Pathogenic Role Of CDA1 Via Its Profibrotic Action In Diabetic Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$483,737.00
Summary
We cloned a CDA1 several years ago and found that it played a major role in controlling a series of molecular events leading to production and accumulation of extracellular matrix causing scarring, as seen in diabetic nephropathy. This project aims to study the biological functions and molecular mechanisms of CDA1 in the context of diabetic nephropathy, hence allowing us to consider CDA1 as a molecular target for drug development to treat this condition and related complications.
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
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
Treatment Of Diverse Renal Diseases With Regulatory Cells
Funder
National Health and Medical Research Council
Funding Amount
$566,946.00
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 tranplantation 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. Some forms of kidney disease are self-limited whereas oth ....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 tranplantation 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. Some forms of kidney disease are self-limited whereas others are characterised by chronic kidney scarring and the eventual development of endstage disease. This project will explore whether natural protective cells (regulatory T cells) can be used to treat differing types of CKD, including those characterised predominantly by inflammation or by fibrosis. In addition, the protective mechanisms of regulatory T cells (including their interaction with resident kidney cells) will be explored, as will ways of increasing the efficacy of regulatory T cell therapy.Read moreRead less
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.
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.