Molecular Mechanisms Of Macrophage-mediated Renal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$437,036.00
Summary
The complete loss of kidney function means that survival of the patient is dependent upon lifelong dialysis or a kidney transplant. Dialysis patients have a poor quality of life, and the provision of dialysis and transplantation treatments are very costly. Our current therapies have only limited efficacy and are associated with significant side-effects. Therefore, we need to understanding the way in which the kidney is damaged in disease in order to identify new and specific approaches to the tr ....The complete loss of kidney function means that survival of the patient is dependent upon lifelong dialysis or a kidney transplant. Dialysis patients have a poor quality of life, and the provision of dialysis and transplantation treatments are very costly. Our current therapies have only limited efficacy and are associated with significant side-effects. Therefore, we need to understanding the way in which the kidney is damaged in disease in order to identify new and specific approaches to the treatment of kidney disease. Our studies have shown that white blood cells, called macrophages, enter the kidney in large numbers during disease. Indeed, the greater the number of macrophages within the kidney, the more severe the kidney injury. We believe, on the basis of animal studies, that these macrophages cause kidney injury. However, we do not know the mechanisms by which this happens. To address this question, we have developed a rat model of kidney disease in which we can take macrophages, which we have cultured in the laboratory, and inject them into animals and they will enter the kidney and cause injury. This allows us to modify specific macrophage functions in culture and then determine whether this affects the ability of these macrophages to cause kidney injury in the animal. In this way, we will be able to understand the mechanisms by which macrophages cause kidney injury. We hope that these studies will can be a starting point for the development of new and specific approaches to the treatment of human kidney disease.Read moreRead less
The glomerulus is the filtering component of the kidney. In many diseases, it can be the target of an inappropriate inflammatory response. As part of this response, white blood cells accumulate in the glomerulus where they cause damage. In this project, we make use of special microscopes to examine the glomerulus during an inflammatory response, with the aim of understanding the actions of leukocytes present in glomeruli and how they cause inflammation and damage the glomerulus.
Current therapy for AAV has major toxicities and 30% of Patients are dead or on dialysis within 3 years. This proposal aims to study a unique form of cell death termed Neutrophil extracellular traps (NETs) that initiates and perpetuates inflammation in this disease. We will use an animal model of the disease that mirrors human disease. We will inhibit crucial molecules in NET production to attenuate disease. This will provide proof of concept evidence to promote clinical trials in patients.
Inflammation of the kidneys is an important, yet poorly understood cause of kidney disease in Australia. This project will define the role of some of the immune cells, called Th17, that usually act to protect us from infection, but can turn rouge and may cause kidney damage.
TLR9 AGGRAVATES GLOMERULONEPHRITIS AND KIDNEY INJURY IN RENAL VASCULITIS
Funder
National Health and Medical Research Council
Funding Amount
$349,336.00
Summary
Renal failure is a significant cause of morbidity and mortality in Australia. Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis associated glomerulonephritis (GN) is a significant cause of renal failure. The molecular mechanisms underlying ANCA vasculitis are poorly understood, while treatments are associated with considerable morbidity and mortality. This grant aims to explore key molecular events involved in the disease pathogenesis to facilitate the use of safer more targeted therapies.
Kidney disease occurs in up to 50% of patients with insulin-dependent (type 1) and non-insulin-dependent (type 2) diabetes. The increasing rate of diabetes in our community has made it a major cause of kidney disease and a growing health problem. Despite clinical attempts to control blood glucose and blood pressure levels, kidney disease in most diabetic patients progresses towards a complete loss of kidney function. In severe cases, the survival of the patient is dependent upon lifelong dialysi ....Kidney disease occurs in up to 50% of patients with insulin-dependent (type 1) and non-insulin-dependent (type 2) diabetes. The increasing rate of diabetes in our community has made it a major cause of kidney disease and a growing health problem. Despite clinical attempts to control blood glucose and blood pressure levels, kidney disease in most diabetic patients progresses towards a complete loss of kidney function. In severe cases, the survival of the patient is dependent upon lifelong dialysis or transplantation, which are costly and complicated treatments. Therefore, there is an urgent need to improve treatment stategies in diabetic patients to avoid kidney failure. Recent evidence in human and experimental models of diabetic kidney disease has indicated that macrophages infiltrate the kidney during the disease process. Our previous knowledge from other inflammatory kidney diseases suggests that macrophages play an important role in promoting the progression of disease and, in some of these diseases, treatment strategies which block macrophage function and accumulation have been shown to be effective in inhibiting the disease. The overall aim of these studies will be to determine the importance of macrophages in the pathogenesis of diabetic kidney disease and identify the mechanisms regulating their recruitment and activation within the diabetic kidney. This will be achieved by examining the progression of kidney disease in type 1 and type 2 diabetic mice which have been genetically modified to prevent macrophage accumulation and activation within the kidney. These studies will provide valuable information into the pathogenesis of diabetic kidney disease and will identify whether therapeutic strategies targeting macrophages can help prevent kidney loss in diabetes.Read moreRead less
Apoptosis Signal-regulating Kinase 1 (ASK1) Is A Major Pathway Of Stress-induced Renal Injury In Different Types Of Progressive Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$678,865.00
Summary
Oxidative stress plays an important role in progressive kidney disease. We have identified a stress-activated mechanism (the ASK1 pathway) through which oxidative stress may cause kidney disease. We will perform preclinical studies in models of different types of kidney disease with an ASK1 inhibitor drug and genetically modified mice. These studies will provide new insights into the pathogenesis of kidney disease and will determine the potential of ASK1 as therapeutic target in kidney disease.
Stress-activated Protein Kinases - A Common Pathway Of Progressive Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$581,750.00
Summary
Patients who progress to end-stage renal failure require treatment by life-long dialysis or kidney transplantation. In addition, renal failure is a strong and independent risk factor for heart attack. Renal failure is a major health problem in our community in terms of patient welfare and the substantial financial cost of renal replacement therapy and cardiac complications. Even with recent improvements in the control of blood pressure, we still have far to go in terms of halting progression and ....Patients who progress to end-stage renal failure require treatment by life-long dialysis or kidney transplantation. In addition, renal failure is a strong and independent risk factor for heart attack. Renal failure is a major health problem in our community in terms of patient welfare and the substantial financial cost of renal replacement therapy and cardiac complications. Even with recent improvements in the control of blood pressure, we still have far to go in terms of halting progression and disease remission. Current therapies are still based on non-specific anti-inflammatory drugs which have substantial, dose-limiting side effects. Indeed, our current therapies do not even target the some of the critical pathogenic processes of progressive kidney disease, such as apoptotic cell death and fibrosis. Therefore, it is important to identify common mechanisms of progressive kidney disease. Irrespective of the nature of the initial renal insult, progressive forms of kidney disease show common pathogenic processes of inflammation, apoptotic cell death and fibrosis that inexorably lead to end stage renal failure. Recent studies from our laboratory, and others, suggest that these three pathogenic processes operate via a common pathway called the SAPK (stress-activated protein kinases). This hypothesis will be tested by blocking the SAPK pathway in three different animal models of kidney disease which feature these key pathogenic processes (inflammation, apoptosis cell death and fibrosis). Blockade of the SAPK pathway will be achieved by means of pharmaceutical drugs and using gene deficient mice. If this hypothesis were proven, this would provide a well-defined therapeutic target for the treatment of progressive kidney disease. Indeed, since inhibitors of the SAPK pathway are already in clinical trials for other indications, targeting this mechanism in progressive kidney disease is a realistic goal.Read moreRead less
Mechanistic And Translational Studies Targeting Kidney Inflammation And Fibrosis.
Funder
National Health and Medical Research Council
Funding Amount
$697,209.00
Summary
The progression of kidney disease to end-stage renal failure requires support by dialysis or kidney transplantation, leading to reduced quality of life, loss of productivity, and the huge cost of renal replacement therapy in Australia ($1 billion in 2010). This research program focuses on two areas; advancing our understanding of the basic mechanisms of disease pathogenesis, and working with commercial partners to translate my current research effort towards new therapies for kidney disease.
New Roles For The Spleen Tyrosine Kinase In Antibody-independent Renal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$574,890.00
Summary
This study investigates the novel hypothesis that a particular cell activation pathway (called Syk) is important not only in antibody-based kidney disease, but that it also plays a previously unrecognised role in other forms of antibody-independent kidney disease. Drugs that inhibit the Syk pathway are in clinical development for treatment of diseases such as arthritis. Hence, a positive outcome of this project could lead to the use of Syk inhibitors in many different types of kidney disease.