Molecular Investigations Of Antithrombin Instability And Heparin Binding Mechanism
Funder
National Health and Medical Research Council
Funding Amount
$195,691.00
Summary
Thrombosis is a significant disease affecting a large number of people. The primary treatment for episodes of acute thrombosis is administration of the anticoagulant, heparin. The effector molecule through which heparin carries out its action is the serine proteinase inhibitor, antithrombin. This molecule regulates blood clotting by inhibiting the proteinases which carry out this process. Antithrombin is converted from a poor inhibitor of coagulation proteases to a very good inhibitor on binding ....Thrombosis is a significant disease affecting a large number of people. The primary treatment for episodes of acute thrombosis is administration of the anticoagulant, heparin. The effector molecule through which heparin carries out its action is the serine proteinase inhibitor, antithrombin. This molecule regulates blood clotting by inhibiting the proteinases which carry out this process. Antithrombin is converted from a poor inhibitor of coagulation proteases to a very good inhibitor on binding heparin. This provides a control point for coagulation. The mechanism by which antithrombin is converted to a very good inhibitor of coagulation proteases involves a large change in the structure of this protein. These changes in structure are linked to the changes which occur when antithrombin becomes inactive through the process of polymerisation. Certain patients with thrombosis have been found to have changes in both the stability and heparin affinity of their antithrombin molecules, which forms the underlying basis for the disease. We wish to study the reasons for the effects of mutations in the antithrombin variants by making recombinant mutants which mimic the molecules in the thrombotic patients and carrying out detailed, sophisticated molecular analyses of their interaction with heparin and proteases and their stability under various conditions. Additionally we will engineer recombinant mutants of antithrombin which we believe will stabilise the molecule and potentially act as an improved supplement for therapy. This analysis will provide important insights into the functioning of both heparin and antithrombin and thereby significantly improve our understanding of the control of coagulation.Read moreRead less
Investigation Of A New Rheology Dependent Platelet Aggregation Mechanism
Funder
National Health and Medical Research Council
Funding Amount
$509,447.00
Summary
We plan to examine a new mechanism promoting blood clot formation that involves the clumping (aggregation) of blood platelets. Our central hypothesis is that disturbances of blood flow, as occurs in diseased arteries, activates this clotting mechanism through a unique platelet activation process. Defining this new activation mechanism has the potential to lead to new approaches to prevent blood clot formation in patients with heart disease.
Development Of A Fibre-optic Flow Sensor To Monitor Blood Platelet Adhesive Function.
Funder
National Health and Medical Research Council
Funding Amount
$187,550.00
Summary
The ability to accurately diagnose platelet dysfunction is key to the clinical management of many cardiovascular diseases which represent a major cause of mortality in the industrialised world. At present there is no clinically robust instrument that can accurately assess abnormal platelet function under conditions that closely mimic the physiological environment. We aim to develop a sensitive prototype instrument for the clinical assessment of platelet function. We propose to develop this medic ....The ability to accurately diagnose platelet dysfunction is key to the clinical management of many cardiovascular diseases which represent a major cause of mortality in the industrialised world. At present there is no clinically robust instrument that can accurately assess abnormal platelet function under conditions that closely mimic the physiological environment. We aim to develop a sensitive prototype instrument for the clinical assessment of platelet function. We propose to develop this medical device as a relatively cheap and portable point of care instrument that can be marketed internationally.Read moreRead less
Defining The Roles Of Platelet Protease-activated Receptors In Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$330,690.00
Summary
Inappropriate blood clot formation is the cause of most heart attacks and some strokes. Platelets are the blood cells responsible for such clots. We are interested in the signals which control platelet incorporation into clots because drugs that interfere with this may be effective at inhibiting unwanted clot formation. Our studies determining the importance of platelet signals will provide strong clues to the likely effectiveness of blocking such signals as anti-clotting agents.
Development Of Recombinant RsolCD39-PSGL As A Novel Therapeutic With Anti-thrombotic And Anti-inflammatory Effects
Funder
National Health and Medical Research Council
Funding Amount
$186,367.00
Summary
Heart disease and stroke are due to a narrowing of arteries followed by occlusion, due a combination of clot formation initiated by platelet clumping, and inflammation surrounding the vessel wall. The currently available drugs are often limited by the adverse reaction of bleeding. We will investigate the efficiency of a new drug to prevent clot formation and inflammation.
The prevalence of heart disease and stroke is increasing in the affluent world. These disorders are due to a narrowing of arteries due to clot formation, thereby reducing available blood supply to the heart and brain. Blood vessel occlusion is due a combination of clot formation initiated by platelet clumping, and inflammation surrounding the vessel wall. Drugs that prevent the clumping of platelets on the inner lining of the blood vessels play an important role in the prevention and treatment o ....The prevalence of heart disease and stroke is increasing in the affluent world. These disorders are due to a narrowing of arteries due to clot formation, thereby reducing available blood supply to the heart and brain. Blood vessel occlusion is due a combination of clot formation initiated by platelet clumping, and inflammation surrounding the vessel wall. Drugs that prevent the clumping of platelets on the inner lining of the blood vessels play an important role in the prevention and treatment of heart attack and stroke. The currently available drugs are not universally effective and their use is often limited by adverse reactions. In this submission, we propose to investigate the efficiency of a new drug that will prevent clot formation and will also tackle inflammation. This drug is a derivative of an enzyme that is already present on platelets and cells that line blood vessels. We have modified this enzyme in a manner that will increase the enzyme activity on the surface of platelets and on the cells that line the blood vessel wall. We will thoroughly study this new drug by performing experiments in the laboratory as well as by studying its effect in mice.Read moreRead less
Use Of Snake Venom Prothrombin Activators In Blood Collection Tubes To Produce High Quality Serum To Improve Patient Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$284,706.00
Summary
The timely availability of high quality serum and plasma samples are of the utmost importance for accurate biochemical analysis in a clinical setting. This requirement is particularly true for patients on anti-clotting therapeutic agents such as warfarin and heparin. In this study we will employ potent prothrombin activators purified from snake venom to enhance the clotting efficiency of blood for serum preparation for biochemical analysis.
Effects Of Modification Of Dietary Sodium Intake On Endothelial Function In Obese Subjects
Funder
National Health and Medical Research Council
Funding Amount
$252,920.00
Summary
The effects of a high salt intake on blood pressure are well known. The damaging direct effects of salt on blood vessels is less well known. This study will clarify whether reducing salt to the amount recommended by Australian health authorities for 6 weeks has a beneficial effect on blood vessels. It builds on an earlier 2 week study which demonstrated that reducing salt intake had a beneficial effect on blood vessels. The purpose of this study is to show whether this benefit is maintained in a ....The effects of a high salt intake on blood pressure are well known. The damaging direct effects of salt on blood vessels is less well known. This study will clarify whether reducing salt to the amount recommended by Australian health authorities for 6 weeks has a beneficial effect on blood vessels. It builds on an earlier 2 week study which demonstrated that reducing salt intake had a beneficial effect on blood vessels. The purpose of this study is to show whether this benefit is maintained in a longer study over 6 weeks.Read moreRead less
De-differentiation Of Committed Cells Into Haematopoietic Stem Cells By The Instructive Role Of The Transcription Factor HOXB4
Funder
National Health and Medical Research Council
Funding Amount
$683,040.00
Summary
Blood stem cells are long-lived and can give rise to every cell type of the blood system and due to these properties they are currently used in the clinics. Despite their importance, our knowledge of the mechanisms the control the multiplication of these rare cells is very scarce. This proposal aims to identify key factors that have the potential to convert mature, easy available blood cells into stem cells. This knowledge has to potential to lead to novel system that allow the expansion of stem ....Blood stem cells are long-lived and can give rise to every cell type of the blood system and due to these properties they are currently used in the clinics. Despite their importance, our knowledge of the mechanisms the control the multiplication of these rare cells is very scarce. This proposal aims to identify key factors that have the potential to convert mature, easy available blood cells into stem cells. This knowledge has to potential to lead to novel system that allow the expansion of stem cells for transplantations in the future.Read moreRead less