Mechanisms Of Uptake Of 18F-FDG In An In Vivo Model Of C-kit Induced Neoplasia
Funder
National Health and Medical Research Council
Funding Amount
$438,520.00
Summary
Recent advances in the field of tumour biology have created strong interest in development of molecularly targeted anti-tumour drugs. These targeted drugs are expected to yield higher therapeutic indices with fewer side effects than conventional cytotoxic treatments. However, due to the complicated nature of cellular processes affected by a given treatment, and the high cost of bringing new drugs to the clinic, it is important to define both mechanisms of action and in vivo functional effects of ....Recent advances in the field of tumour biology have created strong interest in development of molecularly targeted anti-tumour drugs. These targeted drugs are expected to yield higher therapeutic indices with fewer side effects than conventional cytotoxic treatments. However, due to the complicated nature of cellular processes affected by a given treatment, and the high cost of bringing new drugs to the clinic, it is important to define both mechanisms of action and in vivo functional effects of targeted therapies early in the drug development process. Gastrointestinal stromal tumour (GIST) is a prime example of a cancer for which a rationally designed drug has been successfully used. GISTs are often associated with activating mutations in c-kit, a gene encoding a cell surface protein. A new drug, Imatinib, inhibits the activity of mutated c-kit and blocks growth of many GISTs. However, over time many GISTs become resistant to Imatinib creating the need to develop additional treatments. Unfortunately, this has been hampered by lack of both a good model system for testing new drugs and robust diagnostic procedures for defining response to treatment. We have now developed a mouse model of GIST that grows and responds to treatment in a similar manner to human GIST. Furthermore, using imaging technology specifically designed for small animal studies, we can quickly monitor and evaluate changes in response during treatment. We propose to use the model system together with small animal imaging technology to define mechanisms by which GISTs respond or become resistant to Imatinib. This involves defining specific molecules within cells that change activity after Imatinib treatment as well as testing a series of gene mutations that may be involved in drug resistance. The results of the study will help to define new targets for GIST treatment as well as validate the imaging strategy that may have wide application to monitoring targeted anti-cancer therapies.Read moreRead less
C-Kit Signalling And Cellular Responses In Haemopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$731,115.00
Summary
Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biolo ....Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biology approaches to determine the role of different signalling pathways in cellular responses mediated by the growth factor receptor c-Kit. The c-Kit receptor has essential functions in blood cell development, skin and hair pigmentation, gut function and the reproductive system. It is also essential for the development and function of mast cells which trigger allergic responses such as asthma and eczema. Mutant forms of the receptor have been identified in certain leukaemias and colon cancers. Many new drugs that target specific intracellular signalling pathways have recently been developed and are beginning to be evaluated in clinical trials. Better understanding of how individual pathways contribute to the function of c-Kit and other receptors is essential for optimal use of these new drugs. For example, it may enable the choice of drugs to block c-Kit dependent cancer cell growth or allergic reactions without affecting the growth of normal blood cells.Read moreRead less
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
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
Structure And Function Of Hepatitis C Virus Glycoproteins
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Hepatitis C Virus infects approximately 200 million people world-wide and is the major cause of liver transplantation in the Western world. At present there is no vaccine and interferon alpha is the only therapy available and has only limited success in clearing viral infection. HCV is distantly related to flaviviruses eg tick-borne encephaltitis virus and yellow fever virus. All viruses attach to target cells using receptors to initiate the infection process. In the case of HCV, the envelope gl ....Hepatitis C Virus infects approximately 200 million people world-wide and is the major cause of liver transplantation in the Western world. At present there is no vaccine and interferon alpha is the only therapy available and has only limited success in clearing viral infection. HCV is distantly related to flaviviruses eg tick-borne encephaltitis virus and yellow fever virus. All viruses attach to target cells using receptors to initiate the infection process. In the case of HCV, the envelope glycoproteins interact with as yet unknown receptors on the target cell surface resulting in the virus being internalized into endosomes. It is believed that the low pH environment of these endosomes triggers fusion of the viral and cellular membranes. After fusion the genome of the virus is released into target cells and begins the replication process. The actual events intitiating these processes are not understood for HCV but are believed to be mediated using two envelope glycoproteins. In this project we seek to gain a greater understanding of how viral fusion and entry occurs. We have new information regarding the localisation of the two envelope glycoproteins that will now enable us to carefully examine how viral fusion occurs. Using biochemical approaches, we will study their structure and function and examine how this relates to the well understood flavivirus mode of fusion and entry. We will test the functional consequences of altering the structure of the HCV envelope glycoproteins by developing in vitro assays of HCV fusion. Assays for HCV fusion are essential for future studies to identify viral receptors, examine the role of antibody in viral neutralization and can be used to test novel inhibitors of viral fusion and entry.Read moreRead less
Fine Positioning And Effector Function Of T Cells Recruited To The HCV Infected Liver
Funder
National Health and Medical Research Council
Funding Amount
$321,973.00
Summary
The majority of patients who become infected with hepatitis C virus (HCV) are unable to mount an effective immune response and clear the virus and therefore develop lifelong (chronic) infection. The persistence of virus in the liver of patients with chronic infection results in the recruitment of significant numbers of immune cells, notably T cells, from the bloodstream into the liver where they are involved in both viral control (but not viral clearance) and liver injury. The level of tissue in ....The majority of patients who become infected with hepatitis C virus (HCV) are unable to mount an effective immune response and clear the virus and therefore develop lifelong (chronic) infection. The persistence of virus in the liver of patients with chronic infection results in the recruitment of significant numbers of immune cells, notably T cells, from the bloodstream into the liver where they are involved in both viral control (but not viral clearance) and liver injury. The level of tissue injury observed and the speed of disease progression may be linked to the type of T cells recruited, their function, and their position in the liver. The aims of this project are to determine the factors involved in the fine positioning of T cells in the liver and establish a relationship between T cell recruitment, function, and progression of HCV disease in the liver.Read moreRead less
Behavioural, Virological And Immunological Factors Influencing Hepatitis C Virus Infection In Injecting Drug Users
Funder
National Health and Medical Research Council
Funding Amount
$963,437.00
Summary
The hepatitis C virus (HCV) is a major public health problem affecting over 170 million people worldwide. In Australia an estimated 157,000 people have HCV and are at risk of serious disease, and 16,000 new infections occur each year. Treating HCV-related disease is expensive, and this healthcare burden is projected to grow significantly in coming years. Almost all new HCV infections in Australia occur among injecting drug users (IDUs), and despite our world-leading prevention programs, the viru ....The hepatitis C virus (HCV) is a major public health problem affecting over 170 million people worldwide. In Australia an estimated 157,000 people have HCV and are at risk of serious disease, and 16,000 new infections occur each year. Treating HCV-related disease is expensive, and this healthcare burden is projected to grow significantly in coming years. Almost all new HCV infections in Australia occur among injecting drug users (IDUs), and despite our world-leading prevention programs, the virus is spreading. Consensus is emerging that the best hope for control of HCV and related disease lies in a vaccine; our research will lay much of the groundwork for its development. The applicants' research to date shows that IDUs are being infected with HCV more frequently than previously assumed, that many carry multiple strains, and that dominant strains vary rapidly in individuals over time. These results reinforce the view that our prevention methods will not reduce infection rates and that current anti-viral treatments are not the solution. Nevertheless, we also found that some IDUs remain free of HCV infection despite risky behaviour with infected associates; intensive study of the immune functioning of these persistently non-infected individuals holds promise for vaccine development. In our proposed research, a collaboration of leading Australian epidemiologists, virologists and immunologists, we will recruit 210 young IDUs and follow them regularly for two years. Recruits will describe their social networks and nominate IDUs with whom they inject, provide blood samples and be interviewed about their behaviour at 3-month intervals. Individuals with recent and resolved HCV infection, change of dominant strain and lack of infection despite risky behaviour will be identified and their blood analysed for genetic factors that may be linked to immune protection. The outcomes will be crucial to the development and trialling of a vaccine against HCV.Read moreRead less