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
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
Acute Traumatic Coagulopathy- Mechanisms And Measurement
Funder
National Health and Medical Research Council
Funding Amount
$188,226.00
Summary
Acute traumatic coagulopathy (ATC) refers to impaired blood clotting post major trauma and is associated with high, early mortality. Inability to predict this disorder and poor knowledge regarding its detailed biochemical mechanism has hindered development of evidence based guidelines to manage patients with ATC. This project aims to correlate early biochemical disorders with clinical management and outcomes post trauma to determine mechanisms leading to ATC and determine management strategies.
A Novel Point Of Care (PoC) Device For Predicting And Monitoring Bleeding And Clotting (haemostasis)
Funder
National Health and Medical Research Council
Funding Amount
$608,979.00
Summary
Manipulating the bleeding/clotting system is a critical but expensive part of modern medicine, eg some people need blood thinners while others can bleed too much. Thrombin generation is the ideal overall test for the bleeding/clotting of blood, but current methods have major problems. We developed and patented a test that deals with most of the problems. This proposal will create an assay that is easy for doctors to perform without a specialised laboratory.
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.
This program of research is firmly focussed on the basic mechanisms involved in normal functioning of cells and tissues, followed by a step by step process to understand the abnormal or the diseased. The disease states we are investigating involve the blood and blood vessels, and when there is malfunction it may contribute to conditions as diverse as atherosclerosis, thrombosis, inflammation and cancer. The program thus addresses the fundamentals of diseases which are responsible for most deaths ....This program of research is firmly focussed on the basic mechanisms involved in normal functioning of cells and tissues, followed by a step by step process to understand the abnormal or the diseased. The disease states we are investigating involve the blood and blood vessels, and when there is malfunction it may contribute to conditions as diverse as atherosclerosis, thrombosis, inflammation and cancer. The program thus addresses the fundamentals of diseases which are responsible for most deaths in our society. We will use technology which is proven to provide precise information, the molecular and biochemical processes responsible for cell function (or malfunction). However in each individual project there will be a clear path to a clinical use, diagnostic or therapeutic. Indeed in a number of the components of the program there are already potential treatments and diagnostics in development and trial.Read moreRead less
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