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.
Investigation Of Negative Signalling Mechanisms In Platelets
Funder
National Health and Medical Research Council
Funding Amount
$292,500.00
Summary
Platelets are specialised blood cells essential for normal blood clotting. We are studying the processes that control platelets sticking to the exposed vessel wall, to each other and to other cells to form a stable blood clot at the site of injury to stop bleeding. The same processes, when unchecked, could lead to the formation of harmful large blood clots that may block blood vessels in the heart or brain, resulting in heart attack or stroke. Platelets stick to the blood vessel wall and each ot ....Platelets are specialised blood cells essential for normal blood clotting. We are studying the processes that control platelets sticking to the exposed vessel wall, to each other and to other cells to form a stable blood clot at the site of injury to stop bleeding. The same processes, when unchecked, could lead to the formation of harmful large blood clots that may block blood vessels in the heart or brain, resulting in heart attack or stroke. Platelets stick to the blood vessel wall and each other through sticky proteins called receptors on the cell surface. Receptors are able to bind to their specific ligands such as von Willebrand factor (vWf) and collagen which become exposed following vessel wall damage. The interaction between the ligands and receptors will trigger many biochemical changes within platelets, called signal transduction, that control platelet stickiness. The aim of this research project is to investigate the signalling processes that are utilised by the major platelet receptor called integrin alpha IIb beta 3. We are particularly interested in identifying the negative signalling process utilised by this receptor to dampen the positive signals required for platelet stickiness, to achieve a balanced clotting process. The identification of these specific signalling pathways will not only increase our knowledge of blood clot formation in health and disease, but also help develop potential new therapies for the prevention of heart diseases and strokes.Read moreRead less
Targeting A Novel Anti-platelet Mechanism For Improved Anti-thrombotic Therapy
Funder
National Health and Medical Research Council
Funding Amount
$985,938.00
Summary
Blood clots cause heart attacks and most strokes, which are the most common cause of death in the world. Platelets are the cells in the blood that form these clots, and drugs that prevent platelet function are the major approach for heart attack and stroke prevention. However, many patients are resistant to the effects of existing therapies. These studies will develop a unique approach to prevent platelet function that may help overcome the limitations of current drugs.
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.
Dissecting The Role Of The IL-3 Receptor Alpha Subunit And Beta-catenin In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
Leukaemia is a devastating form of blood cancer affecting both young and old. We aim to understand the mechanisms of uncontrolled cell growth associated with acute myeloid leukaemia. We focus on the role of key growth regulators that are abnormally active in the critical leukaemia stem cells. Understanding the biological and molecular properties of these cells is of considerable importance for development of the next generation of leukaemia therapies.
Investigation Of Shear-sensitive Signalling Pathways In Human Platelets
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Platelets are extremely important cells that control bleeding by sticking to injured blood vessels to form a blood clot. Excessive clotting can lead to fatal vascular events such as heart attacks and strokes. On the other hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to the wall of a blood vessel when receptors on the surface of these cells interact with materials (ligands) that are exposed when the vessel wall is injured. The stickiness or adh ....Platelets are extremely important cells that control bleeding by sticking to injured blood vessels to form a blood clot. Excessive clotting can lead to fatal vascular events such as heart attacks and strokes. On the other hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to the wall of a blood vessel when receptors on the surface of these cells interact with materials (ligands) that are exposed when the vessel wall is injured. The stickiness or adhesive behaviour of platelets is controlled by many proteins (enzymes) which are contained inside these cells. These enzymes transmit messages from platelet receptors on the surface into the cell interior, thereby controlling platelet behaviour. We are in the process of identifying several types of enzymes which are responsible for controlling platelet stickiness. Our research will provide a better understanding of the complicated pathways regulating platelet stickiness and clot formation. The knowledge gained from these studies may ultimately asssist in the design of specific drugs for the prevention and-or treatment of heart attacks and strokes.Read moreRead less
Development And Assessment Of Novel Assays To Predict Response To Second-line TKI Therapy In Imatinib-resistant CML
Funder
National Health and Medical Research Council
Funding Amount
$491,308.00
Summary
Patients with chronic myeloid leukaemia (CML) respond well to imatinib, the first small molecule developed to block the kinase activity of the causative oncogene in CML, BCR-ABL. However some patients develop resistance. Several new kinase inhibitors are now available that are effective in some patients with imatinib resistance. We plan to develop biological and molecular assays to predict if a CML patient will respond to a specific second-line kinase inhibitor to optimise second-line therapy.
Use Of Retroviral Expression Libraries To Characterise Mechanisms Of Drug Resistance In Leukaemia.
Funder
National Health and Medical Research Council
Funding Amount
$362,545.00
Summary
At present, treatment of leukaemia is based either on established chemotherapeutic drug treatment or newly identified inhibitor drugs currently being tested as part of clinical trials. Both these treatments are known to induce or select for resistance to the drugs in some cases. Resistance usually reduces the success rate of any further treatment with the same or similar drugs. To discover possible ways of overcoming drug resistance it is important to understand the mechanisms that are responsib ....At present, treatment of leukaemia is based either on established chemotherapeutic drug treatment or newly identified inhibitor drugs currently being tested as part of clinical trials. Both these treatments are known to induce or select for resistance to the drugs in some cases. Resistance usually reduces the success rate of any further treatment with the same or similar drugs. To discover possible ways of overcoming drug resistance it is important to understand the mechanisms that are responsible. To date a number of mechanisms that cause resistance are known, but there are still unidentified mechanisms that are associated with drug resistance. The aim of our work is to use a new method to identify unknown drug resistance mechanisms in leukaemia. Once a mechanism is identified, we will determine its relevance in leukaemia by screening a number of patients that have shown resistance to treatment. If identified as a common mechanism of resistance in leukaemic patients, we will test possible agents able to prevent drug resistance that could be used in conjunction with drug during treatment, and to screen new drugs for susceptibility to resistance mechanisms. Diagnostic tests to detect the presence of the known resistance mechanisms prior to treatment could be used in selection of the most appropriate drug combinations for individual patients. Some of the known drug resistance mechanisms that occur in leukaemia are also operative in other forms of cancer and the project is of general relevance to cancer chemotherapy.Read moreRead less