Role Of Growth And Transcription Factors In Tubulointerstitial Injury In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Progressive kidney disease occurs as a result of a range of molecular and cellular pathways. One of the commonest causes of kidney disease is diabetes and this appears to be partly related to increased expression and action of certain growth factors such as CTGF. These factors promote the deposition of scar tissue in the kidney and one of the ways these promote this scarring is to change a cell s behaviour so that it now lays down collagen. This proposal will not only focus on how CTGF promotes ....Progressive kidney disease occurs as a result of a range of molecular and cellular pathways. One of the commonest causes of kidney disease is diabetes and this appears to be partly related to increased expression and action of certain growth factors such as CTGF. These factors promote the deposition of scar tissue in the kidney and one of the ways these promote this scarring is to change a cell s behaviour so that it now lays down collagen. This proposal will not only focus on how CTGF promotes scarring but will explore 2 novel factors called Snail and Slug which can act directly on particular genes such as CTGF to inhibit these deleterious effects. By further characterising these pathways involving Snail, Slug and CTGF in the kidney it will be possible to generate new targets and therapies for various forms of progressive kidney disease including diabetic kidney disease.Read moreRead less
E-CADHERIN AS A KEY MOLECULE IN RENAL EPITHELIAL-MESENCHYMAL TRANSITION AND FIBROSIS
Funder
National Health and Medical Research Council
Funding Amount
$318,267.00
Summary
Chronic kidney disease (CKD) is a major cause of death and disability in the Australian population. Current treatments for CKD are non-specific and frequently ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year more than 1700 Australians require kidney replacement therapy for this reason and many more die of kidney failure or its complications. Kidney fibrosis is the final common result of diverse CK ....Chronic kidney disease (CKD) is a major cause of death and disability in the Australian population. Current treatments for CKD are non-specific and frequently ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year more than 1700 Australians require kidney replacement therapy for this reason and many more die of kidney failure or its complications. Kidney fibrosis is the final common result of diverse CKD. This project proposes to investigate EMT, a key event in the development of renal fibrosis, whereby kidney cells are converted to fibrogenic cells. The project focuses on matrix enzymes (metalloproteinases) and E-cadherin (a molecule which is involved in adherence of kidney cells to one another, but which we think may actually be involved in the causation of EMT). This focus is novel, and could provide new understanding about the process of EMT in renal fibrosis, knowledge relevant to all diseases characterised by eventual loss of organ function due to fibrosis. It will identify new targets for therapy aimed at preventing fibrotic diseases of all types.Read moreRead less
Differentiation Of Pro-fibrotic From Anti-inflammatory Effects Of TGF-? In Kidney Fibrosis By Targeting ?-catenin
Funder
National Health and Medical Research Council
Funding Amount
$593,019.00
Summary
More than 2500 Australians commence kidney replacement therapy each year and many more die of kidney failure as a result of kidney fibrosis. TGF-?, a growth factor causing kidney fibrosis, is also anti-inflammatory. Our project aims to prove that targeting a downstream messenger (?-catenin) of TGF-? will prevent kidney fibrosis while leaving TGF-?’s anti-inflammatory actions untouched. A successful outcome will lead to a novel cure for preventing kidney fibrosis and fibrosis of other organs.
Preventing Kidney Fibrosis By Targeting Matrix Metalloproteinase-9 In Chronic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$516,972.00
Summary
More than 2300 Australians commence kidney replacement therapy each year and many more die of kidney failure or its complications. Kidney fibrosis is the final pathway of damage in all chronic kidney diseases. Our data demonstrates that a matrix enzyme MMP-9 is likely to be an important cause of kidney fibrosis. We aim to investigate mechanisms by which MMP-9 causes kidney fibrosis, and develop strategies involving inhibition of MMP-9 to prevent kidney fibrosis.
Epithelial-mesenchymal Transformation In Diabetic Nephropathy: Roles Of Oxidative Stress And KLF Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$557,523.00
Summary
Diabetes mellitus is responsible for the majority of kidney disease in the Western world . Diabetic nephropathy now accounts for the single largest cost to the health system in the USA. In Australia diabetic nephropathy, together with glomerulonephritis accounts for over 50% of the cases of dialysis-requiring renal failure. As the incidence of diabetes is increasing, current projections indicate an expotential rise in patient population with kidney disease. As the presence of kidney dysfunction ....Diabetes mellitus is responsible for the majority of kidney disease in the Western world . Diabetic nephropathy now accounts for the single largest cost to the health system in the USA. In Australia diabetic nephropathy, together with glomerulonephritis accounts for over 50% of the cases of dialysis-requiring renal failure. As the incidence of diabetes is increasing, current projections indicate an expotential rise in patient population with kidney disease. As the presence of kidney dysfunction is possibly the greatest predictor of subsequent cardiovascular events (including heart attack, heart failure and stroke) a thorough understanding of the mechanism of progressive kidney failure in patients with diabetes is required so that effective therapeutic strategies may be developed. Preliminary data leading to the development of this proposal, has shown that normal kidney tubule cells 'transform' into fibroblastic-like cells, in a process known as epithelial-mesenchymal transformation (EMT), under the metabolic disturbances inherent in diabetes mellitus. These fibroblast-like cells are likely to be responsible for the progressive scarring in the kidney that is characteristic of irreversible renal failure. We have documented that a specific factor, transforming growth factor beta (TGFB1) is increased in kidney cells in the presence of diabetes mellitus, and our preliminary data suggests the action of TGB1 is regulated by the KLF-family of transcription factors. This project aims to determine whether metabolic conditions such as exposure to high glucose and oxidative stress induced by diabetes mellitus modifies the KLF factors within cells that then alter susceptibility to TGFB1 induced EMT. The specific pathways involved in EMT will be dissected using both cell culture models and animal models of diabetes mellitus. These pathways will be selectively interrupted to assess reversibility of the EMT process.Read moreRead less