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
Post Transcriptional Regulation Of The Plasminogen Activator Inhibitor Type 2 Gene
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins, mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the most important enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its activ ....The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins, mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the most important enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA). Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that inhibits u-PA activity. The degree of u-PA activity therefore depends on the relative levels of u-PA and PAI-2. In addition to controlling u-PA activity, PAI-2 also influences intracellular events including cell proliferation, differentiation and apoptosis. PAI-2 protein and mRNA levels are substantially modulated by many cytokines and growth factors. This project addresses the molecular mechanisms underlying the regulation of PAI-2 gene expression. We have recently shown that a significant degree of PAI-2 regulation occurs at the level of PAI-2 mRNA stability, and we have identified two regions within the PAI-2 mRNA that play a role in this process. Both regions provide binding sites for cellular proteins. We have identified one of these binding proteins to be HuR, a protein that has recently been shown to control the stability of other mRNAs. The specific aims of this project are firstly, to determine the role of HuR in the control of PAI-2 mRNA stability, and secondly, to clone a characterise the other PAI-2 mRNA binding proteins we have identifed. An understanding of how cells modulate levels of PAI-2 mRNA will significantly add to the broader field of gene regulation and may also provide new clues to influence PAI-2 levels in the body.Read moreRead less
Investigation Of The Anticancer Action And Cytotoxic-synergism Of Matrix Metalloproteinase Inhibition.
Funder
National Health and Medical Research Council
Funding Amount
$272,036.00
Summary
In virtually all cases, death from solid tumors (including breast cancer) results from invasion and metastasis. The exciting recent pre-clinical observations that a new class of anticancer agents (which primarily target tumour invasion and metastasis) operate synergistically with a number of standard chemotherapy cytotoxics (such as those already used to treat breast cancer) suggests a new and significant additional therapeutic potential for both agents. The basis of this synergism is completely ....In virtually all cases, death from solid tumors (including breast cancer) results from invasion and metastasis. The exciting recent pre-clinical observations that a new class of anticancer agents (which primarily target tumour invasion and metastasis) operate synergistically with a number of standard chemotherapy cytotoxics (such as those already used to treat breast cancer) suggests a new and significant additional therapeutic potential for both agents. The basis of this synergism is completely unknown however, and it is our contention that this mechanism needs to be explored at the molecular level in order to identify which combinations will have most potential in the clinic. This proposal aims to characterize synergistic combinations in an animal model of breast cancer progression, and to determine the specific molecular mechanism of the process. Each phase of the proposed study is a worthwhile undertaking in itself, and while it makes primary use of a breast cancer growth and metastasis system, the information revealed should be relevant to many tumour types. This information can be used to formulate new therapeutic strategies for the treatment of solid tumours and their metastasis in patients.Read moreRead less
Regulation Of Expression Of The MicroRNA-200 Family
Funder
National Health and Medical Research Council
Funding Amount
$573,557.00
Summary
The majority of deaths from cancer are due to tumour metastasis. To metastasize, tumour cells must convert to a migratory form that can allow tumor cells to migrate and disseminate in the body. This process requires a genetic reprogramming of the cell. We have discovered that this genetic reprogramming is under the control of small RNA molecules called microRNAs. In this project we investigate what controls the levels of the microRNAs, to allow metastasis to occur in colon tumours.
Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inf ....Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inflammation, and disorders of the immune system. The action of CSF-1 is mediated by the CSF-1 receptor (CSF-1R) which, when activated, controls gene regulation. In this proposal we will study CSF-1R activation and identify the genes regulated by CSF-1 with a view to characterize genes critical for macrophage development. These genes may provide potential targets for new pharmacological agents.Read moreRead less
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