Research Interests
Molecular pathogenesis of polycystic kidney disease
ADPKD is the most common human genetic disease known with an incidence of 1 in 500. It accounts for ~10% of patients with kidney failure in most renal units and could affect up to 5 million people worldwide. A major focus in defining the molecular basis of this disease has been to investigate the structure and function of the ADPKD proteins, polycystin-1 and polycystin-2, and to understand how mutations in PKD1 and PKD2 may alter function (Professor Albert Ong). This has been complemented by work defining a role for protein phosphorylation in regulating polycystin trafficking and function (Dr Andrew Streets) and the development of human cell lines, zebrafish and murine models to model disease in vitro and in vivo.
Enzymatic modulation of extracellular matrix
Excessive deposition of extracellular matrix (ECM) is the pathological process that characterises progressive chronic kidney disease leading to end-stage kidney failure. We have a major interest in the role of the ECM cross-linking enzyme, tissue transglutaminase 2 (TG2), which has been shown to modify matrix turnover in experimental models and chronic human kidney diseases (Dr Tim Johnson). Specifically, we are seeking to understand the process of extracellular TG2 export and to develop antibodies, small molecule and natural inhibitors to this enzyme to test in experimental models.
Drug discovery in kidney disease models
Preclinical testing of disease modifying drugs is an important step in translating basic research findings to man. We have an international reputation in the preclinical testing of disease modifying drugs utilising rodent models of chronic kidney disease which now include ischaemia reperfusion and chronic allograft nephropathy (Dr John Haylor). Recent examples include the use of TG2 inhibitors (Dr Tim Johnson) and ET receptor antagonists (Professor Albert Ong) in diabetes and PKD models.
Urinary biomarkers of kidney disease progression
We are seeking to identify more sensitive and specific urinary biomarkers of disease progression in rodent models and in man by proteomics analysis (Professor M El-Nahas, Dr Tim Johnson, Dr John Haylor). This will help identify rapid progressors early in their disease and be useful as surrogate markers of treatment response.
Vascular complications of kidney disease
Patients with kidney disease have an increased prevalence of cardiovascular mortality and hypertension. We are seeking to identify those at highest risk through non-invasive measures of vascular stiffness (pulse wave velocity), endothelial function (flow mediated dilatation) and risk factor (clinical and biochemical) assessment (Professor M El-Nahas). A novel link between insulin resistance, nitric oxide and endothelial dysfunction in patients with ADPKD is currently under investigation (Professor Albert Ong).
The kidney and fibrosis in other organs
We have developed a rodent model of nephrogenic systemic fibrosis (NSF) to study the safety of gadolinium-based contrast agents used in magnetic resonance imaging of patients with renal failure (Dr John Haylor). A model of encapsulating peritoneal sclerosis (EPS) is being developed to study the pathogenesis of this rare but serious complication of peritoneal dialysis (Dr Tim Johnson, Dr Martin Wilkie).