Kantharidis research group

Key terms: diabetic complications, nephropathy, atherosclerosis, microRNA, biomarkers, fibrosis

Research goal

To understand the interplay between genetic, fibrotic and inflammatory factors in diabetes that contribute to diabetic complications.

The group

2019 group L-R: Dr Madhura Bose, Dr Phillip Kantharidis, Mr Muthu Mohan.

Research Overview

Our research is focused on understanding the role of various cytokines and growth factors that drive the development of diabetic complications and in particular end stage kidney disease and atherosclerosis. Our laboratory has demonstrated that several cytokines and growth factors are elevated in diabetes and this results in dysregulation of certain microRNA, which are important regulators of fibrotic and inflammatory pathways in the kidney and the aorta. Targeting of these factors and microRNA directly has remained difficult due to their normal physiological roles.

More recently, we have made an exciting discovery in that a family of small endogenous molecules known as “resolvins” are able to attenuate the pathological signaling in diabetes by dampening both inflammatory and fibrotic pathways in tissues where complications occur. We are currently testing various analogues as novel treatments for dealing with multiple complications.

Another aspect of our work focusses on the identification of genetic markers in biological fluids by the use of RNA-seq in order to establish a biomarker profile that is predictive of the development of diabetic complications.

Projects and Opportunities

Honours, Masters and PhD research projects are available in the laboratory. Please contact us to discuss the details of the projects and to see how they fit in your specific interests. Please refer to the following general description of our current projects.

Project 1: Targeting fibrosis in diabetic nephropathy by the use of Lipoxins
Description: This project examines the anti-fibrotic and protective effect of Lipoxin A4 (and 2 analogues) in the kidneys of diabetic mice. We hypothesize that inflammatory and fibrogenic pathways are attenuated bt Lipoxins and the generation of reactive oxygen species will be decreased. Characterisation of these signaling pathways and analysis of gene and microRNA expression profiles may identify new therapeutic targets for the treatment of diabetic nephropathy.

Project 2: Lipoxins as a novel treatment of diabetes associated atherosclerosis
Description: The focus of this project is on understanding the effect of diabetes on vascular smooth muscle cells and endothelial cells and the development of atherosclerosis. The anti-inflammatory effects of Lipoxins may be protective against the development and progression of atherosclerosis by targeting VEGF, PDGF and TNFα signalling pathways which are known to be pathogenic in this disease. Our hypothesis is that Lipoxins dampens inflammatory pathways which in turns is protective against atherosclerosis and can reverse established atherosclerotic disease. RNA-seq experiments in isolated cell populations from atherosclerotic plaque may identify new therapeutic targets to combat this complication of diabetes.

Project 3: Urinary biomarkers of diabetic complications
Description: Approximately 30% of patients with diabetes will go on to develop nephropathy, a condition of increased fibrosis in the kidney such that kidney function is affected. Analysis of microRNAs released from renal cells exposed to high glucose and TGF-β differ significantly  to those from control cells. Differences are also evident in urinary microRNA isolated from control and diabetic patients. This project involves cellular and molecular techniques with a reliance on RNA-seq to identify patterns of differentially expressed microRNAs and RNAs. Human urine samples will be used for this project.

Current project funding

  • 2017-19 NHMRC project grant (APP1122176, Cooper ME Kantharidis P) A novel endogenous inhibitor for the treatment of diabetic nephropathy.

Recent publications

Pubmed link [Kantharidis P]

  • McClelland AD, Herman-Edelstein M, Komers R, Jha JC, Winbanks CE, Hagiwara S, et al. miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7. Clin Sci (Lond). 2015;129(12):1237-49.
  • Wang B, Jha JC, Hagiwara S, McClelland AD, Jandeleit-Dahm K, Thomas MC, et al. Transforming growth factor-beta1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b. Kidney Int. 2014;85(2):352-61.
  • Wang B, Komers R, Carew R, Winbanks CE, Xu B, Herman-Edelstein M, et al. Suppression of microRNA-29 expression by TGF-beta1 promotes collagen expression and renal fibrosis. J Am Soc Nephrol. 2012;23(2):252-65.
  • Wang B, Koh P, Winbanks C, Coughlan MT, McClelland A, Watson A, et al. miR-200a Prevents renal fibrogenesis through repression of TGF-beta2 expression. Diabetes. 2011;60(1):280-7.