Host Determinants Of Hepatitis C-associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$610,376.00
Summary
Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat ....Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat (steatosis) in the liver. This results in the production of biochemical products that lead to tissue damage and to eventual destruction of the liver. Further evidence has recently emerged to suggest that the susceptibility to, and outcome of HCV infection may be influenced by genetic variation in the infected population. The chief investigators on this project have established the best characterised clinical cohort of HCV infected persons worldwide. Further, they have developed considerable expertise in the field of genetics, i.e. the analysis of genes that influence the host's response to an illness. Using this information and expertise, we propose in the present study to analyse in detail the host genetic factors that contribute to variations in the response to HCV, and its correlation with HCV-associated liver damage. This data could allow the development of better patient care strategies and the design of novel therapeutics.Read moreRead less
Angiotensin II AT2 Receptor In Diabetic Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$477,472.00
Summary
Activation of the angiotensin 2 receptor may have effects leading to large artery disease in diabetes. We will investigate the role of the AT2 receptor in diabetes using knockout animals, novel blockers and activators and most importantly the role of the AT2 receptor in macrophages in diabetes.
Acoustic Blood Pressure Measurement On Implanted Biomedical Surfaces
Funder
National Health and Medical Research Council
Funding Amount
$184,687.00
Summary
Measurement of local blood pressure in is of great clinical importance. An application of particular interest is the pressure measurement in and around endoluminal stents grafts, which are used for the treatment of Abdominal Aortic Aneurysms (AAAs). These grafts are implanted by keyhole surgery and are used to reduce the pressure on the aneurysm walls so that the artery can revert to its more anatomically correct shape on a timescale of one to two years. If the seal between the graft and the art ....Measurement of local blood pressure in is of great clinical importance. An application of particular interest is the pressure measurement in and around endoluminal stents grafts, which are used for the treatment of Abdominal Aortic Aneurysms (AAAs). These grafts are implanted by keyhole surgery and are used to reduce the pressure on the aneurysm walls so that the artery can revert to its more anatomically correct shape on a timescale of one to two years. If the seal between the graft and the artery wall is not blood tight, then the aneurysm can become repressurised and may keep on expanding. Over time, an untreated, expanding AAA is likely to rupture with severe consequences for the patient. Thus a convenient, non-invasive means of measuring the pressure within the aneurysm and within the graft is highly desirable. In this proposal, we seek to produce a device that can be incorporated into the walls of the endoluminal graft, which can measure absolute pressure inside and outside the graft and where the pressure measurements can be obtained via standard acoustic or medical ultrasound equipment. To do this, we would use specially designed 'bubbles' which can be incorporated onto either side of the graft walls, where the resonant frequency of the bubbles provides a direct measurement of the pressure around the bubbles. Trials at the CSIRO have found that pressures can be measured to a resolution of better than 10 mmHg by using this technique on air bubbles in water. In this proposal, we wish to develop flexible, but semi-permanent bubbles that can be incorporated onto a biomedical implant surface. If such bubbles can be made, the researchers will use CSIRO-developed software and acoustic equipment such that local blood pressure can be measured in real time.Read moreRead less
Hepatocyte Replicative Arrest, Hepatic Progenitor Cells And The Ductular Reaction In Hepatic Fibrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$527,683.00
Summary
Chronic liver diseases such as hepatitis C and obesity-related fatty liver can be associated with scarring that eventually results in cirrhosis and liver failure. We are unsure why this scarring occurs, but as hepatitis and fatty liver are becoming more common it is necessary to understand this process so that effective therapies can be developed. This study looks at one possible mechanism to explain the development of liver scarring. We believe that the normal repair mechanisms of the liver lea ....Chronic liver diseases such as hepatitis C and obesity-related fatty liver can be associated with scarring that eventually results in cirrhosis and liver failure. We are unsure why this scarring occurs, but as hepatitis and fatty liver are becoming more common it is necessary to understand this process so that effective therapies can be developed. This study looks at one possible mechanism to explain the development of liver scarring. We believe that the normal repair mechanisms of the liver lead to the production of liver cells to replace those that have died, but in some circumstances also produce small bile ducts that drain bile from the hepatocytes. These small bile ducts may have a previously unsuspected role in stimulating the scar formation. The study will see if the small bile ducts are produced in a range of liver diseases in humans, and will use rodent models to find the factors responsible for stimulating the scarring. When the process is understood more clearly, it could lead to the development of new or more effective therapies to reduce or even reverse liver scarring.Read moreRead less
MECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NON-ALCOHOLIC STEATOHEPATITIS
Funder
National Health and Medical Research Council
Funding Amount
$449,591.00
Summary
Fatty liver is the commonest form of liver disease. It is strongly associated with obesity and maturity onset diabetes. The majority of cases of fatty liver disease cause no complications, but when inflammation and liver damage also occur, in the condition of non-alcoholic steatohepatitis or NASH, liver scarring and eventually cirrhosis or liver cancer can result. The reason why some people with fatty liver disease develop NASH and others do not (benign or simple steatosis) is unknown and is the ....Fatty liver is the commonest form of liver disease. It is strongly associated with obesity and maturity onset diabetes. The majority of cases of fatty liver disease cause no complications, but when inflammation and liver damage also occur, in the condition of non-alcoholic steatohepatitis or NASH, liver scarring and eventually cirrhosis or liver cancer can result. The reason why some people with fatty liver disease develop NASH and others do not (benign or simple steatosis) is unknown and is the subject of this research. The studies will be performed in a novel mouse model of obesity and diabetes, the fat aussie mouse, in which all animals develop fatty liver disease after a few months. When fat aussie mice are fed a Macdonald's diet [high in saturated fat] they develop full-blown NASH with liver scarring. Before NASH develops in fat aussie mice, blood levels of adiponectin (a protein produced from fat storage cells) fall. Together with high blood insulin and high blood sugar levels, it is proposed that these changes are what leads to an extraordinarily high build up of fat (lipid) molecules in the liver, to the extent that the fat ultimately damages the liver in a process called lipotoxicity. The planned research will first test whether this hypothesis is correct, and then set about ways to prevent or reverse such a dangerous build up of fats in the liver. Strategies include a high olive oil diet (which is protective in another model of steatohepatitis), correction of blood adiponectin levels, lowering of insulin and blood sugar levels. The anticipated results are a much better understanding of how complications come about in fatty liver disease, and therefore insights into how this disorder can be prevented or reversed in those who are predisposed.Read moreRead less