All cells in the blood are the descendants of a single cell type, the stem cell. Stem cells are found in the bone marrow and throughout life have the unique ability to generate more of themselves (termed self-renewal) as well as to produce the functional cell types of the blood, ie. red and white blood cells. This project concentrates on the processes by which these stem cells can achieve these two functions. What are the genes that enable a stem cell to have this self-renewal characteristic and ....All cells in the blood are the descendants of a single cell type, the stem cell. Stem cells are found in the bone marrow and throughout life have the unique ability to generate more of themselves (termed self-renewal) as well as to produce the functional cell types of the blood, ie. red and white blood cells. This project concentrates on the processes by which these stem cells can achieve these two functions. What are the genes that enable a stem cell to have this self-renewal characteristic and conversely what are the genes that are activated when a cell becomes committed to become, for example, a white blood cell ? We have identified a gene, Pax5, which is essential in the process whereby a stem cell commits to become a lymphocyte . Our aim is to understand the function of Pax5 as a model for understanding how the commitment process as a whole works in the blood. These studies, as well as having an underlying fundamental scientific importance, are relevant to the clinical development of a number of stem cell therapies which rely on boosting stem cell production in procedures such as bone marrow transplantation for leukaemia and immune deficiency. In addition a number of characterised human blood malignancies indicate that inappropriate lineage commitment may be a factor in cancer.Read moreRead less
Characterisation of the oxygen-sensing asparaginyl hydroxylase, FIH-1, and hydroxylase-specific antagonists. This research will provide fundamental information on how cells and whole organisms can sense and respond accordingly to oxygen deficiency. This information is fundamental for our understanding of embryo development and adult life in different environments, and central to the diagnosis and treatment of diseases such as stroke, cardiovascular disease, and cancer. This research will contrib ....Characterisation of the oxygen-sensing asparaginyl hydroxylase, FIH-1, and hydroxylase-specific antagonists. This research will provide fundamental information on how cells and whole organisms can sense and respond accordingly to oxygen deficiency. This information is fundamental for our understanding of embryo development and adult life in different environments, and central to the diagnosis and treatment of diseases such as stroke, cardiovascular disease, and cancer. This research will contribute to our basic knowledge of these processes, provide invaluable information about the specific genes and proteins involved, and provide direct information about the therapeutic potential of specific drugs or inhibitors designed to target this oxygen response in human disease.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0347607
Funder
Australian Research Council
Funding Amount
$306,000.00
Summary
FishWorks - collaborative infrastructure for zebrafish research. Zebrafish have emerged as a powerful and cost-effective animal model for studying development, biology, and disease. FishWorks represents a large-scale co-operative initiative to develop state-of-the-art zebrafish housing, manipulation, genomics and screening infrastructure in Australia. This will both support and further enhance a core group of high quality researchers to engage in cutting-edge research in areas of acknowledged ex ....FishWorks - collaborative infrastructure for zebrafish research. Zebrafish have emerged as a powerful and cost-effective animal model for studying development, biology, and disease. FishWorks represents a large-scale co-operative initiative to develop state-of-the-art zebrafish housing, manipulation, genomics and screening infrastructure in Australia. This will both support and further enhance a core group of high quality researchers to engage in cutting-edge research in areas of acknowledged expertise as well as priority within their respective institutions. In addition, it will facilitate wide-ranging collaborative arrangements to further develop and exploit this research area.Read moreRead less
Function and regulation of the Schlafen gene family: novel regulators of blood cell proliferation and function. The immediate outcomes of the proposed research will be in fundamental knowledge and understanding of important cellular and biological processes in which the Schlafen genes are involved. In particular, Schlafen genes are likely to play a role in inflammatory responses and in blood cell growth. These process clearly have relevance to a range of major human (and animal) diseases includ ....Function and regulation of the Schlafen gene family: novel regulators of blood cell proliferation and function. The immediate outcomes of the proposed research will be in fundamental knowledge and understanding of important cellular and biological processes in which the Schlafen genes are involved. In particular, Schlafen genes are likely to play a role in inflammatory responses and in blood cell growth. These process clearly have relevance to a range of major human (and animal) diseases including infectious disease, auto-immune disease and leukaemia, and thus a long-term outcome may be improved treatments for such disease. Read moreRead less
Tissue specific regulation of gene expression. Despite the polarized public debate concerning the use of stem cells for tissue regeneration, fundamental questions relating to the identity and hierarchy of these cells remain unanswered. The benefit to Australia will be scientific in terms of providing an understanding of how stem and progenitor cells integrate transcriptional control systems during differentiation and the networks that are involved. This is fundamental to the future isolation a ....Tissue specific regulation of gene expression. Despite the polarized public debate concerning the use of stem cells for tissue regeneration, fundamental questions relating to the identity and hierarchy of these cells remain unanswered. The benefit to Australia will be scientific in terms of providing an understanding of how stem and progenitor cells integrate transcriptional control systems during differentiation and the networks that are involved. This is fundamental to the future isolation and manipulation of these stem cell types to benefit the community. The work will also provide postgraduate students with training in state of the art genomic techniques and in the interface between bioinformatics and experimental science. Read moreRead less
Epigenetic Silencing Of Retroelements In Mammalian Stem Cells: A Role For RNA Interference?
Funder
National Health and Medical Research Council
Funding Amount
$296,980.00
Summary
Now that the human genome has been sequenced, all the genes which encode the bricks and mortar of our cells have been defined. A major question remains: how are all these genes controlled and co-ordinated? What turns them on or off at precisely the right time? In this project we wish to test whether a newly-discovered mechanism of turning genes off in plants and flies also works in mammals. If we demonstrate this mechanism then it may help us to improve gene therapy - a novel form of medical tre ....Now that the human genome has been sequenced, all the genes which encode the bricks and mortar of our cells have been defined. A major question remains: how are all these genes controlled and co-ordinated? What turns them on or off at precisely the right time? In this project we wish to test whether a newly-discovered mechanism of turning genes off in plants and flies also works in mammals. If we demonstrate this mechanism then it may help us to improve gene therapy - a novel form of medical treatment in which healthy genes are used to replace defective genes in cells. Both inherited diseases, like hemophilia, and acquired diseases, like cancer, have been considered appropriate targets for gene therapies. Surprisingly, however, the promises of gene therapy have not kept up with expectations. In attempting to achieve clinically relevant results, viruses (masters of forcing infected cells to do their bidding) have been harnessed to deliver healthy genes into diseased cells. A major problem has been that the modified, safe viruses used clinically have not been efficient at achieving sustained production of healthy gene products. In examining the question of what turns gene off, we will attack the problem of sustainability of gene therapy by defining the mechanisms involved in switching gene therapy viruses off. If we can understand what switches viral genes off in cells, then we should be able to devise means to avoid the 'off switch' and thereby provide durable treatments for many types of cancer. In the studies described , we will attack this problem using a number of different, but complementary approaches.Read moreRead less
Regulation Of Adult Colonic Crypt Homeostasis And Activation Of Colon Cancer Metastasis Genes By C-Myb
Funder
National Health and Medical Research Council
Funding Amount
$666,116.00
Summary
Regulation of normal colon biology and activation of genes involved colon cancer The c-myb gene is essential for the normal biology of the blood system and the colon. This gene is involved in regulating the balance between the production of new cells and their timely removal once they have completed their assigned tasks. There is a large body of evidence that supports the role of c-myb in the regulation of the blood system. We believe that the rules that govern the production of the huge number ....Regulation of normal colon biology and activation of genes involved colon cancer The c-myb gene is essential for the normal biology of the blood system and the colon. This gene is involved in regulating the balance between the production of new cells and their timely removal once they have completed their assigned tasks. There is a large body of evidence that supports the role of c-myb in the regulation of the blood system. We believe that the rules that govern the production of the huge number of cells needed to have a healthy blood system are similar if not identical to the rules used by the colon. This is because the colon also produces a massive number of cells each with special tasks and a defined life span of a few days. It is this rapid expansion of cell numbers and the programmed short life span of cells that necessitates multiple controls and very tight regulation. Furthermore if this process is hijacked by genetic changes that undermine these controls then there are numerous opportunities to initiate and potentiate malignant change or cancer. This project examines the role of the same genes in two contexts. Firstly when the genes are expressed at normal, highly regulated levels associated with the normal biology of the colon. The second context is when these genes are permitted to be over-expressed and thus drive processes for longer or in inappropriate situations leading to malignant growth.Read moreRead less
Regulation Of Tissue-type Plasminogen Activator Gene Expression In Endothelial Cells And In Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$244,009.00
Summary
Tissue-type plasminogen activator (t-PA) is an enzyme which plays an important role in the removal of blood clots from the circulation. One of the major sites of production of t-PA are endothelial cells which line the blood vessel wall. The rate of t-PA production is greatly influenced by factors released from other cells. One of these factors is tumour necrosis factor (TNF). The t-PA gene is switched off in endothelial cells exposed to TNF. One of the aims of this project is to understand how t ....Tissue-type plasminogen activator (t-PA) is an enzyme which plays an important role in the removal of blood clots from the circulation. One of the major sites of production of t-PA are endothelial cells which line the blood vessel wall. The rate of t-PA production is greatly influenced by factors released from other cells. One of these factors is tumour necrosis factor (TNF). The t-PA gene is switched off in endothelial cells exposed to TNF. One of the aims of this project is to understand how the t-PA gene is suppressed by TNF in human endothelial cells and in transgenic mice. The transgenic mice we have available express the regulatory region of the t-PA gene (called the gene promoter) connected to a reporter gene called LacZ. We will use these animals to visualise the expression pattern of LacZ expression under normal conditions and in mice treated with TNF. The results of these experiments will provide new information as to how the t-PA gene is controlled in cells and in the body.Read moreRead less
Transcriptional regulation of erythropoiesis. The major expected outcome from this proposal will be development of a pipeline for the study of how transcription factors work at a genome level. There will be national benefit in the areas of Frontier Technologies, and Promoting and Maintaining Good Health. There will be specific outcomes with respect to development of tests for human blood diseases, future design of drugs to target the aberrant activities of transcription factors in genetic and de ....Transcriptional regulation of erythropoiesis. The major expected outcome from this proposal will be development of a pipeline for the study of how transcription factors work at a genome level. There will be national benefit in the areas of Frontier Technologies, and Promoting and Maintaining Good Health. There will be specific outcomes with respect to development of tests for human blood diseases, future design of drugs to target the aberrant activities of transcription factors in genetic and degenerative diseases. Also, a strong bridge will be built upon the previous collaborations of the research teams in Brisbane and Pennsylvania, which will facilitate advanced teaching and training of Australian PhD and post-doctoral scientists.Read moreRead less
Oxidative Damage and Cell Ageing. This research will benefit Australia by providing a fundamental understanding of how cells age. This will have immediate international impact at the scientific level and will inform strategies to reduce the rate of ageing and alleviation of age-related disorders. In the longer term the research may provide commercial and social outcomes by identifying antioxidant systems that will provide a genuine benefit in reducing ageing.