Characterising the complement cascade in diabetic kidney disease

Background: Over 400,000 Australians are affected by diabetic kidney disease. Current clinical therapies only delay the progression to end stage renal disease and thus new therapies are urgently required. The main aim of our group is to understand why people develop complications from diabetes, and the mechanisms responsible for those complications, in the hope of finding new therapeutic targets that can halt progression to end stage renal disease. The complement cascade is a highly sophisticated network of immune proteins that are activated in response to invading pathogens or tissue injury. Under normal conditions complement is tightly regulated by a number of fluid-phase and cell surface proteins; however, when complement is hyperactivated it drives a severe inflammatory response. Complement comprises four key pathways that all result in the formation of C5a, a major effector molecule which, via ligation with its receptor C5aR1, initiates pathology in a number of inflammatory diseases. Previous studies have suggested that the complement system may be involved in the pathophysiology of diabetic kidney disease, though the role of specific complement pathways in the development of this disease remains incompletely defined. The aim of this study is to define the predominant complement cascade activated in human diabetic kidney disease using a mass spectrometry proteomics-based approach and to assess if complement activation products can serve as biomarkers for patients with diabetes at risk of progression to end stage renal disease. Genetic and/or pharmacological inhibition of complement receptors in the context of experimental diabetes will also be explored. Project related methods/skills/technologies: • Human kidney biospecimen collection and processing. • Western immunoblotting, ELISA and immunohistochemistry. • Proteomics (LC-MS/MS). • Imaging This study is being offered as an Honours or a PhD project and would suit students interested in pathology and translational studies.