Regulators Of Cell Cycle As Therapeutic Drug-targets For Cortical Tubular Hyperplasia In Proteinuric Renal Disease
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
Currently in Australia, it has been estimated that approximately 60 000 people suffer from chronic kidney failure (CKF). In at least 80% of people with CKF, the kidney function will continue to worsen (due to disease progression) to the point where end-stage kidney failure (ESKF) has developed. When the latter occurs daily treatment by either dialysis or kidney transplantation is mandatory for a person to survive. At present, there are nearly 10 000 patients with ESKF who are being treated by di ....Currently in Australia, it has been estimated that approximately 60 000 people suffer from chronic kidney failure (CKF). In at least 80% of people with CKF, the kidney function will continue to worsen (due to disease progression) to the point where end-stage kidney failure (ESKF) has developed. When the latter occurs daily treatment by either dialysis or kidney transplantation is mandatory for a person to survive. At present, there are nearly 10 000 patients with ESKF who are being treated by dialysis or transplantation, in Australia. Although these treatments have allowed patients to survive, they are associated with significant and unacceptable patient morbidity and mortality. Current medical treatments to reduce the disease progression of CKF (and thereby extend the time taken to reach ESKF) are non-specific, partially effective and have a variable response. Also, these treatments are NOT known to arrest the progression of CKF. To compound the overall problem even further, the number of new patients starting chronic dialysis programmes is increasing (by 6% per year). Consequently, ESKF has been described by leading authorities as a medical catastrophe of world-wide dimensions, and research into ways to reduce-arrest the progression of CKF has been recommended as an urgent priority by the Australian Kidney Foundation. In CKF, the kidneys undergo compensatory growth which is harmful and paradoxically contributes to disease progression. The aim of this research program is to advance knowledge about the molecular mechanisms of kidney growth in CKF, with specific goals of: (i) identifying new molecular targets for drug-based manipulation of kidney growth; and (ii) to test the efficacy of experimental drugs which have an ability to alter kidney growth, and thereby reduce the progression of CKF.Read moreRead less
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
Costimulation In Progressive Non-immune Tubulointerstitial Renal Disease.
Funder
National Health and Medical Research Council
Funding Amount
$434,875.00
Summary
Current treatments for chronic kidney disease 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 about 1700 Australians commence dialysis for this reason and many more die of kidney failure or its complications. This project will examine the role of costimulatory molecules in causing chronic kidney disease (CRD) to progress and their potential as targets for specific ....Current treatments for chronic kidney disease 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 about 1700 Australians commence dialysis for this reason and many more die of kidney failure or its complications. This project will examine the role of costimulatory molecules in causing chronic kidney disease (CRD) to progress and their potential as targets for specific therapy to slow the progression of CRD. In chronic kidney diseases of all types, the kidney becomes infiltrated with inflammatory cells. The amount of inflammation has an important bearing on the severity of kidney failure and the rate at which kidney disease progresses. There are a range of different cells that invade the inflamed kidney, some may worsen disease while some may protect against it. Current treatments are non-selective and may, by suppressing inflammation, prevent both repair and protection. Costimulatory molecules have been shown to be important in the regulation of inflammatory cell activation in transplantation and some autoimmune diseases. We, and others, have evidence to suggest that costimulatory molecules may be pivotal to the development and progression of kidney inflammation in CRD as well. This project will use two robust animal models of human CRD to define the role of costimulatory molecules in progression of kidney disease. If, as our preliminary evidence suggests, costimulatory molecules are shown to alter disease progression, then they will provide excellent targets for new treatments. Eventually, treatment directed against costimulatory molecules may be used as more effective and safer therapy for human kidney disease.Read moreRead less
EFFECTOR AND REGULATORY INTERSTITIAL INFLAMMATORY CELLS IN CHRONIC PROTEINURIC RENAL DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$289,150.00
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 almost 1600 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. This project will lead to a greater understanding of why kidney failure progresses, and will define more effective treatments for preventing progression. In progressive chronic kidney ....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 almost 1600 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. This project will lead to a greater understanding of why kidney failure progresses, and will define more effective treatments for preventing progression. In progressive chronic kidney diseases of all types, the supporting tissue within the kidney (the interstitium) becomes infiltrated with inflammatory cells. The amount of interstitial inflammation has an important bearing on the severity of kidney failure, and the rate at which kidney disease progresses to endstage. The reasons that these inflammatory cells infiltrate the interstitium, and their exact role in the progression of kidney disease are only partially understood. For example, some of these inflammatory cells appear to cause kidney scarring, whereas others appear to be protective. Moreover, even though they are obvious targets for treatment aimed at slowing the progression of kidney disease, current treatments are largely ineffective as they do not differentiate between the different types of inflammatory cells, and whether these cells are causing or preventing damage. Our laboratory has recently developed a robust model of chronic kidney disease, which will be used to examine the effect of individual types of interstitial inflammatory cells on the progression of kidney disease. So far we have shown that depletion of one type of inflammatory cell (CD4 lymphocytes) worsened the disease process, whereas depletion of two other cell types (CD8 lymphocytes or macrophages) was protective. This raises the real and exciting possibility that treatment directed against specific inflammatory cells may be effective in the treatment of progressive kidney disease in humans.Read moreRead less
Acute injury can lead to chronic immune activation in both chronic kidney disease and in transplantation. We will study the role of a class of molecules, the purines, that are released by injury and lead to immune activation. We will focus on the molecular variations and pharmacological blockade of their receptors as potential treatments for kidney disease and transplant graft failure.
Treatment Of Chronic Proteinuric Renal Disease With DNA Vaccines Against TCR Subsets Of Effector T Cells And Chemokines
Funder
National Health and Medical Research Council
Funding Amount
$282,750.00
Summary
Current treatments for chronic kidney disease 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 about 1700 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. This project will develop and test a novel therapeutic strategy of DNA vaccination targeted specifically at groups of white cells, and specific regulatory mo ....Current treatments for chronic kidney disease 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 about 1700 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. This project will develop and test a novel therapeutic strategy of DNA vaccination targeted specifically at groups of white cells, and specific regulatory molecules in order to prevent chronic kidney disease (CPRD). In chronic kidney diseases of all types, the kidney filters and surrounding tissue becomes infiltrated with inflammatory cells. The amount of inflammation in the filters and the tissues has an important bearing on the severity of kidney failure, and the rate at which kidney disease progresses. There are a range of different cells that invade the inflamed kidney, some worsen the disease while some may protect against it. Current treatments are non-selective and may, by suppressing inflammation, prevent both repair and protection. We have established a central role for two groups of white cells called macrophages and T lymphocytes in two animal models of kidney disease. In one of these models, we used DNA vaccination, which represents a novel means of switching off these disease-causing T cells. The results showed that DNA vaccination against T cell subsets was protective in our model. This raises the real and exiting possibility that DNA vaccination directed at specific disease-causing cells, and their products are much more likely to be specific and effective therapy for chronic kidney diseases. Eventually, such DNA vaccination may be used as a more effective and safer therapy for human kidney disease.Read moreRead less
TOLERANCE OR REJECTION – THE ROLE OF INNATE IMMUNITY IN DETERMINNG THE FATE OF A KIDNEY ALLOGRAFT
Funder
National Health and Medical Research Council
Funding Amount
$506,413.00
Summary
Transplantation is the optimal management for people with organ failure. Tolerance, to retain transplant function without immunosuppression, remains the key goal but is seldom achieved. We propose to block Toll-like receptor signalling to achieve kidney transplant tolerance in mice. If successful, we would translate this into clinical trials in human, seeking to achieve organ transplantation without the risks of cancer, infection and premature death that are currently faced by organ recipients.
Mechanisms Of Infection Triggered Renal Vasculitis
Funder
National Health and Medical Research Council
Funding Amount
$413,900.00
Summary
Kidney disease, including glomerulonephritis, is an important cause of ill-health in Australia. Some forms of kidney inflammation are linked to infection, but we don�t understand why. This project explores products from bacteria, particularly S.aureus, to work out how bacterial infection affects a form of kidney inflammation - ANCA-associated glomerulonephritis. It will establish how infection related signals activate local and immune cells, and define links between infection and the disease.