1. TGFbeta isoforms differentially regulate fibrosis and inflammation in diabetic nephropathy via KLF transcription factors. 2. The role of miRNA in preventing development of diabetic renal fibrosis. 3. Kruppel-like factors KLF4 and KLF6 and their regulation on modifying inflammation and repair process in diabetic nephropathy.

Summary

The Kolling Institute of Medical Research is the major biomedical research centre at the Royal North Shore Hospital, and represents the discipline of Molecular Medicine at the University of Sydney. Renal Medicine headed by Professor Carol Pollock in Kolling Institute is one of the leading renal research groups in Australia. There are opportunities currently available for a higher degree study by research including the Master of Biomedical Sciences and Doctor of Philosophy in Renal Medicine. The research projects: 1. The thioredoxin system and vascular dysfunction in diabetes mellitus 2. The role of miRNAs in preventing the development of diabetic renal fibrosis 3. The regulation of Krüppel-like factors KLF4 and KLF6 on MIF and DDR1 in diabetic renal   interstitial fibrosis

Supervisor(s)

Dr Xin-Ming Chen, Professor Carol Pollock

Research Location

Kolling Institute of Medical Research

Program Type

PHD

Synopsis

1. The thioredoxin system and vascular dysfunction in diabetes mellitus Patients with diabetes are at significant risk of both microvascular and macrovascular disease resulting in myocardial infarction, renal failure, blindness and stroke. Endothelial cell loss and vascular smooth muscle cell (VSMC) proliferation are observed in established vascular disease. However, endothelial dysfunction precedes VSMC pathology and is regarded as a key factor in the pathogenesis of diabetic vasculopathy. Improved glycaemic control is associated with improvement of endothelial function, which underlines the central role of hyperglycaemia in the pathogenesis of diabetic vascular disease. Hyperglycaemia is known to increase the formation of reactive oxygen species (ROS) and reduced anti-oxidant defences are known to be crucial in the accelerated atherosclerosis of diabetes. It has been recognized in vascular tissues that hyperglycaemia promotes oxidative stress and alters cellular function through inhibition of thioredoxin (TRX) function by increased expression and activity of thioredoxin interacting protein (Txnip). The central hypothesis to be tested is that the induction of Txnip in endothelial and VSMC under high glucose conditions is responsible for the downstream alterations in cell growth and cell signalling; and that therapeutic agents demonstrated to improve vascular function or pathology do so via inhibition of Txnip expression and activity. 2. The role of miRNAs in preventing the development of diabetic renal fibrosis The normal tubular cell epithelial cell phenotype is maintained by expression of E-cadherin and repression of vimentin. During EMT, downregulated E-cadherin expression allows epithelial cells to undergo changes in cell morphology and motility, facilitating the subsequent acquisition of mesenchymal characteristics. Expression of E-cadherin is under the control of several transcriptional repressors including Zeb1 and Zeb2. The collagen receptor discoidin domain receptor-1 (DDR1) may be a major mediator of the inflammatory response because it is essential for the maturation and differentiation of monocytes to macrophages and significant renal protection was observed in DDR1-deficient mice. The central aim of the project is to investigate the role of miRNA-200b in mediating molecular and cellular processes that drive renal tubular EMT and interstitial fibrosis. 3. The regulation of Krüppel-like factors KLF4 and KLF6 on MIF and DDR1 in diabetic renal interstitial fibrosis It is clear that tubular and endothelial pathology are integral to the development of diabetic nephropathy. In addition to our own data demonstrating that KLF-4 and -6 regulate proximal tubular function, recent studies have suggested that the KLF transcription factors play a significant role in endothelial biology influencing leukocyte and macrophage adhesion, endothelial proliferation, thrombotic function and vascular reactivity. Furthermore, data using alternative inflammatory models suggest that macrophage migration inhibitory factor (MIF) may indeed be important in promoting resolution, rather than participating in the inflammatory process. We have shown that KLF-4 and KLF-6 expression is modified in the tubulointerstitium of progressive diabetic nephropathy and in human tubular cells exposed to high glucose and TGFβ1; modification of KLF-4 and KLF-6 differentially regulate inflammatory cytokines and pro-inflammatory transcription factors in in vitro models of diabetic nephropathy; and MIF expression is upregulated in the tubulointerstitum of models of diabetic nephropathy and in human tubular cells exposed to high glucose and TGFβ1. The proposed project will extend our knowledge by determining the specific interaction between KLFs and MIF/DDR1 on inflammation and extracellular matrix production in both the human endothelium and proximal tubules. 

Keywords

Renal fibrosis, progressive kidney diseases, diabetic nephropathy, miRNA, Krϋppel-like transcription factors, fibrotic responses, chronic inflammatory responses

Opportunity ID

The opportunity ID for this research opportunity is: 920

Other opportunities with Professor Carol Pollock

• The Role of Toll-like receptors in Diabetic Nephropathy