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A Gene Therapy Approach To Acute Myeloid Leukaemia: Reversion Of The Disease Phenotype
Funder
National Health and Medical Research Council
Funding Amount
$744,911.00
Summary
Acute myeloid leukaemia is a cancer of white blood cells in which there is uncontrolled cell growth filling up the blood with cells that do not function properly. The cells also invade various tissues causing further damage. The patient becomes increasingly compromised due to the lack of appropriate normal cell types. The present standard therapy involves radiation or chemicals which are toxic to the leukaemic cells. However, these treatments are also toxic to normal cells so very high doses tha ....Acute myeloid leukaemia is a cancer of white blood cells in which there is uncontrolled cell growth filling up the blood with cells that do not function properly. The cells also invade various tissues causing further damage. The patient becomes increasingly compromised due to the lack of appropriate normal cell types. The present standard therapy involves radiation or chemicals which are toxic to the leukaemic cells. However, these treatments are also toxic to normal cells so very high doses that might be more effective to kill the leukaemic cells can not be given. At the doses which can be administered, the leukaemia often (in greater than 50% of patients) becomes resistant. The present project seeks to use a novel treatment strategy in which genes are used to modify the genetic abnormalities present in these leukaemic cells thereby stopping their growth. This growth suppression will be specific to the leukaemic cells as it targets their abnormal genetics leaving normal cells alone. The gene therapeutics have already been identified in part and the aims of this grant are: 1. To show that the gene therapeutic approach is justified to selectively stop the leukaemic cells from growing. 2. To confirm novel means to identify the inhibitory genes. 3. To determine the best inhibitory gene(s). 4. To show how these inhibitory genes can be delivered to the patients' cells and to model their effect in animal models. This project would represent a paradigm shift in the treatment of leukaemia and also has implications for the treatment of other cancer types.Read moreRead less
THE ROLE OF NOVEL TUMOUR SUPPRESSORS DURING DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are intereste ....Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, Drosophila. Central to the control of cell proliferation in all organisms are the Cyclin dependent protein kinases. Cyclin E-dependent protein kinase is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer causing mutations result in up-regulation of this critical cell cycle regulator and premature entry into the cell cycle. We have used a genetic approach using a weak mutation in Drosophila Cyclin E to isolate mutations in other important regulators of the G1 to S phase transition. We have identified a number of genes that act to negatively regulate the cell cycle, 2 of which have characteristics typical of tumour suppressors. We have identified candidate genes for 3 of these mutations, all of which encode novel proteins related to mammalian proteins involved in negative regulation of cell proliferation or tumour suppressors. In this proposal we seek to determine the way in which these proteins function to control cell proliferation in Drosophila. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is likely to be highly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
Analysis Of The Scrib, Dlg And Lgl Tumour Suppressors In Cell Cycle Regulation Using The Drosophila Animal Model System
Funder
National Health and Medical Research Council
Funding Amount
$476,500.00
Summary
Cancer is a disease that is likely to affect 1-3 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in th ....Cancer is a disease that is likely to affect 1-3 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, the vinegar fly, Drosophila. A key regulator of cell proliferation in all multicellular organisms is Cyclin E, which is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer-causing mutations result in up-regulation of this critical cell cycle regulator. We have used a genetic approach to identify novel negative regulators of Cyclin E. This proposal focuses on a group of these regulators, the Drosophila tumour suppressors, Scrib, Dlg and Lgl, which act in a common genetic pathway to link cell polarity (cell shape) to cell proliferation. In mutants of these genes, cyclin E is up-regulated and inappropriate cell proliferation occurs. The aims of this proposal are to determine the signalling pathway and the transcription factors that act to upregulate cyclin E in scrib-dlg-lgl mutants. We will use the powerful genetics of Drosophila to examine candidate genes and to screen for novel genes involved in the upregulation of cyclin E in scrib-dlg-lgl mutants. The expected outcome of this project is to elucidate how Scrib-Dlg-Lgl act to control cell proliferation. scrib, dlg and lgl are present in mammals, therefore, this study is directly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
Role Of The Microtubule Network In Nuclear Transport: Potential Use In Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$491,767.00
Summary
Transport of key proteins that regulate growth and other processes, into and out of the nucleus, the site of gene transcription, is central to the function of eukaryotic cells. Knowledge of the process is largely based on studies using semi-intact cell systems, however, meaning that the role of cytoskeletal elements in nuclear transport has been largely overlooked. Intriguingly, in vivo studies, including our own relating to signalling molecules important in the regulation of cancer, clearly imp ....Transport of key proteins that regulate growth and other processes, into and out of the nucleus, the site of gene transcription, is central to the function of eukaryotic cells. Knowledge of the process is largely based on studies using semi-intact cell systems, however, meaning that the role of cytoskeletal elements in nuclear transport has been largely overlooked. Intriguingly, in vivo studies, including our own relating to signalling molecules important in the regulation of cancer, clearly implicate the cellular microtubule (MT) network as playing an integral role in nuclear import. We propose to carry out a detailed examination of the mechanistic basis of the dependence of nuclear import on the MT network of 3 molecules regulating cancer. We will compare the properties of these molecules to those of other nuclear localizing molecules, as well as examine the ability to mediate nuclear import of similar MT-associating sequences from viral and other proteins. The results will establish for the first time, the generality of the dependence of nuclear protein import on cytoskeletal elements. Since the movement of large DNA molecules by simple diffusion is a limiting factor in non-viral gene delivery approaches, the possibility of applying this knowledge to facilitate the transport of DNA encoding therapeutic gene products to the nucleus of target cells, will also be assessed for the first time. We will use the modular sequences that confer interaction with the MT network to assist gene transfer by including them in modular constructs we have designed with this in mind. We will thus be able to test directly for the first time whether MT-interaction can enhance the delivery of DNA to the nucleus and reporter gene expression, with obvious application in gene therapy approaches.Read moreRead less
Cell polarity is the property of cells to be spatially oriented in a tissue or organ. We have now shown that the gene Scribble, a key regulator of cell orientation, may keep tumour development in check. In this proposal, we will examine how disruption of Scribble promotes cancer using a combination of tissue culture studies and a newly established mouse model. Understanding how this new pathway can regulate tumour development may provide novel targets for therapeutic intervention in cancer.
Malaria is characterised by defective T cell responses, particularly suppressed T cell growth. T cells are critical to malaria protection and defective immune responses are likely to benefit the parasite. We want to find out how immune-responses are turned off in malaria, so that then we can do something about this, and help fight off the parasite. Malaria kills over 2 million children each year and there is no effective vaccine. We have two important clues as what may be happenning to cause sup ....Malaria is characterised by defective T cell responses, particularly suppressed T cell growth. T cells are critical to malaria protection and defective immune responses are likely to benefit the parasite. We want to find out how immune-responses are turned off in malaria, so that then we can do something about this, and help fight off the parasite. Malaria kills over 2 million children each year and there is no effective vaccine. We have two important clues as what may be happenning to cause suppressed T cell growth during malaria infection. Firstly, we found a massive increase in T cells expressing a surface molecule called CD38 duirng infection. Increases in these cells correlated with decreases in the ability of the T cells from the animals to grow. Indeed, other researchers had observed that in mice CD38 T cells can suppress immunity. Secondly, we hypothesized that they may be responsible for the impaired T cell reactivity observed during acute malaria, and the general poor state of immune responses in humans living in areas where they are being constantly infected by the parasite. Indeed, when we removed cells expressing CD38 from blood cells from such individuals, these 'recovered' and were able to grow much better in our assays. Therefore we propose that CD38 T cells are importnat mediators of malaria immuno-suppression. We now want to understand how the parasite induces these CD38 T cells, and how their ability to suppress T cell responses can benefit the parasite. Knowing this we aim to develop vaccines which can avoid being turned off by malaria. T cells expressing CD38 are also increased in cancer and acute viral disease, such as late stage HIV. Understanding their role in malaria will also give us new clues to fight such diseases.Read moreRead less