidity and mortality (Adams et al. J. Med. Genet. 45: 257-267). There are no preventative treatments currently available due to a lack of understanding of the pathogenic molecular mechanisms of these conditions. This research project will investigate the function of two ciliary proteins that are key to understanding the defects in developmental signalling in cystic kidney diseases. This may lead to the rational design of therapeutics to prevent disease progression.
In preliminary work, we have characterized two animal models of Meckel-Gruber syndrome (MKS), a severe human ciliopathy that is characterized by renal cystic dysplasia (Smith et al. Nat. Genet. 38: 191-196). The models are knock-outs for the MKS genes Mks1 and Mks3 which encode the basal body protein MKS1 and the putative Frizzled-like orphan receptor meckelin. Both models have a severe and unexpected impairment of canonical Wnt signalling. Our overall hypothesis is that the normal differentiation of renal tubular epithelium is dependent on the precise regulation of canonical Wnt signalling, and that defects in this signalling are causal for cyst formation. In the first instance, the PhD student will do further functional characterization of the Wnt signalling defects during kidney development of mouse embryos and neonates, and during ex vivo kidney organogenesis. Depending on the initial findings, we will then test if dysregulation of Wnt signalling in the disease state can be prevented by treatment with small molecule inhibitors, and whether this ameliorates cystogenesis. During the studentship, we also anticipate that there will be further opportunities to develope and characterize other models of human ciliopathies such as that described by Valente et al. Nat. Genet. 42: 619-625).
The aim of the project is to use a broad range of techniques to establish a pre-clinical animal model of a severe human inherited condition. The PhD student will gain experience of developmental biology and molecular biology laboratory techniques including cell culture, ex vivo embryonic kidney organoculture, confocal microscopy, live cell imaging, transcript analysis, RT-PCR and immunohistochemistry.