Discovery Of Novel T Cell Oncogenes By Using A Functional Retroviral CDNA Library Screen.
Funder
National Health and Medical Research Council
Funding Amount
$692,470.00
Summary
T cells mature in an organ called the thymus which is located on top of the heart. Blood borne T cell precursors enter the thymus after being resident in the bone marrow. T cell leukaemia is a disease where a blood cell that is committed to becoming a T cell is blocked from maturing into a functional cell. Instead, the leukaemic immature T cell uncontrollably divides to make endless non-functional copies of itself. As a result, normal functional T cells are outcompteted and the immune system is ....T cells mature in an organ called the thymus which is located on top of the heart. Blood borne T cell precursors enter the thymus after being resident in the bone marrow. T cell leukaemia is a disease where a blood cell that is committed to becoming a T cell is blocked from maturing into a functional cell. Instead, the leukaemic immature T cell uncontrollably divides to make endless non-functional copies of itself. As a result, normal functional T cells are outcompteted and the immune system is crippled. Patients generally die due to opportunistic infection. The molecular causes of T cell leukaemia are slowly being discovered. Up to 50% of all human T cell leukaemias overexpress SCL-TAL-1. Other T cell leukaemia-causing genes (oncogenes) include Ras and Notch. Current leukaemia treatments include chemotherapy and bone marrow transplants but even these fail ~30% of the time. Consequently, all T cell oncogenes need to be discovered so that disease-specific treatments can be generated. This proposal will utlise a functional retroviral cDNA library screen to uncover novel T cell lineage commitment genes and T cell oncogenes. This will be accomplished by constructing a coloured [GFP] cDNA library (a library of genes) that will be transfected (inserted) into immature T cells that cannot develop down the T cell pathway owing to the lack of a crucial gene (Rag-1). The T cell oncogene Ras and the T cell lineage commitment gene Notch can move cells past the Rag-1 block. If there is a gene in the cDNA library that can compensate for the lack of Rag-1 and allow the cells to mature we will detect it using high speed flow cytometryic cell sorting (like sieving weevils from flour very quickly). Once we find this cell we will isolate the gene using the colour tag. The potential oncogenes uncovered will provide the foundation for next generation drug development that targets each leukaemia based on its cause.Read moreRead less
Regulation Of Mesenchymal To Epithelial Transitions By Netrin Receptors
Funder
National Health and Medical Research Council
Funding Amount
$646,995.00
Summary
The formation of 2D cellular sheets is important during development, tissue repair, and tumor growth. The mechanisms involved, however, remain largely unknown. Recent findings in the fly and in human cells suggest Frazzled/Neogenin receptors drive this process, by establishing polarised scaffolds in the cell. We will test this hypothesis using fly genetics and analysis of 3-dimensional culture of mammalian cells. Our results will help guide future therapies for human disease.
Apo2L/TRAIL Killing Of Tumour Cells And The Role Of Inhibitor Of Apoptosis Proteins
Funder
National Health and Medical Research Council
Funding Amount
$390,321.00
Summary
Melanomas and Gliomas are tumour types that respond poorly to current treatments. Current treatments are not only sometimes ineffective, but also unpleasant and may cause co-lateral damage. We will test 2 new targetted anti-cancer treatments, that so far appear to have minor side effects in small animal models, on these difficult to treat tumour types to see if and how they kill them. We also want to know whether these independent treatments can work together to kill tumours more effectively. Al ....Melanomas and Gliomas are tumour types that respond poorly to current treatments. Current treatments are not only sometimes ineffective, but also unpleasant and may cause co-lateral damage. We will test 2 new targetted anti-cancer treatments, that so far appear to have minor side effects in small animal models, on these difficult to treat tumour types to see if and how they kill them. We also want to know whether these independent treatments can work together to kill tumours more effectively. Although we will not personally test these drugs in clinical settings, these drugs or similar are currently in preclinical and clinical trials. This means that understanding how these drugs function is of paramount importance and may result in better clinical trials and possibly more rapid acceptance of the use of these drugs in patients.Read moreRead less
Molecular Characterisation Of A New Survival Pathway In Haematopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$571,631.00
Summary
It is critical for normal health that cells regulate their responses to changes in the the extracellular environment. Receptors on the cell surface are triggered by specific proteins called cytokines, and relay information to the cell interior. These messages include signaling whether cells should survive and proliferate. Inappropriate activation of signals for survival and proliferation is a hallmark of cancer. We are investigating a new survival signal and how this contributes to the survival ....It is critical for normal health that cells regulate their responses to changes in the the extracellular environment. Receptors on the cell surface are triggered by specific proteins called cytokines, and relay information to the cell interior. These messages include signaling whether cells should survive and proliferate. Inappropriate activation of signals for survival and proliferation is a hallmark of cancer. We are investigating a new survival signal and how this contributes to the survival of normal cells and to diseases such as leukaemia.Read moreRead less
Regulation Of The Drosophila C-Myc Homologue In Stem Cell Growth And Division.
Funder
National Health and Medical Research Council
Funding Amount
$613,397.00
Summary
The mechanisms controlling stem cell growth and division require elucidation if we are to use stem cells in regenerative medicine and find cancer treatments. Due to experimental limitations such mechanisms are largely unknown in humans. We aim to use the vinegar fly as a model system to understand the importance of microenvironment to cancer gene control in stem cells. We will identify the secreted signals, from the neighbouring cells, required to control cancer initiation in stem cells.
Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Centr ....Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Central to the apoptosis execution are a group of enzymes called caspases that target many cellular proteins for specific cleavage. In this proposal, we will investigate the function of one of the caspases (called caspase-2), in order to better understand its potential role in the apoptosis of cancer cells. A number of recent reports suggest that caspase-2 levels are reduced in many cancer cells. The human caspase-2 gene localizes to a chromosomal region frequently affected- deleted in leukaemia, and caspase-2 levels have been proposed to be predictors of remission and survival in patients with some types of leukaemia. We will study if loss of caspase-2 in cancer cells makes them resistant to killing by drugs and if mice lacking caspase-2 have an increased potential to develop cancer. Understanding caspase-2 function and its regulation is likely to provide new therapeutic opportunities and potential targets for cancer therapy.Read moreRead less
Characterising The Mechanisms That Control Blood Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$335,616.00
Summary
Hematopoiesis is a tightly regulated process that provides the body with a constant supply of all the cells of the blood system. My studies aim to characterize the molecular mechanisms that regulate the expansion and differentiation of hematopoietic stem cells (HSCs) into each cell lineage. These studies will be key to the effective use of cellular transplantation therapeutic strategies and aim to provide a greater understanding of the mechanisms that underpin proliferative disorders such as can ....Hematopoiesis is a tightly regulated process that provides the body with a constant supply of all the cells of the blood system. My studies aim to characterize the molecular mechanisms that regulate the expansion and differentiation of hematopoietic stem cells (HSCs) into each cell lineage. These studies will be key to the effective use of cellular transplantation therapeutic strategies and aim to provide a greater understanding of the mechanisms that underpin proliferative disorders such as cancer.Read moreRead less
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in general, to maintain the correct number of cells in the body. As such, misregulation of apoptosis is associated with the pathogenesis of a wide array of diseases. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases called caspases, that target many cellular proteins for specific cleavage. The activation of caspases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. In this proposal we will use vinegar fly as a model to study the function of caspases in development. We believe that results from this proposal will have several major benefits. Firstly, they will provide important insight into the mechanisms of developmental apoptosis thereby filling many gaps in our current knowledge. Secondly, the study will endeavour to identify new molecules-pathways that lead to caspase activation. Finally, the proposed studies will shed light on the function of caspases in non-apoptotic pathways.Read moreRead less