To Improve The Accuracy And Precision Of Estimated GRF (eGFR) Measurements In Indigenous Australians
Funder
National Health and Medical Research Council
Funding Amount
$959,349.00
Summary
There is an overwhelming burden of chronic disease in Indigenous Australians. In order to attempt to improve kidney disease in this high-risk population, it is vital that we are able to accurately measure kidney function. This study will provide evidence to accurately assess kidney function in Indigenous Australians. This will then enable development of appropriate clinical guidelines and more effective monitoring of future interventions to slow progression of kidney disease.
The Role Of The Cytoplasmic Domain Of Tissue Factor In Maintenance Of The Glomerular Filtration Barrier.
Funder
National Health and Medical Research Council
Funding Amount
$487,066.00
Summary
This research aims to understand mechanisms of normal kidney function and the development of chronic kidney damage associated with diseases such as nephritis and diabetes. These diseases represent a significant burden of illness in Australia.
Role Of The Lysosomal Protein SCARB2 In Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$475,658.00
Summary
Loss of protein in the urine is one of the most important things that happens before the kidneys fail. Losing protein seems to damage the kidneys, but we are still not sure how it happens in most people. We are studying the 'waste management system' of cells, that enables them to get rid of proteins that are no longer required. We have some evidence that this system is abnormal in inherited proteinuria and now want to find out if this is also a problem in more common diseases.
DNA Vaccination Using Chemokine And Costimulatory Pathways As A Treatment For Chronic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$450,390.00
Summary
Chronic kidney disease (CKD) is a great burden on Australia. Treatments are mostly ineffective. Our DNA vaccination against mediators of inflammation can protect against CKD. On the basis of ongoing studies we have identified 5 candidate molecules involved in recruitment and activation of inflammatory cells. We outline studies to generate DNA vaccines to these molecules, enhance their efficacy, and test them in models that represent the 3 most important causes of human CKD.
Targeting Innate Immunity To Prevent Chronic Dysfunction Of The Transplanted Kidney
Funder
National Health and Medical Research Council
Funding Amount
$497,057.00
Summary
Kidney transplantation is the optimal treatment for patients suffering from end-stage kidney disease. Chronic transplant dysfunction is the major barrier to long-term health after transplantation, and is the subject of this application. Our studies suggest a signaling system activates immunity and leads to chronic transplant dysfunction. We aim to block this signaling system in mouse models to identify clinically applicable treatments to prevent kidney transplant failure.
MODIFICATION OF TUBULE CELL CYTOKINES REGULATING INTERSTITIAL INFLAMMATION IN CHRONIC PROTEINURIC RENAL DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$294,121.00
Summary
Current treatments for chronic kidney disease are ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year 1500 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. One of the major reasons for progression of kidney failure is that kidney cells produce a complex network of inflammatory mediators (cytokines) which attract inflammatory cells into the suppo ....Current treatments for chronic kidney disease are ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year 1500 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. One of the major reasons for progression of kidney failure is that kidney cells produce a complex network of inflammatory mediators (cytokines) which attract inflammatory cells into the supporting tissue of the kidney (the interstitium). Recently, drugs that inhibit these cytokines have been used in animal models of chronic kidney disease. Such treatment regimens have been at most only partially effective because they have been directed against only one cytokine, and because they have ignored the fact that the profile of cytokines varies with stage of disease. This project will use a rodent model (Adriamycin nephrosis) of human chronic kidney disease to define strategies for preventing interstitial inflammation using anti-cytokine therapy. Our laboratory has identified three cytokines which appear to play a pivotal role in the development of interstitial inflammation in Adriamycin nephrosis, and shown that their production varies with time. Knowledge of the time-dependent interactions among and regulation of these cytokines will be used to define optimal delivery of therapy directed against all three cytokines. As anti-cytokine therapy is already being trialled in other types of (non-kidney) disease in humans, the success of such a therapeutic approach to treating progressive kidney disease in this animal model will have important and immediate implications for the treatment of chronic kidney disease in humans.Read moreRead less
Progressive Renal And Vascular Disease: Pivotal Role Of The AT2 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$283,875.00
Summary
Diabetes and renal disease are commonly associated with a range of vascular complications. I have been investigating a particular hormone system known as the renin-angiotensin system in promoting kidney and vascular complications in various diseases including diabetes. This system is a pathway which ultimately generates a hormone called angiotensin II which has many actions which could be harmful to the kidney and blood vessels. The importance of this hormone system has been demonstrated by the ....Diabetes and renal disease are commonly associated with a range of vascular complications. I have been investigating a particular hormone system known as the renin-angiotensin system in promoting kidney and vascular complications in various diseases including diabetes. This system is a pathway which ultimately generates a hormone called angiotensin II which has many actions which could be harmful to the kidney and blood vessels. The importance of this hormone system has been demonstrated by the beneficial effects particularly on the kidney of drugs which block this pathway. It has been demonstrated that angiotensin II acts via 2 different receptors, the AT1 and AT2 subtypes. Initially the AT1 receptor was viewed to mediate most of the biological effects of angiotensin II. However, as demonstrated by our own and other groups, the AT2 receptor may play a role in mediating various effects of angiotensin II particularly in disease states. We have identified expression of this receptor in the adult kidney and in the vessel wall which may be upregulated in various disease states. The status of the AT2 receptor is not well characterised in diabetes and many other kidney diseases and this proposal will address this issue in a comprehensive manner by evaluating various sites of injury in diabetes including the kidney and vascular tree. This proporsal includes different approach to moduate this receptor involving drug blockers and animal model where this receptoris either deleted or overexpressed. These studies potentially have major implications for the management of diabetic and renal complications. It remains to be determined if the AT2 receptor confers beneficial or deleterious effects in diabetic nephropathy or other renal diseases, if these effects vary among the various organs to be studied and whether AT2 receptor antagonists may themselves be of therapeutic value in individuals at high risk of kidney and vascular disease such as people with diabetes.Read moreRead less
Kidney failure is a major health disorder in Australia and with more diabetes the number of patients waiting for transplant on dialysis is increasing. Current treatments give good initial survival of the kidney transplant but most kidneys are lost due to chronic damage . We propose a number of tolerance strategies in a model of kidney transplantation that will allow transplantation without longterm immunosuppression.
Glomerulonephritis (Bright's Disease) is the commonest cause of destruction of kidney function that leads to patients requiring artificial kidney treatment (dialysis) and renal transplantation. The glomeruli or filters of the kidney are attacked by inflammation and destroyed. The attack is usually auto-immune, that is the bodys' immune system loses tolerance to kidney tissue and mounts a destructive attack on the glomeruli. In many patients, this attack is mild and resolves with current treatmen ....Glomerulonephritis (Bright's Disease) is the commonest cause of destruction of kidney function that leads to patients requiring artificial kidney treatment (dialysis) and renal transplantation. The glomeruli or filters of the kidney are attacked by inflammation and destroyed. The attack is usually auto-immune, that is the bodys' immune system loses tolerance to kidney tissue and mounts a destructive attack on the glomeruli. In many patients, this attack is mild and resolves with current treatments to dampen the immune response. In others, current treatment is inadequate to dampen the attack and the kidney is destroyed. This research uses experimental models of nephritis to examine how the immune system injures the glomeruli. In particular, how T cells attack and mediate injury. This is a novel concept, as hither to it has been thought antibodies and other factors in the blood (complement) mediate injury. Our group was one of the first to identify T cells mediate injury in forms of glomerulonephritis, previously thought to be solely mediated by antibody and complement. This project will further define which molecules produced by the T cell effect injury of glomeruli. With the potential aim of turning off the T cell attack mechanisms in a more specific way than is achieved by non specific immunosuppressive drugs such as corticosteroids, cytotoxic (anti-cancer) drugs or cyclosporine (an anti-rejection drug). A major part of this project will be to examine the role of cytokines, hormone like molecules that are produced by white cells and mediate injury or regulate other white cells, in effecting injury and in turning off the immune injury.Read moreRead less