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
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.
Contribution Of Bone Marrow-derived Cells To Renal Fibrosis And Elucidation Of Cell Signalling Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$427,703.00
Summary
This study investigates the contribution of bone marrow-derived adult stem cells to the development of renal scarring, an important process proceeding to end-stage renal disease (ESRD). There is increasing evidence demonstrating that bone marrow (BM)-derived cells can transform into renal cells and participate in the repair of damaged renal blood vessels. Our recent study demonstrated BM-derived stem cells can also transform to renal myofibroblasts, the major cell type that contributes to the de ....This study investigates the contribution of bone marrow-derived adult stem cells to the development of renal scarring, an important process proceeding to end-stage renal disease (ESRD). There is increasing evidence demonstrating that bone marrow (BM)-derived cells can transform into renal cells and participate in the repair of damaged renal blood vessels. Our recent study demonstrated BM-derived stem cells can also transform to renal myofibroblasts, the major cell type that contributes to the development of kidney scarring. This suggests that BM-derived adult stem cells have dual roles: to repair or worsen the development of renal scarring. The present study investigates this adult stem cell's transformation and explores the potential measures to enhance the benefits and to block the harmful roles from these adult stem cells. The importance of BM-derived stem cells in the repair of damaged kidney will be determined and thus will provide preliminary insights into the future utilization of BM-derived stem cells in the treatment of chronic renal disease. Understanding the dual roles of BM-derived stem cells in experimental renal scarring, will lead us to question our current thinking and approaches to the treatment and management of renal fibrosis, and perhaps fibrosis in other organs. Evidence of two opposite roles which BM-derived adult stem cells play in the process of renal scarring may be helpful not only for the design of novel therapies to prevent or retard the progression of renal fibrosis, but also for manipulating adult stem cells for the treatment of renal disease.Read moreRead less
Control Of Uterine Contraction: Role Of Interstitial Cells
Funder
National Health and Medical Research Council
Funding Amount
$587,206.00
Summary
Being born premature may increase risk of below average IQ, poor performance at school and behavioural difficulties in the child, and increased obesity and blood pressure as an adult, predisposing to life long socio-economic disadvantage. We have come up with a new approach to understanding the control of uterine contraction, namely, that cells other than muscle cells, recently identified in the uterine wall, are essential for inducing forceful and orderly muscle cell contraction during labour.
Intramuscular Interstitial Cells Of Cajal; Ion Channels And Their Modulation By Calcium Ions And Neurotransmitters.
Funder
National Health and Medical Research Council
Funding Amount
$523,261.00
Summary
Disorders of gut motility manifest themselves in several ways, as either patterns of hyperactivity or patterns of reduced activity. Under normal conditions gut motility reflects a balance between myogenic, neuronal and hormonal factors but as yet how this balance is normally achieved is not understood. This project will examine the properties of a class of cells, whose importance in both myogenic and neural control mechanisms has only been recognized over the last 10 years. The muscular wall of ....Disorders of gut motility manifest themselves in several ways, as either patterns of hyperactivity or patterns of reduced activity. Under normal conditions gut motility reflects a balance between myogenic, neuronal and hormonal factors but as yet how this balance is normally achieved is not understood. This project will examine the properties of a class of cells, whose importance in both myogenic and neural control mechanisms has only been recognized over the last 10 years. The muscular wall of the gut is made up of two distinct types of cells. One group, smooth muscle cells, contains contractile elements and the coordinated behavior of these cells leads to the contractions of the gut wall, so ensuring the controlled passage of gut contents along the gastrointestinal tract. The other group of cells, Interstitial cells of Cajal, lack contractile elements. One set of these cells have recently been found to be the pacemaker cells of the gut responsible for the initiation of myogenic activity. They generate pacemaker waves which ensure that the gut contracts rhythmically. Another set of these cells are densely innervated, they receive messages from the nervous system and translate these messages into signals which alter the activity of the gut. Thus these cells play a key role in the neural control of the gut. In many disease states, the numbers of interstitial cells of Cajal have been found to be reduced. However as yet we know very little about these cells. This project will, for the first time, examine the properties of the interstitial cells involved in neural control and will determine how they carry out these essential functions.Read moreRead less
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.