How does cytokine signalling cause kidney hyperplasia?

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder, with more than 12 million people are affected worldwide. Approximately 50% of these patients will reach end-stage renal failure by the age of 50 requiring lifelong dialysis or renal transplant to survive. New therapies are urgently needed, discovery of which is heavily depends on gaining a deeper understand of the pathobiology of this condition.

Our group, led by Dr Fragiadaki, uses cutting-edge technologies including next-generation RNA sequencing, functional siRNA screening and advanced in vitroand in vivomouse/human models to study the pathobiology of this genetic condition. Our ultimate goal is to better understand 1) the cellular mechanisms that govern cystogenesis (how a tubule increases cellularity and becomes cystic via altered proliferation, apoptosis and migration) 2) which are the key signalling events leading to cystogenesis and 3) how can we best integrate this information to rationally identify and test novel therapeutics.

In this project we will select up to 10 genes from our next-generation single-cell RNA-sequencing that was designed to uncover novel regulators of the JAK/STAT in the polycystic kidney (funded by the Academy of Medical Sciences, via a Springboard award). To understand how these 10 newly identified genes contribute to renal tubular epithelial cell proliferation we will use flow-cytometry for proliferation, BrdU incorporation to study S-phase of the cell cycle, and KI67 staining, in human ADPKD-derived easy to transfect cells where the gene of interest will be either knockdown (with siRNA) or overexpressed (with plasmids). To determine if these 10 novel genes are bona de fide JAK/STAT targets JAKs will be inhibited with a drug or siRNA and expression of the genes monitored with qPCR. Novel findings will then be taken forward into our in vivo systems and experiments will be carried out to determine the spatial and temporal expression of novel JAK/STAT regulators in the kidney with and without established ADPKD disease.

This project is poised to uncover novel regulators of cystogenesis, some of which will be targets for therapy. In addition, it will provide a complete dataset of JAK/STAT regulators in the kidney, which can be used for collaborative projects.

We are looking for a highly motivated, and driven individual, ideally with a honors degree and/or a MSc in a relevant discipline (molecular or cellular biology). Full training in molecular biology techniques will be provided.