Superoxide And The Nitric Oxide-peroxynitrite Pathway In Renal Ischaemia-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$202,755.00
Summary
Acute renal failure is common and has 50% mortality. Free radicals are vey reactive, unstable molecules that alter normal metabolic reactions. The study aims to determine the role of oxygen-derived free radicals and nitric oxide and their interaction in renal ischaemic injury. The balance between the positive effects of nitric oxide on blood flow and the damaging effects of by-products of the reaction of nitric oxide with superoxide radical (peroxynitrite) on renal tubules may determine the exte ....Acute renal failure is common and has 50% mortality. Free radicals are vey reactive, unstable molecules that alter normal metabolic reactions. The study aims to determine the role of oxygen-derived free radicals and nitric oxide and their interaction in renal ischaemic injury. The balance between the positive effects of nitric oxide on blood flow and the damaging effects of by-products of the reaction of nitric oxide with superoxide radical (peroxynitrite) on renal tubules may determine the extent of cell damage and hence recovery from ischaemic and hypoxic renal injury. Modulation of these opposing forces may lead to strategies to protect and improve renal function in acute renal failure in man.Read moreRead less
The Role Of Tissue Factor In Renal Ischaemia-Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$268,500.00
Summary
Reestablishment of blood flow to an organ (reperfusion) following temporary cessation or obstruction is essential for survival and recovery of the organ. However while essential for organ survival reperfusion results in damage to the organ in a number of cases, including heart, brain, kidney, and gastrointestinal tract, with important implications for patient morbidity and mortality. In the kidney lack of blood flow can result in acute kidney failure that is a costly condition to manage often re ....Reestablishment of blood flow to an organ (reperfusion) following temporary cessation or obstruction is essential for survival and recovery of the organ. However while essential for organ survival reperfusion results in damage to the organ in a number of cases, including heart, brain, kidney, and gastrointestinal tract, with important implications for patient morbidity and mortality. In the kidney lack of blood flow can result in acute kidney failure that is a costly condition to manage often requiring admission to an intensive care unit and is still associated with a significant risk of death. Reperfusion injury that occurs during renal transplantation is currently thought to be an important contributor to delayed establishment of kidney function following transplantation that in turn may increase the incidence of acute and chronic rejection. The studies outlined in this proposal will investigate how molecules involved in the blood clotting system may contribute to the inflammatory response that occurs upon reperfusion of the kidney following prior obstruction of blood flow. We will study a mouse model of kidney reperfusion injury and using genetically modified mice determine the role of various blood clotting-related proteins in subsequent inflammation and organ damage. The approach to be employed will provide a powerful method to determine the role of various molecules and pathways in contributing to kidney damage after reperfusion injury. Interventions that may reduce the incidence or severity of renal damage following kidney reperfusion injury have the potential to be of major benefit to patients and to reduce health care costs.Read moreRead less
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
Molecular Mechanisms Of Macrophage-mediated Renal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$59,756.00
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 reply upon steroids and cytotoxic drugs. These therapies have only limited efficacy and are associated with significant side-effects. Therefore, we need to develop new and specific approaches to the treatment of kidney di ....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 reply upon steroids and cytotoxic drugs. These therapies have only limited efficacy and are associated with significant side-effects. Therefore, we need to develop new and specific approaches to the treatment of kidney disease. To do this, we need to begin by understanding the way in which the kidney is damaged in 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, one 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 enable us to develop new and specific approaches to the treatment of human kidney disease.Read moreRead less
Targeting Innate Immunity To Prevent Chronic Dysfunction Of The Transplanted Kidney
Funder
National Health and Medical Research Council
Funding Amount
$497,057.00
Summary
Kidney transplantation is the optimal treatment for patients suffering from end-stage kidney disease. Chronic transplant dysfunction is the major barrier to long-term health after transplantation, and is the subject of this application. Our studies suggest a signaling system activates immunity and leads to chronic transplant dysfunction. We aim to block this signaling system in mouse models to identify clinically applicable treatments to prevent kidney transplant failure.
Identification Of Mechanisms By Which Mesenchymal Stromal Cells Ameliorate Renal Ischaemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$104,985.00
Summary
Acute kidney injury (AKI) is a common clinical entity which is associated with an increased risk of death and chronic kidney disease. Infusing adult mesenchymal stromal cells (cells which usually reside in the bone marrow but migrate to sites of inflammation or injury) has been shown to be beneficial in animal models of AKI, but it is not known how they have this effect. This project is designed to investigate the mechanism of action of mesenchymal stromal cells in AKI.
The Role Of Renal Dendritic Cells In Infection And Immunity Under Immunosuppression
Funder
National Health and Medical Research Council
Funding Amount
$475,143.00
Summary
Kidney transplantation is the best treatment for kidney failure but it is frequently complicated by bacterial and viral infections that can cause rejection and may cause loss of the kidney. This grant will study the role that dendritic cells in the kidney play in causing rejection and preventing infection. With the knowledge gained from these studies, we will be able to discover new ways to prevent rejection and treat infections of the kidney post transplant.