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
Gene Profiling To Develop A Neuroprotective Strategy In A Large Animals Model Of Following Ischaemic Stroke.
Funder
National Health and Medical Research Council
Funding Amount
$359,897.00
Summary
Stroke affects 15 million people worldwide each year. At present, the diagnosis and treatment of stroke is not optimal. The use of gene profiling may provide us with information that could allow us to more accurately identify individuals at risk of stroke, predict stroke outcome and effectively treat stroke patients. In addition, by using a targeted approach to therapy we have the potential to reduce brain swelling and improve outcome following stroke with neuroprotective agents.
To Understand The Role Of The Plasminogen Activating And Matrix Metalloproteinase Systems In Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$499,321.00
Summary
Tissue-type plasminogen activator (t-PA) is known for its role as a clot dissolving protein. It is present in the brain and following traumatic brain injury (TBI), it can worse brain cell damage. We have established a mouse model of TBI . We will compare brain damage in mice that are deficient in or have high amounts of t-PA. We will also determine whether the recovery rate post-TBI can be improved using specific t-PA blockers. This project may provide new therapies for TBI.
Inhibition Of Retinoblastoma Protein Degradation By Interaction With The Serpin PAI-2 Via A Novel Consensus Motif
Funder
National Health and Medical Research Council
Funding Amount
$463,500.00
Summary
Plasminogen activator inhibitor-2 (PAI-2) has previously been shown to inhibit the activity of enzymes outside the cell that are involved in blood clotting and cell migration. We have discovered that this activity is probably not the major role of PAI-2. PAI-2 also has a function inside cells that protect and increases the activity of an important tumour suppressor protein called the retinoblastoma tumour suppressor protein (Rb). Rb is involved in many cellular functions such as, cell death, cel ....Plasminogen activator inhibitor-2 (PAI-2) has previously been shown to inhibit the activity of enzymes outside the cell that are involved in blood clotting and cell migration. We have discovered that this activity is probably not the major role of PAI-2. PAI-2 also has a function inside cells that protect and increases the activity of an important tumour suppressor protein called the retinoblastoma tumour suppressor protein (Rb). Rb is involved in many cellular functions such as, cell death, cell differentiation, cell growth, and most importantly prevention of cancer development. Rb is attacked and destroyed by several viruses which causes cells to become cancerous. This grant seeks to fully understand how PAI-2 protects and interacts with Rb. We have already found a new site on Rb to which PAI-2 binds. This site is also used by other proteins in the cell as well as disease causing virus proteins. Examples of these proteins are BRCA1, a protein involved in breast cancer development, and EBNA6, a protein from Epstein Barr virus that causes glandular fever and tumours. We have also found, and seek to explore further, how PAI-2 reverses the activities of the cervical cancer causing proteins of the human papilloma virus. Although at an early stage, these studies may lead to the development of new therapeutic drugs based on PAI-2 for the treatment of various types cancers or warts caused by HPV. Analysing the activity of PAI-2 inside cells will have implications for understanding much of the confusing scientific literature on PAI-2 and will provide a better comprehension of the role of PAI-2 in inflammation, cell differentiation, wound healing and cancer. For example it has long been known that the presence of PAI-2 in cancerous tumours is linked with a better prognosis, an activity that can now be understood in terms of the PAI-2 interaction with Rb. This new understanding may lead to the development of PAI-2 based prognostic assays for cancer.Read moreRead less
Activating Mitochondria In White Adipose Tissue To Reduce Obesity Related Complications
Funder
National Health and Medical Research Council
Funding Amount
$708,447.00
Summary
A major obstacle to managing obesity has been the inability to allow the body to store fat appropriately in fat tissue, leading to their unhealthy storage in other organs. We will test the prediction that drugs already available in the clinic which promote proper fat storage (but come with side-effects), work through a previously unacknowledged pathway. We will activate this pathway to test if it can reduce obesity associated complications without presenting with significant side effects.
Major Xenoantigens For Neovascularised Porcine Xenografts: The Role Of PERV And MHC In Rejection And Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$504,750.00
Summary
Cross-species transplants (xenografts) of pig organs which use donor pig blood vessels are rejected by antibody which recognises a special target (xenoantigen) on the pig blood vessels; other pig tissue transplants (cellular transplants) which use recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We plan to identify the major target(s) involved in cellular xenograft rejection. Thi ....Cross-species transplants (xenografts) of pig organs which use donor pig blood vessels are rejected by antibody which recognises a special target (xenoantigen) on the pig blood vessels; other pig tissue transplants (cellular transplants) which use recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We plan to identify the major target(s) involved in cellular xenograft rejection. This information can then be used to specifically remove or disable only those CD4 T cells capable of recognising the pig tissue and hence facilitate xenograft survival or tolerance without immunosuppression. In this way, the remainder of the CD4 T cell population and immune system is preserved intact. Recent studies have demonstrated that a pig virus (PERV) can be transmitted from pig tissue xenografts to recipient tissues. Our studies have also suggested that the process of xenograft rejection and the immunological recognition of transplant recipient cells infected with the pig virus, are closely related. We plan to investigate this relationship and ascertain whether the immunological destruction of the pig tissue xenograft is largely due to an immune response generated against the pig virus(es) it carries. As an extension of this concept, we will investigate whether long-term xenograft survival (tolerance) is associated with lack of immune reactivity to the pig virus and hence a continual capacity for pig virus to be transmitted to host tissues. This outcome could result in the development of unwanted disease(s) in transplant patients. To prevent these problems, our studies will determine whether it will be essential for such pig virus to be eliminated from the donor pig tissue before transplantation, e.g. by the development of potent anti-viral agents and-or via the development of pig herds that have been genetically engineered to be pig virus (PERV)-deficient.Read moreRead less
A Novel Non-invasive Diagnostic Imaging Technique Of Metastatic Cancer Using Plasminogen Activator Inhibitor Type 2.
Funder
National Health and Medical Research Council
Funding Amount
$187,750.00
Summary
This project aims to develop a non-invasive tumour diagnostic imaging agent based on a non-toxic protein (PAI2) that we know specifically identifies a critical marker of malignancy. PAI2 will be labelled with commonly used imaging radioisotopes. This novel imaging technique has important potential clinical uses including, determination of the most appropriate treatment for individual patients, assessing the success of such treatments, and a novel non-invasive prognostic indicator of malignancy.