Post Transcriptional Regulation Of Plasminogen Activator Inhibitor Type 2 Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$318,000.00
Summary
The process of wound healing, cell migration and the spread of cancers requires the recruitment of specialised proteases to the cell surface . These proteases act to degrade other proteins, mainly in the extracellular space, which in turn allows cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA) a ....The process of wound healing, cell migration and the spread of cancers requires the recruitment of specialised proteases to the cell surface . These proteases act to degrade other proteins, mainly in the extracellular space, which in turn allows cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA) and the activity of u-PA is regulated by its natural inhibitor called plasminogen activator inhibitor type 2 (PAI-2). u-PA is strongly implicated in the progression of metastatic cancer and high levels of PAI-2 relative to u-PA is regularly seen as a positive prognostic indicator for metastatic cancer. In this situation, PAI-2 acts to limit the activity of u-PA thereby restricting the migration potential of the cancer. PAI-2 is unusual because it exists both inside and outside the cell. Outside the cell, PAI-2 acts to inhibit u-PA activity, while inside the cell, PAI-2 also plays a role in the inhibition of cell growth and differentiation. It is therefore important to understand how the production of PAI-2 is regulated in cells. A significant component of PAI-2 regulation occurs post-transcriptionally, particularly at the level of mRNA stability. We have identified some of the proteins that bind to PAI-2 mRNA and influence its longevity in the cell. This project aims to further undertand how these as well as other PAI-2 mRNA binding proteins influence the expression of the PAI-2 gene.Read moreRead less
Molecular Mechanisms For The Cell-type Specific Regulation Of The Tissue-type Plasminogen Activator Gene
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will ....Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will address the mechanisms underlying the cell-type specific regulation of the t-PA gene. Endothelial cells, fibroblasts and neuronal cell cultures will be used to study the regulation of t-PA expression. Information gained will not only add to the understanding of the broader field of gene regulation, but may also provide clues to manipulate the expression of the t-PA gene in different cells.Read moreRead less
Plasmin is a complex enzyme that performs major roles in removal of blood clots, wound healing and in tumor metastasis. Here we will understand how plasmin function is regulated at the molecular level. These key insights will be of future use in the development of therapeutics targeting the plasmin system in cancer and clotting diseases.
Pre-hospital Antifibrinolytics For Traumatic Coagulopathy And Haemorrhage (The PATCH Study)
Funder
National Health and Medical Research Council
Funding Amount
$1,668,152.00
Summary
About 2500 Australians die annually from severe injuries. Bleeding is exacerbated by early-onset clotting defects, which are associated with high mortality. The antifibrinolytic agent tranexamic acid has been shown to reduce mortality due to bleeding when given in hospital in less developed trauma systems, but its usefulness as a pre-emptive strike at the scene of injury in developed systems is unknown. Building on our prehospital clinical trials expertise, we will conduct a trial to assess its ....About 2500 Australians die annually from severe injuries. Bleeding is exacerbated by early-onset clotting defects, which are associated with high mortality. The antifibrinolytic agent tranexamic acid has been shown to reduce mortality due to bleeding when given in hospital in less developed trauma systems, but its usefulness as a pre-emptive strike at the scene of injury in developed systems is unknown. Building on our prehospital clinical trials expertise, we will conduct a trial to assess its effect on 6-month death and disability.Read moreRead less
Under this fellowship the applicant will study a n important group of enzymes and molecular delivery machines involved in clotting disease, immune dysfunction and cancer.