A Novel Endogenous Inhibitor For The Treatment Of Diabetic Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$774,606.00
Summary
In various kidney diseases including the most common cause of end stage kidney disease, diabetic nephropathy, identifying the molecular mechanisms responsible for kidney failure are needed to assist in defining new targets and to develop more effective treatments. The proposed studies highlight the potential of a naturally occurring endogenous molecule called Lipoxin, as a modulator of kidney injury which may provide us with a novel approach to tackle the problem of diabetic nephropathy.
To investigate alternative strategies to treat end stage renal disease we have transplanted embryonic kidneys into the wall of the abdominal cavity of adult hosts where they become vascularised and undergo continued but limited development. Strategies to enhance their growth-development and decrease immunogenicity-rejection will now be determined, and the origin of a 'ureter-like' tube of tissue that grows to connect the transplanted embryonic kidney with the recipient bladder investigated.
We have validated CDA1 as an effective target to retard kidney disease in diabetes using a mouse model where we deleted the CDA1gene. We have also developed a novel agent to inhibit CDA1 in order to retard diabetic kidney disease. In this application, we propose to confirm the efficacy of targeting CDA1 using various diabetes models and a range of strategies to target CDA1. We will also rigorously explore translation of these findings to a new treatment for diabetic renal disease.
Lefty - A Novel Anti-fibrotic Molecule For The Treatment Of Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$425,920.00
Summary
Patients with progressive forms of kidney disease go on to develop end-stage renal failure which requires intensive medical support of dialysis or organ transplantation. This is an increasingly common condition in Australia, and the Western world in general. It is devastating for the individual and it places an enormous economic strain upon our healthcare system. In addition, renal failure is a strong and independent risk factor for cardiovascular disease. Current treatments can at best slow the ....Patients with progressive forms of kidney disease go on to develop end-stage renal failure which requires intensive medical support of dialysis or organ transplantation. This is an increasingly common condition in Australia, and the Western world in general. It is devastating for the individual and it places an enormous economic strain upon our healthcare system. In addition, renal failure is a strong and independent risk factor for cardiovascular disease. Current treatments can at best slow the rate of progression of kidney disease, but cannot prevent the relentless progression to end-stage renal failure. Thus, there is a major medical need to be able to halt, and hopefully reverse, this relentless disease. Scarring of the kidney (termed fibrosis) is the common final pathway leading to end-stage renal failure regardless of the nature of the underlying kidney disease. Our preliminary studies have shown that a naturally occurring protein called Lefty can act to inhibit renal fibrosis in cell culture and animal studies. These very promising results have lead to the hypothesis that Lefty can halt, and perhaps even reverse, scarring of the kidney in progressive kidney disease. We will test this hypothesis by using Lefty as a treatment in animal models of renal fibrosis. Further cell culture studies are also planned to examine the mechanisms by which Lefty modulates renal fibrosis. If successful, these studies will provide critical data to support the development of Lefty as a clinical treatment for patients with progressive forms of kidney disease.Read moreRead less
We have shown that premature birth leads to abnormalities in kidney structure and function. This project will determine in human infants, whether premature birth when combined with poor growth in the womb leads to an increase in these kidney abnormalities. Using animal studies we will examine specific factors which may adversely impact on kidney growth before and after premature birth. The findings are very relevant to the long-term kidney health of indigenous Australians.
Kidney fibrosis is a serious complication seen in diabetic subjects. This process is mainly controlled by transforming growth factor beta (TGF-beta). However, direct targeting of TGF-beta as a therapeutic approach is inappropriate due to its other important functions. Our preliminary data show that Cell Division Autoantigen 1 (CDA1) is critical for the disease causing activity of TGF-beta. We propose to use our recently generated unique CDA1 gene knockout mouse to demonstrate this important role ....Kidney fibrosis is a serious complication seen in diabetic subjects. This process is mainly controlled by transforming growth factor beta (TGF-beta). However, direct targeting of TGF-beta as a therapeutic approach is inappropriate due to its other important functions. Our preliminary data show that Cell Division Autoantigen 1 (CDA1) is critical for the disease causing activity of TGF-beta. We propose to use our recently generated unique CDA1 gene knockout mouse to demonstrate this important role of CDA1.Read moreRead less
Cyclin Dependent Kinases As Drug-Targets To Reduce Renal Cyst Formation And Scarring In Polycystic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
Polcystic kidney disease (PKD) is one of the most common genetic diseases in humans. The most common type (autosomal dominant-PKD) affects approximately 1:400 to 1:1000 individuals worldwide. Kidney failure is the most debilitating and serious complication of PKD, and it accounts for approximately 10% of the cases of end-stage kidney requiring artificial kidney treatment (dialysis) or transplantation. Over the last decade, major advances have been made in preventing kidney failure due to diabeti ....Polcystic kidney disease (PKD) is one of the most common genetic diseases in humans. The most common type (autosomal dominant-PKD) affects approximately 1:400 to 1:1000 individuals worldwide. Kidney failure is the most debilitating and serious complication of PKD, and it accounts for approximately 10% of the cases of end-stage kidney requiring artificial kidney treatment (dialysis) or transplantation. Over the last decade, major advances have been made in preventing kidney failure due to diabetic kidney disease, but these are ineffective for PKD. As such, currently, there is no treatment to prevent kidney failure due to PKD, and new therapies are needed. PKD is characterised by the development of multiple cysts in the kidney, which enlarge and destroy normal kidney tissue. The growth of the cysts is due to uncontrolled growth (cell division) of the cells of the kidney (epithelial cells), which causes cyst formation. In recent years, gene mutations in proteins called polcysytins are thought to be responsible for the cause of the disease. However, the genetic mutations in PKD are complex (>30 types for autosomal dominant PKD alone), and it is unlikely that gene therapy will be possible with current technology in the near future. A simpler approach is to develop 'drugs' that target the consequences of the mutation. This project will investigate the role of a group proteins, called cyclin-dependent kinases (CDKs) in PKD. CDKs which are enzymes that are critical in promoting cell division. Our preliminary data shows that CDKs are upregulated in PKD. The aim of this project is to establish the importance of CDKs in PKD, and examine the effect of new drugs (CDK inhibitors) in maintaining in preventing cyst growth and kidney scarring in PKD. CDK inhibitors are currently being tested in phase 1 and 2 clinical trials in patients with cancer, and this will facilitate the translation of the findings of this project to humans with PKD.Read moreRead less