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Novel Genes And Protein In Non-alcoholic Fatty Liver Disease: Potential Basis Of A Serum-based Assessment Of Disease Sta
Funder
National Health and Medical Research Council
Funding Amount
$200,000.00
Summary
The most common cause of elevated liver function tests is non-alcoholic fatty liver disease (NAFLD). NALFD is a spectrum of disease ranging from steatosis, to non-alcoholic steatohepatitis (NASH), a condition associated with the development of fibrosis in the majority of individuals. Approximately 20% and 3% of adults are affected with NAFLD and NASH, respectively, and NAFLD is expected to become the next major liver epidemic facing the western world, far exceeding the prevalence of chronic infe ....The most common cause of elevated liver function tests is non-alcoholic fatty liver disease (NAFLD). NALFD is a spectrum of disease ranging from steatosis, to non-alcoholic steatohepatitis (NASH), a condition associated with the development of fibrosis in the majority of individuals. Approximately 20% and 3% of adults are affected with NAFLD and NASH, respectively, and NAFLD is expected to become the next major liver epidemic facing the western world, far exceeding the prevalence of chronic infection with the hepatitis C virus. We obtained liver biopsies from patients with NAFLD, 80% of whom had NASH, and determined the expression profile analysis of each subject using 19,200 element microarrays. Our data demonstrates the concordant differential expression of 130 genes, in subjects with NAFLD that were categorizes into 6 major metabolic and regulatory pathways. Many of these genes represented uncharacterised genes. Utilising an extensive bioinformatics approach we have been able to define the genes and their protein product. The use of these proteins as a diagnostic tool for the detection of NAFLD forms the basis of a provisional patent application. However, measurements of protein levels in tissue and sera from patients with NAFLD are needed for the development of a diagnostic method. Such information would also provide significant insight into the pathogenesis of NAFLD. The AIMS are: 1) Production of antibodies against proteins encoded by candidate genes Expression profile of candidate genes 3) Expression of proteins encoded by candidate genes in patients with NAFLDRead moreRead less
Targeting Protein Kinase C In Diabetes Management Using Novel Polyunsaturated Fatty Acids
Funder
National Health and Medical Research Council
Funding Amount
$150,000.00
Summary
PKC regulates a diverse range of cellular processes in an isozyme-specific manner. There is strong recent evidence to implicate PKC, especially PKC _, in mediating the actions of glucose in diabetes. This includes the action of glucose in renal glomeruli, retina, aorta and heart of diabetic animals and in cultured cells from these organs. More importantly, inhibition of PKC_ with the PKC_-specific inhibitor, LY333531, blocks the actions of glucose. Recently, our research group designed and synth ....PKC regulates a diverse range of cellular processes in an isozyme-specific manner. There is strong recent evidence to implicate PKC, especially PKC _, in mediating the actions of glucose in diabetes. This includes the action of glucose in renal glomeruli, retina, aorta and heart of diabetic animals and in cultured cells from these organs. More importantly, inhibition of PKC_ with the PKC_-specific inhibitor, LY333531, blocks the actions of glucose. Recently, our research group designed and synthesised a family of novel polyunsaturated fatty acids. One of these, MP5 (_-oxa- 21:3n-3), inhibited high glucose-induced activation of PKC? in cultured mesangial cells as well as in glomeruli of diabetic rats in a relatively selective manner. The overall aim of this proposal is to evaluate the potential for a chemically engineered novel polyunsaturated fatty acid, MP5 (_-oxa-21:3n-3), to treat pathogenesis associated with diabetes by targeting the PKC system. The specific aims are to: 1. Characterise the effects of MP5 on glucose- or advanced glycosylation end product-stimulated activation of protein kinase C (PKC). 2. Determine whether esterification of MP5 into diacylglycerol is essential for the action of MP5 3. Investigate whether MP5 is efficacious at preventing the actions of glucose in vitro e.g. glucose stimulated TGF_ production in mesangial cells, and in vivo in streptozotocin-diabetic rRead moreRead less
Non-invasive Measurement And Imaging Of Hepatic Iron Concentrations Using Nuclear Magnetic Resonance
Funder
National Health and Medical Research Council
Funding Amount
$341,210.00
Summary
Iron overload diseases such as genetic haemochromatosis and thalassaemia affect up to 0.5% of the world's population. These diseases result in deposition of dangerously high concentrations of iron in tissues of the body. Organs such as the liver and heart are at particular risk of being damaged. In order to manage a patient's condition optimally, a knowledge of their tissue iron concentrations is required. Currently the most direct and reliable way of achieving this is to remove a small sample o ....Iron overload diseases such as genetic haemochromatosis and thalassaemia affect up to 0.5% of the world's population. These diseases result in deposition of dangerously high concentrations of iron in tissues of the body. Organs such as the liver and heart are at particular risk of being damaged. In order to manage a patient's condition optimally, a knowledge of their tissue iron concentrations is required. Currently the most direct and reliable way of achieving this is to remove a small sample of the patient's liver for chemical analysis. Apart from the fact that the procedure is unpleasant and carries some risk, the measurement made by this method has some uncertainty because the liver iron concentration can vary significantly from place to place within the liver. The aim of this project is to test the validity of a new non-invasive method of measuring and imaging the liver iron concentrations of a patient. In addition, the potential to use the new technology for detecting and imaging liver cirrhosis in iron overloaded patients will be evaluated. If successful, the project may lead to a more accurate method of measuring tissue iron concentrations and eliminate the need for invasive procedures.Read moreRead less
Performance And Safety Testing Of The BioQ Cardiac Assist System In A Chronic Ovine Heart Failure Animal Model
Funder
National Health and Medical Research Council
Funding Amount
$142,800.00
Summary
This proposal will test a novel cardiac assist system in safety and performance studies using a chronic sheep heart failure model. This device has been tested in cardiovascular simulators and in an acute animal model showing attractive proof-of-concept data. Specifically, the device increased left coronary artery blood flow and reduced aortic pulse and mean pressures using our novel self-powered fully implantable stand alone device, a potential therapy treatment for heart failure.
The Effect Of Stress/strain And Fatigue Fracture Sites On Durability Of Modular Aortic Endografts And Arterial Walls
Funder
National Health and Medical Research Council
Funding Amount
$300,919.00
Summary
Aneurysmal disease is an age related phenomenon. The mean life expectancy of western populations has doubled in 100 years because of the reduction in deaths from preventable and treatable diseases, and prolongation of life with chronic and incurable diseases. The older community (>65 years) continues to be active and productive contrary to prior predictions. Aneurysmal disease has emerged as a result of the changing pattern of diseases in the community. As with many other diseases, prophylaxi ....Aneurysmal disease is an age related phenomenon. The mean life expectancy of western populations has doubled in 100 years because of the reduction in deaths from preventable and treatable diseases, and prolongation of life with chronic and incurable diseases. The older community (>65 years) continues to be active and productive contrary to prior predictions. Aneurysmal disease has emerged as a result of the changing pattern of diseases in the community. As with many other diseases, prophylaxis against aneurysmal disease is the most effective approach since 80% of those that rupture will result in death. Endoluminal grafting provides a much less invasive procedure and provides an attractive and elegant alternative to open surgery. The danger is that structural strengths will be compromised with failures due to lack of strength and inadequate device durability. The most practical endografts are those that are built up from modules but vulnerable sites affected by fatiguing and disruptive forces are being identified, in particular where a tube divides into two outflow channels – the bifurcation - and joins. To improve and protect the current device, and enable sound engineering for future devices, we need to know the nature, magnitude and location of these forces. The existing collaboration with medical specialist, Cook Aust., the Advanced Fluid Dynamics Laboratory (CSIRO, Melb.) and University of WA combines a multidisciplinary team working towards the design and durability of the next generation of endoluminal devices and percutaneous insertions. While Australia is at the forefront of development, its current place in the market can only be maintained by further product development. Optimising and improving endoluminal grafts will reduce the suffering of major surgery while prolonging a higher quality of life with a much less invasive procedure whose long-term effectiveness, and thereby acceptance is dependent upon reliable durability.Read moreRead less
Mechanical Mobility Of The Thorax For Continuous Determination Of Lung Gas Volume
Funder
National Health and Medical Research Council
Funding Amount
$165,000.00
Summary
Percussion is a valuable clinical method for physical examination of parts of the body. A sharp tap (impulsive force) is applied to the body wall and the sound radiated in response is observed. This sound may be dull (over liver) or stony dull (pleural effusion), or resonant (over normal lung) or hyper-resonant (over bowel). While the variation in radiated sound is not fully understood, it is apparent that the presence of gas, which is highly compliant, increases mobility of the overlying tissue ....Percussion is a valuable clinical method for physical examination of parts of the body. A sharp tap (impulsive force) is applied to the body wall and the sound radiated in response is observed. This sound may be dull (over liver) or stony dull (pleural effusion), or resonant (over normal lung) or hyper-resonant (over bowel). While the variation in radiated sound is not fully understood, it is apparent that the presence of gas, which is highly compliant, increases mobility of the overlying tissue and allows it to resonate; where the sub-tissue is largely fluid, tissue mobility is low and the percussive sound is dull. Percussion is useful for examining the adult chest and lung, but cannot for example be applied in infant intensive care as only limited impulsive force can be used, and the adult finger, which is both a coupling device and sounding board, is too large. As well, percussion requires skill and quiet conditions. Accordingly, we developed a device to measure mobility of the chest and other tissues in real time. The VibroPulse applies a known low-level force to the body surface and records the resultant velocity induced in the surface. The force is generated by a vibrating mass set in motion by an electromagnetic motor driven by pseudo-random noise. Tissue mobility, defined as velocity-force, is derived simultaneously across the frequency range, providing an easily interpreted quantitative output unaffected by ambient noise. This proposal has two aims we can achieve in 1 year: (1) to continue evaluating VibroPulse sensitivity to tissue composition, using symmetrical percussive sites on the human chest and abdomen that are dull on one side and resonant on the other, and the chest of anaesthetised animals with experimentally induced pneumothorax and lung collapse, two life-threatening conditions for which percussion is a key diagnostic method, and (2) to engineer a small device from our bulky prototype that is suitable for clinical use, in infants and adults.Read moreRead less
Development And Evaluation Of Novel Fetal Haemoglobin Inducers For The Therapy Of Beta-thalassaemia
Funder
National Health and Medical Research Council
Funding Amount
$288,899.00
Summary
The most important haemoglobinopathies from the clinical point of view are the beta-thalassaemias, sickle cell disease (SCD), HbE disease and the interactions between them. These beta-haemoglobinopathies are the result of mutations in the beta-globin gene, causing beta-globin chain synthesis that is abnormal, low or absent leading to life-threatening severe anaemia, and blood transfusion-dependency for life. An alternative approach to the therapy of beta-thalassemia is to reactivate fetal haemog ....The most important haemoglobinopathies from the clinical point of view are the beta-thalassaemias, sickle cell disease (SCD), HbE disease and the interactions between them. These beta-haemoglobinopathies are the result of mutations in the beta-globin gene, causing beta-globin chain synthesis that is abnormal, low or absent leading to life-threatening severe anaemia, and blood transfusion-dependency for life. An alternative approach to the therapy of beta-thalassemia is to reactivate fetal haemoglobin (HbF) synthesis. Some chemical agents have been identified to induce HbF and significantly reduce the need for blood transfusion in some thalassaemia patients, while in SCD patients it can ameliorate the clinical symptoms. Despite a number of clinical trials investigating the potential of HbF-inducing agents, many of these drugs have low efficacy, specificity, and cytotoxicity. There is therefore an urgent need to identify novel pharmacological agents with greater efficacy and reduced toxicity. Without a clear understanding of the underlying mechanism(s) involved in the induction of HbF, it is virtually impossible to focus on any molecular target. A promising approach is the use of chemical libraries in a high-throughput (HTP) screening to identify positive regulators of gene products. Our research group created an assay that has allowed us for the first time to perform a side-by-side comparison of several previously described fetal hemoglobin inducers including 2000 existing pharmaceuticals used by patients unrelated to thalassaemia. The screen identified a distinct group of compounds that induced the gamma-globin promoter in primary and secondary screens. The identification of novel inducers of HbF warrants further investigation as alternative therapies for beta-thalassemia. This project will evaluate novel inducers of HbF in our thalassaemia mouse model and provide early 'proof-of-concept' and enable the initiation of preclinical and clinical studies.Read moreRead less
Development Of Non-surgical Approach To Treating Tricuspid Regurgitation
Funder
National Health and Medical Research Council
Funding Amount
$266,427.00
Summary
Heart failure is a common problem in which the heart enlarges and contracts poorly. In association with enlargement of the heart, the heart valves also begin to fail causing further worsening of quality and length of life. Failure of the tricuspid valve occurs in upto 87% of patients with heart failure and presently the only treatment option is high risk heart surgery. We are developing a way of dealing with tricuspid valve failure that does not require cardiac surgery.
Novel Nanoparticle Composites For Molecular Probes In Diagnostic Imaging
Funder
National Health and Medical Research Council
Funding Amount
$170,716.00
Summary
Isotope labelled protein probes, eg. antibodies, are a valuable imaging tool in investigating patient disease. Their biological specificity is their great strength, however, detection sensitivity often limits their use. A novel nanoparticle developed at ANU can increase this signal by a million-fold in comparison with conventional methods of labelling. This approach suits a range of probes and will accommodate many of the isotopes already used in patient diagnostics and therapy.