While there are numerous therapies for relapsing-remitting multiple sclerosis (MS), therapy for progressive MS remains elusive. This project will evaluate the effect of various therapies on the accumulation of irreversible disability in progressive MS. In addition, it will examine the effect of switching between therapies on MS activity. Finally, the project will indicate whether demographic and clinical information can be used as a predictor of individual patient response to MS therapies.
Molecular Mechanisms Linking Proteinuria And Sodium Retention
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
The clinical association between protein loss in the urine and retention of salt, resulting in high blood pressure and progressive decline in kidney function, is well known. Under normal conditions, the kidneys filter 180 litres of water and reabsorb 1.7 kg of salt per day, a function which is principally performed by the kidney tubules in the kidney. Similarly the kidney tubule cells reabsorb and break down up to 3 grams of albumin per day. In the past, it has been considered that excessive pro ....The clinical association between protein loss in the urine and retention of salt, resulting in high blood pressure and progressive decline in kidney function, is well known. Under normal conditions, the kidneys filter 180 litres of water and reabsorb 1.7 kg of salt per day, a function which is principally performed by the kidney tubules in the kidney. Similarly the kidney tubule cells reabsorb and break down up to 3 grams of albumin per day. In the past, it has been considered that excessive protein loss in the urine is primarily due to problems in the filtering units of the kidneys, rather than due to abnormalities in the reabsorption of protein in the kidney tubules. However, we consider that common abnormalities in the processes within the kidney tubules that regulate both the reabsorption of salt and the excretion of acid may result in concomitant high blood pressure and increased protein loss in the kidney. Thus the overall aim of the project is to investigate the interrelationship between protein reabsorption and catabolism and Na+ reabsorption in the human kidney tubule. The project uses the combined methods of cultured human kidney tubules, biochemical and molecular biology techniques which are unavailable in other laboratories in Australia (and internationally). This project will comprehensively characterise the mechanisms of protein uptake and salt reabsorption in human kidney tubule cells when exposed to both normal and high concentrations of protein. The exact nature of the interaction of protein uptake with salt reabsorption and hence high blood pressure will be determined. As both hypertension and persistent proteinuria are the most important predictors of tubulointerstitial pathology and progressive decline in renal function in almost all renal disease, the understanding of the precise interaction between these two factors is essential in the design of renoprotective therapies.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
A Model Of Current & Potential Palliative Care Constituency: Measuring Met & Unmet Needs
Funder
National Health and Medical Research Council
Funding Amount
$145,210.00
Summary
Although many health care providers believe palliative care should be offered to all Australians who need it, there is no population-based data to support this claim. This study will provide much needed population-based evidence by measuring the levels of met and unmet needs of people with active, progressive, advanced disease in the last 12 months of their lives. A model of current and potential palliative care constituency will be developed that will lead to improved access to palliative care ....Although many health care providers believe palliative care should be offered to all Australians who need it, there is no population-based data to support this claim. This study will provide much needed population-based evidence by measuring the levels of met and unmet needs of people with active, progressive, advanced disease in the last 12 months of their lives. A model of current and potential palliative care constituency will be developed that will lead to improved access to palliative care for people who do not traditionally access specialist palliative care services.Read moreRead less
The ClC-5 Cl- Channel, A Key Regulatory Role In Albumin Uptake By The Proximal Tubule
Funder
National Health and Medical Research Council
Funding Amount
$510,500.00
Summary
The clinical association between protein loss in the urine and retention of salt, resulting in high blood pressure and progressive decline in kidney function, is well known. Under normal conditions, the kidneys filter 180 litres of water and reabsorb 1.7 kg of salt per day, a function which is principally performed by the kidney tubules in the kidney. Similarly the kidney tubule cells reabsorb and break down up to 3 grams of albumin per day. In the past, it has been considered that excessive pro ....The clinical association between protein loss in the urine and retention of salt, resulting in high blood pressure and progressive decline in kidney function, is well known. Under normal conditions, the kidneys filter 180 litres of water and reabsorb 1.7 kg of salt per day, a function which is principally performed by the kidney tubules in the kidney. Similarly the kidney tubule cells reabsorb and break down up to 3 grams of albumin per day. In the past, it has been considered that excessive protein loss in the urine is primarily due to problems in the filtering units of the kidneys, rather than due to abnormalities in the reabsorption of protein in the kidney tubules. However, we consider that common abnormalities in the processes within the kidney tubules that regulate both the reabsorption of salt and the excretion of acid may result in concomitant high blood pressure and increased protein loss in the kidney. Thus the overall aim of the project is to investigate the mechanisms by which the complex responsible for protein uptake determines the interrelationship between protein reabsorption and catabolism and the ion transporting proteins in the membrane of the proximal tubule. This project will comprehensively characterise the mechanisms of protein uptake in kidney tubule cells. The exact nature of the interaction of the proteins involved in performing the salt reabsorption and ensuring correct catabolism of protein uptake with the actual protein uptake mechanism will be determined. As persistent proteinuria is the most important predictor of tubulointerstitial pathology and progressive decline in renal function in almost all renal disease, the understanding of the precise mechanism by which this occurs is essential in the design of renoprotective therapies.Read moreRead less
Vitamin D3 Receptor Signalling To Prevent Kidney Failure Due To Polycystic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$468,009.00
Summary
Polycystic kidney disease (PKD) is the most common fatal inherited kidney disease in the world. Kidney failure is the most serious and life-threatening complication of PKD, but currently there is no treatment to prevent this problem. The aim of this project is to determine whether vitamin D3 can prevent kidney failure and hypertension due to PKD. The results of this project could lead to simple and cost-effective treatments to prevent kidney failure in patients suffering from PKD.
TGFbeta Isoforms Differentially Regulate Fibrosis And Inflammation In Diabetic Nephropathy Via KLF Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$540,639.00
Summary
Progressive scarring and inflammation in the kidney represent the final common injury pathway for diseases that lead to kidney failure, including diabetic nephropathy. This project explores the interplay between the molecular processes that are triggered by high glucose levels in patients with diabetic nephropathy, some of which are deleterious and some potentially 'protective'. By understanding these mechanisms we will be able to prevent and more effectively treat kidney disease in diabetes.