Immunoregulatory Immune Responses To A Peripherally Presented Tumour Antigen
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
Tumours express proteins which the body can recognise as foreign. However, the recognition process often goes wrong, leaving the body's defences against infection unable to respond to the tumour. This lack of response may become permanent, and the tumour may then be protected by the immune system. We have a model system, based on cervical cancer, in which we can determine the reasons why tumour tolerance can occur, and explore ways of overcoming the tolerance
Viral disease is a major health hazard in the modern world. SV40 is a relatively simple virus which must enter mammalian cells in order to replicate. As it does so, it causes the infected cell to divide and hence triggers tumour formation in the host. This proposal is aimed at understanding how SV40 enters cells, and then passes to the nucleus where it replicates. Most viruses have hijacked existing pathways into cells. For example, some viruses have used the pathway by which cells take up nutri ....Viral disease is a major health hazard in the modern world. SV40 is a relatively simple virus which must enter mammalian cells in order to replicate. As it does so, it causes the infected cell to divide and hence triggers tumour formation in the host. This proposal is aimed at understanding how SV40 enters cells, and then passes to the nucleus where it replicates. Most viruses have hijacked existing pathways into cells. For example, some viruses have used the pathway by which cells take up nutrients from the external medium. However, we have shown that SV40 uses a completely novel pathway involving surface pits called caveolae. The subsequent steps in the pathway are unknown and have been difficult to study. We have discovered a number of agents which inhibit infection by SV40. In this proposal we will characterise the infectious entry pathway by investigating exactly where in the cell these agents work. We will then isolate the virus from within the cell and attempt to reconstitute part of the viral entry pathway in vitro. These studies will provide insights into the entry pathway of the virus which may lead to new therapeutic strategies to combat viral disease. In addition, study of this pathway, leading from the cell surface to the nucleus, may provide new avenues for drug delivery and-or gene targetting.Read moreRead less
Clonal Proliferation Of Hepatocytes And Progression Of Liver Disease In Chronic Hepatitis B Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$420,558.00
Summary
Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver c ....Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver cell population occur because of the immune response against infected hepatocytes. We hypothesize that the immune response kills infected hepatocytes and provides and growth advantage to hepatocytes that can no longer be infected with HBV. This leads to the clonal proliferation of HBV-negative hepatocytes that over time become the major cell population in the liver. We will study human liver tissue using molecular techniques to detect the HBV DNA that integrates randomly into cell DNA during HBV infection. We will then determine the copy number of specific integrated virus-cell junctions as a measure of hepatocyte proliferation. Sections of fixed liver will also be examined for changes in histology and frequency of HBV infection. These studies will determine if foci of HBV-negative hepatocytes are clonal. This finding would suggest that a major role of the immune system in the development of liver cancer is to restrict the genetic pool of hepatocytes. We hypothesise that liver cancer beings with a very specific survival advantage for hepatocytes that lack HBV replication and antigen expression, and that proliferation of these cells expands the pool of potentially altered HCC precursor cells.Read moreRead less
Regulation Of Nuclear Import Of Viral Oncoproteins And Transcription Factors By Protein-protein Interactions
Funder
National Health and Medical Research Council
Funding Amount
$650,383.00
Summary
The present application examines the controls that exerted over proteins that localize in the nucleus of eukaryotic cells. This relates relates integrally to cellular processes such as growth, development and oncogenesis. This research area is not represented elsewhere in Australia, and the particular experimental strategies to approach the problem, revolving around the use of special quantitative microscopic techniques are novel internationally. One part of the application seeks to examine tran ....The present application examines the controls that exerted over proteins that localize in the nucleus of eukaryotic cells. This relates relates integrally to cellular processes such as growth, development and oncogenesis. This research area is not represented elsewhere in Australia, and the particular experimental strategies to approach the problem, revolving around the use of special quantitative microscopic techniques are novel internationally. One part of the application seeks to examine transport within the cell of complexes of interacting proteins, rather than single proteins, under as close as possible to physiologically relevant conditions. This will be truly unique, and of great importance to our comprehension of eukaryotic cell function. This application examines particular types of negative control over protein nuclear localization. Since many proteins show such regulation, and in particular important proteins controlling cell growth and division, the results are fundamentally important to our understanding of how cells function in general. Further, this understanding may be applied in disease situations, such as viral-mediated oncogenesis. In the work we propose to do, viral proteins with functions relating to cancer will be examined in detail, as well as a cellular protein which is recognised by them - the tumor suppressor Rb. We intend to examine several viral oncoproteins which target Rb; one is a protein (E7) from the Human Papilloma Virus which has been frequently associated with cervical carcinomas and other cancers. Accordingly, the results may have direct application to viral-induced cancer, and our work may lead to understanding of the regulation of protein transport to the nucleus. This may thus afford a new approach at the pharmacological level to combat transformation.Read moreRead less
Defining The Role Of Wnt Signaling In Hepatocellular Carcinoma And The Potential Of Wnt-targeted Therapy For HCC
Funder
National Health and Medical Research Council
Funding Amount
$403,210.00
Summary
Of all cancers, liver cancer is the third biggest killer worldwide and there is currently no effective treatment options for this disease. We now know many of the common genetic changes that occur in liver tumour cells but have yet to develop targeted drug treatments. This project is aimed at determining whether reactivating a tumour cell's normal cancer suppressing functions can stop tumour growth and whether we can use this information to develop specific drugs that target liver tumour cells
Transgenic Expression Of The EWS-WT1 Fusion Protein,inducing The Development Of Tumour That Replicates The Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$112,976.00
Summary
A genetic translocation encoding the EWS-WT1 fusion protein is found desmoplastic small round cell tumours. Our aim is to examine the effect of this protein in inducing tumour growth in tissue cell lines. A virus will then be used to introduce the genetic translocation into mice to examine the effect of this protein on tumour growth in a mammal, thereby serving as a 'solid tumour model' to try and identify therapeutic targets.
Antigen Receptor As Oncogene: Understanding CARD11 Mutations In B Cell Malignancy
Funder
National Health and Medical Research Council
Funding Amount
$607,395.00
Summary
More than 5000 Australians are newly diagnosed as lymphomas. Recent technology identified many candidate genes for lymphomas, however it still remains unclear how each mutated gene distorts signalling molecules inside tumours cells. By introducing one of recurrent mutated genes, CARD11 into mouse B cells, we will examine how this mutation affects normal signalling pathways and B cell functions. We hope this project will provide a guidance to use forthcoming drugs to target specific molecules.
Therapeutic Targeting Of MYCN Oncoprotein Stability In Neuroblastoma
Funder
National Health and Medical Research Council
Funding Amount
$590,206.00
Summary
A high level of MYCN protein is a major indicator of aggressive neuroblastoma (NB) but unfortunately there have been many barriers to the design of targeted therapies. We have identified a protein called PA2G4 which is a cofactor for MYCN in promoting cancer cell growth. We have developed a compound which inhibits PA2G4 and MYCN protein levels and reduces tumour growth. We will examine how PA2G4 cause aggressive tumour characteristics and test new methods to block PA2G4.