I am an immunologist with a background in virology and peptide chemistry and my work is therefore inter-disciplinary but focused on the design of synthetic, epitope-based vaccines against infectious agents particularly influenza and hepatitis C viruses an
Hepatitis C virus (HCV), the main cause of of post-transfusion and community -acquired non-A, non-B hepatitis, infects approximately 170 million humans world-wide with some 135,000 infections in Australia alone. HCV is hyper-endemic in intravenous blood users with typical prevalence rates of 60-70%. About 75-80% of infected individuals develop a chronic infection, usually resulting in recurrent, progressively worsening liver damage. Cirrhosis develops in 10-20% of chronic cases while 1-5% of chr ....Hepatitis C virus (HCV), the main cause of of post-transfusion and community -acquired non-A, non-B hepatitis, infects approximately 170 million humans world-wide with some 135,000 infections in Australia alone. HCV is hyper-endemic in intravenous blood users with typical prevalence rates of 60-70%. About 75-80% of infected individuals develop a chronic infection, usually resulting in recurrent, progressively worsening liver damage. Cirrhosis develops in 10-20% of chronic cases while 1-5% of chronic carriers develop liver cancer. Development of an effective vaccine is complicated due to the highly variable nature of the virus. Approved therapies include alpha-interferon and alpha interferon-ribavirin combinations but these treatments induce efficacious responses in only 20-30% of patients and often have severe side-effects. It is assumed that after attachment of HCV to the cell surface, the virus is internalised by the cell and undergoes fusion with a cellular compartment referred to as an endosome. The low pH environment of the endosome is presumed to trigger viral fusion via its cell surface glycoproteins and empties the replication machinery of the virus into the cell. No reliable systems for the propagation of HCV are available thereby limiting studies into the mechanisms of how HCV infects cells and the development of vaccines. Recently a cell surface molecule, CD81, was identified as a possible receptor for the attachment of HCV to susceptible cells. Our aim is to 1) develop model systems for studying HCV entry and fusion and 2) further characterise the interaction of the HCV glycoproteins with CD81 with the goal of obtaining a three-dimersional structure of the interaction . These studies will address the fundamental questions of how HCV enters cells leading new avenues for the design of inhibitors of HCV entry.Read moreRead less
Role Of The Hepatitis C Virus Glycoprotein E2 Variable Regions In Viral Entry And Antibody Mediated Neutralization.
Funder
National Health and Medical Research Council
Funding Amount
$542,462.00
Summary
The first stage of Hepatitis C Virus replication involves attaching to liver cells. This study is aimed at understanding how the virus attaches to liver cells and how antibodies raised during infection, block this interaction. In addition, this study aims to examine how the virus modulates its structure to evade the immne system, allowing the virus to establish chronic infections. The results of this study will guide future vaccine design for HCV.
Hepatitis C Virus-specific Cellular Immune Responses Post-liver Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$470,233.00
Summary
Liver diseases associated with Hepatitis C, including liver failure and liver cancer, are now the leading indication for liver transplantation globally. However, the virus re-infects the new liver and eventually results in scarring and liver failure. This work aims to understand the role of the immune response to the virus in this liver damage, thus allowing modification of existing treatments and development of new therapies that will lead to improved outcomes for these individuals.
Roles Of Enzymes Of The Dipeptidyl Peptidase Gene Family In Human Liver
Funder
National Health and Medical Research Council
Funding Amount
$79,750.00
Summary
Chronic liver diseases, particularly those caused by autoimmune disease, alcohol and Hepatitis B and C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. Each year 15,000 Australians become infected, probably for life, with hepatitis C virus. Unless more effective treatments are developed approximately 20% of these infe ....Chronic liver diseases, particularly those caused by autoimmune disease, alcohol and Hepatitis B and C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. Each year 15,000 Australians become infected, probably for life, with hepatitis C virus. Unless more effective treatments are developed approximately 20% of these infections will progress to liver failure or liver cancer within 30 years. Diabetes afflicts 150 million people, and 90% have Type 2 diabetes. We request funding of our research on a family of enzymes highly prospective as targets for novel therapies for these diseases. We are internationally recognised experts on this enzyme family and on liver disease. The prototype member of this enzyme family, dipeptidyl peptidase (DP) IV, is being targeted by novel drugs that are in phase III clinical trials for Type 2 diabetes. Family member fibroblast activation protein (FAP) is targeted by novel anti-cancer drugs We were first to clone and lodge patent applications for two new enzymes of this family, DP8 and DP9. Our research proposal would lead to determination of whether FAP, DP8 and-or DP9 are valuable targets for novel liver disease therapeutics and facilitate generating the development of such therapeutics by a more thorough understanding of the activities and roles of these enzymes Completion of this project will greatly increase our understanding of these enzymes and their roles in chronic liver injury. This work can potentially lead to the development of specific inhibitors of enzyme function designed to relieve liver damage.Read moreRead less
Ecstasy, Methamphetamine And Their Combination: Assessment Of Adverse Effects
Funder
National Health and Medical Research Council
Funding Amount
$384,250.00
Summary
MDMA (Ecstasy) and Methamphetamine (METH) are popular party drugs that are frequently used by young Australians. Health problems associated with MDMA and METH use are (1) many people suffer complications arising from the high body temperature (hyperthermia) that these drugs produce, and (2) MDMA and METH may both cause long-term loss of key neurotransmitters in the brain. This effect on the brain may well lead to psychological problems such as anxiety, depression, increased impulsive behaviour a ....MDMA (Ecstasy) and Methamphetamine (METH) are popular party drugs that are frequently used by young Australians. Health problems associated with MDMA and METH use are (1) many people suffer complications arising from the high body temperature (hyperthermia) that these drugs produce, and (2) MDMA and METH may both cause long-term loss of key neurotransmitters in the brain. This effect on the brain may well lead to psychological problems such as anxiety, depression, increased impulsive behaviour and memory impairment. However the link between MDMA and METH use and subsequent brain damage is still very controversial. Recently, we have found that when MDMA and METH are combined, a particularly toxic effect is seen with very high body temperatures and lasting adverse effects on mood and brain function. This is a major cause for concern because of evidence that many Australian drug users are combining METH and MDMA on a regular basis. This project will investigate the short and long-term effects of MDMA, METH and METH-MDMA combinations. Phase 1 is aimed at investigating whether different doses of the drugs lead to lasting changes in mood, behaviour and brain function and to compare the relative toxicity of the three treatments. Phase 2 will determine whether lack of fluid intake, high environmental temperatures and advanced age are risk factors in determining the toxicity of MDMA and METH. Phase 3 will assess whether the toxicity of these drug treatments depends upon whether an animal takes the drugs voluntarily or whether they are injected with the drug by the experimenter. The final part of the project will use a wide variety of advanced techniques to track the brain damage caused by these drug treatments given under a range of conditions. The significance of this project will be in increasing our understanding of how MDMA and METH affect the brain and behaviour and how the harms posed by these drugs may be predicted and therefore minimised.Read moreRead less
Multi-variable based vegetation monitoring and prediction during droughts. This project aims to reduce the uncertainties in characterizing and predicting drought impacts on Australian ecosystems. This project is expected to better understand how vegetation responded to hydro-meteorological conditions from the onset to termination stages during Australian droughts in the past 40 years, by investigating the newly developed first global long-term vegetation water content record from satellites. Exp ....Multi-variable based vegetation monitoring and prediction during droughts. This project aims to reduce the uncertainties in characterizing and predicting drought impacts on Australian ecosystems. This project is expected to better understand how vegetation responded to hydro-meteorological conditions from the onset to termination stages during Australian droughts in the past 40 years, by investigating the newly developed first global long-term vegetation water content record from satellites. Expected outcomes of this project will be the enhanced capacity to better identify early warning signals and more accurately predict vegetation responses to future droughts. This should provide significant benefits in developing drought mitigation strategies for national agricultural production and water resource allocation.Read moreRead less
MDMA (Ecstasy) has recently become one of the most popular recreational drugs in the world. A major concern with MDMA use is the mounting evidence from animal studies that even moderate doses may cause irreversible damage to nerve cells that utilize serotonin (5-HT) for neurotransmission. What is not known is how this damage might be expressed in terms of altered emotion, cognition and behaviour. Existing evidence suggests an important role for 5-HT in anxiety, depression and impulsiveness, but ....MDMA (Ecstasy) has recently become one of the most popular recreational drugs in the world. A major concern with MDMA use is the mounting evidence from animal studies that even moderate doses may cause irreversible damage to nerve cells that utilize serotonin (5-HT) for neurotransmission. What is not known is how this damage might be expressed in terms of altered emotion, cognition and behaviour. Existing evidence suggests an important role for 5-HT in anxiety, depression and impulsiveness, but whether MDMA use will increase the likelihood of such problems is uncertain. A major aim of this project is to examine the behavioural, cognitive and emotional changes in rats following exposure to MDMA. Using a variety of sophisticated tasks, we will determine the acute and the long term effects of MDMA in relation to memory, attention, impulsivity, and anxiety. A further concern is whether MDMA use may increase vulnerability to the addictive effects of other drugs of abuse . We aim to examine whether rats pre-exposed to MDMA are subsequently sensitised to the rewarding effects of cocaine and opioids. MDMA users may also suffer a temporary depression a few days after taking the drug. We will assess the possible anhedonic or depressing effects of MDMA. Finally, there is still a lot to understand about the way MDMA affects the brain. Our recent work shows that many diverse brain regions are affected by this drug. We want to extend this work to see how this pattern of brain activation is altered by fluid deprivation and high ambient temperatures - conditions experienced at rave parties. The present project will help further our understanding of MDMA and its neurotoxic effects and to highlight any potential long-term dangers to health that may exist for people who are currently using or are planning to use this drug.Read moreRead less
A Multi-site RCT Comparing Spinal And General Anaesthesia On Neurodevelopmental Outcome And Apnoea In Infants
Funder
National Health and Medical Research Council
Funding Amount
$512,072.00
Summary
5% of Australian children have surgery when they are infants. Recent studies have shown that surgery in babies is associated with poorer neurological outcomes. The reason for this is unclear but animal experiments suggest it may be due to some anaesthetic agents. This trial will determine if the anaesthetic is the cause of the problem. 660 babies who need surgery will be randomised to receive a general or local anaesthetic, and then followed for 5 years.
Multi-scale ensemble modelling of coastal systems in a changing climate. This project aims to incorporate sandy shoreline adaptation by developing a time-varying framework for model ensemble averaging. This will significantly advance our ability to predict shoreline change over a range of management timescales from days to decades along high-value coastlines. This project expects to generate new knowledge in Coastal Engineering using new methods to train models and deliver unprecedented new shor ....Multi-scale ensemble modelling of coastal systems in a changing climate. This project aims to incorporate sandy shoreline adaptation by developing a time-varying framework for model ensemble averaging. This will significantly advance our ability to predict shoreline change over a range of management timescales from days to decades along high-value coastlines. This project expects to generate new knowledge in Coastal Engineering using new methods to train models and deliver unprecedented new shoreline data. The expected outcomes are enhanced capacity to predict shoreline change over a range of timescales and a better understanding of how sandy coastlines adapt to future climate variability. This should provide significant benefits by enabling a better assessment of coastal hazards along our high-value coastline.Read moreRead less