Characterising The Role Of Streptokinase Polymorphism In Invasive Pathogenesis Of Streptococcus Pyogenes.
Funder
National Health and Medical Research Council
Funding Amount
$480,535.00
Summary
Invasive bacterial pathogens such as Streptococcus pyogenes, can hijack host proteins and use them to facilitate the disease process. S. pyogenes secrete streptokinase to activate a host protease (plasminogen) which is used by the bacterium to invade through host tissue. This project will characterise the molecular mechanisms involved in streptokinase mediated activation of plasminogen which will assist the generation of novel therapeutics to treat invasive diseases.
Investigation Of A New Approach To Regulate Fibrin Clot Retraction And Arterial Thrombolysis
Funder
National Health and Medical Research Council
Funding Amount
$483,171.00
Summary
Pathological blood clots are removed in patients by administering clot dissolving drugs (fibrinolytics). However these drugs are quite often ineffective and cause bleeding. We have identified a new platelet-mediated pathway controlling contraction of blood clots, important for clot stability. In this proposal, we will examine the potential for inhibitors of this pathway to loosen blood clots, and facilitate the actions of fibrinolytics to promote clot dissolution.
To Determine The Means By Which Plasminogen Activators Modulate Integrity Of The Blood Brain Barrier
Funder
National Health and Medical Research Council
Funding Amount
$523,084.00
Summary
Tissue-type plasminogen activator (t-PA) is used clinically to remove blood clots. However, t-PA can also cause brain injury and influence the blood brain barrier (BBB) which has implications for the treatment of patients with ischaemic stroke. This project will use in vitro and in vivo models to understand the mechanism by which t-PA modulates the BBB. A novel tPA variant will also be created that ultimately may be of benefit for patients with ischaemic stroke.
Thrombolysis is a method of dissolving the blood clot that is the cause of the majority of strokes in Australia. The first major trial to demonstrate benefit for this treatment was published some 11 years ago but treatment has not been widely implemented across Australia because of the difficulties in giving treatment within the very tight time window for which treatment is currently approved (patients must get to hospital, be scanned and start treatment within 3 hours of the onset of the stroke ....Thrombolysis is a method of dissolving the blood clot that is the cause of the majority of strokes in Australia. The first major trial to demonstrate benefit for this treatment was published some 11 years ago but treatment has not been widely implemented across Australia because of the difficulties in giving treatment within the very tight time window for which treatment is currently approved (patients must get to hospital, be scanned and start treatment within 3 hours of the onset of the stroke). Other factors which have limited implementation of treatment in Australia are continued debate over the trial data for this treatment as only one of the 5 major trials was positive. In addition, virtually no patients aged over 80 years old were included in the previous trials, and as this age group represents about a third of all stroke in Australia, new data in this age group is required. As a result of the difficulty in giving a treatment within such a tight time window and the ongoing debate about the trial data, few Australians are currently treated and thus the public health impact is negligible. In to change clinical practice, we need reliable data from a large convincing further trial of thrombolysis with the more realistic time window of 6 hours. The Third International Stroke Trial (IST-3) is a large international collaborative effort to determine whether thrombolysis treatment offered to a wider range of patients up to 6 hours from stroke onset results in an increase in long-term independent survival. Data from such a trial is most likely to change clinical practice and lead to an important public health benefit.Read moreRead less
Low-Dose Tenecteplase Vs Standard-Dose Alteplase For Acute Ischaemic Stroke: An Imaging Based Safety And Efficacy Study
Funder
National Health and Medical Research Council
Funding Amount
$349,281.00
Summary
This study compares standard dose alteplase (a proven stroke thrombolytic) with a low dose of the new medication tenecteplase for stroke treatment. We propose that the clot-dissolving activity of low-dose tenecteplase will be superior to alteplase, with a lower risk of brain bleeding. MRI scanning is the most effective way of assessing outcomes and will be used to measure how well the medication restores blood flow, the amount of permanent brain damage, and whether any brain bleeding occurs.
To Determine The Role And Mechanism Of Action Of Tissue-type Plasminogen Activator In The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
Tissue-type plasminogen activator (t-PA) is used clinically to remove blood clots. Recently, a role for t-PA in the brain was discovered where under pathological conditions it can promote ischaemic and excitotoxic brain injury. This project will examine the mechanisms by which t-PA promotes injury to brain cells. It is anticipated that results obtained could be used to devise a means to reduce t-PA toxicity in the brain that would be of therapeutic benefit for patients with ischaemic stroke.
Investigation Of A New Platelet Contractile Mechanism Regulating Thrombus Stability
Funder
National Health and Medical Research Council
Funding Amount
$499,670.00
Summary
Platelets are small blood cells that form clots to stop bleeding. We have found a new contraction process that causes tight packing of platelets in a clot, enabling the clot to avoid detachment under blood flow. We will study this process and explore the possibility that its inhibition may provide a new way in which to loosen clots, promoting their removal. These studies will provide new insight into clot stability, and may provide clinical benefit in the delivery of clot dissolving agents .
2-Methoxyestradiol Analogues: Prototype Modulators Of Annexin II-dependent Plasminogen Activation
Funder
National Health and Medical Research Council
Funding Amount
$369,690.00
Summary
The enzyme system that enables us to dissolve blood clots is similar to the system that enables cancer cells to escape from the primary tumour and travel in the blood to another organ to form a secondary cancer growth. We have new results showing that some drug candidates can distinguish between these two closely related enzyme systems. We are now working to develop inhibitors that will stop cancer cells from spreading without compromising the ability to dissolve blood clots.