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.
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.
Tetraspanins Serve As Molecular Facilitators To Regulate Platelet Thrombus Formation
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Platelets are small fragments of megakaryocytes that circulate in the blood stream. They play an important role in preventing excessive blood loss at sites of tissue injury by sticking together and forming a haemostatic plug. Excessive platelet clumping in diseased blood vessels can lead to blockages and cause thrombotic diseases such as heart attack and stroke. We have discovered that tetraspanins serve to regulate platelet glycoproteins including integrin alphaIIbbeta, P2Y12 and thrombosis.
The mechanisms regulating expression and function of surface receptors on blood platelets are critical for understanding cardiovascular diseases involving aberrant platelet function, not only thrombotic diseases such as heart attack or stroke, but other pathology involving platelets including coagulopathy and autoimmune thrombocytopenia caused by anti-platelet antibodies. Improved diagnosis and therapeutic targeting of platelet-specific receptors mediating arterial thrombosis can save many lives ....The mechanisms regulating expression and function of surface receptors on blood platelets are critical for understanding cardiovascular diseases involving aberrant platelet function, not only thrombotic diseases such as heart attack or stroke, but other pathology involving platelets including coagulopathy and autoimmune thrombocytopenia caused by anti-platelet antibodies. Improved diagnosis and therapeutic targeting of platelet-specific receptors mediating arterial thrombosis can save many lives given the prevalence and severity of disease.Read moreRead less
Investigating A Potential New Treatment For Stroke
Funder
National Health and Medical Research Council
Funding Amount
$878,522.00
Summary
Blood clots blocking blood flow to the brain (stroke) are a major cause of death and disability. Safety concerns limit approved therapies to a small subset of patients, highlighting an urgent need for safer, more effective drugs. Our studies show that inhibitors of the enzyme PI3Kbeta increase blood clot permeability, increasing clot ‘dissolvability’, without increased bleeding. This raises the possibility that PI3Kbeta inhibitors may represent a safe and effective adjuvant therapy for stroke.
Formation of clots to prevent blood loss is initiated by the platelet receptors, glycoprotein (GP)Ib-IX-V and GPVI. Unfortunately, there is a gap in our knowledge regarding the events immediately following activation of these receptors and the known downstream signalling. We have identified a novel binding partner for these platelet receptors, which we believe links reactive oxygen species to platelet signalling events. This opens new avenues for therapies to prevent aberrant clotting.
Investigation Of The Role For GPVI In Platelet Function And Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$542,772.00
Summary
Blood cells play an important role in maintaining healthy blood vessels. We are studying the role of platelets in blood clots following vessel injury. However, while critical for normal blood vessel maintenance, these cells also contribute to diseases including thrombosis. We will examine how an important platelet receptor called GPVI promotes blood clot formation, and examine whether combining anticoagulant drugs with GPVI deficient platelets leads to a more effective anticlotting approach.