The outcomes to be assessed are recurrent ischaemic stroke, intracranial haemorrhage, myocardial infarction, parenchymal embolism and vascular death. Should these outcomes be significantly reduced, the public health and economic issues which will be addressed in this study are considerable. Approximately 40,000 new and recurrent cases of stroke occur in Australia each year, and about 80% of these are ischaemic. There is an average prevalence of about 20% of large or complex aortic plaque among p ....The outcomes to be assessed are recurrent ischaemic stroke, intracranial haemorrhage, myocardial infarction, parenchymal embolism and vascular death. Should these outcomes be significantly reduced, the public health and economic issues which will be addressed in this study are considerable. Approximately 40,000 new and recurrent cases of stroke occur in Australia each year, and about 80% of these are ischaemic. There is an average prevalence of about 20% of large or complex aortic plaque among patients with ischaemic stroke. About the same proportion of cases of ischaemic stroke yearly are associated with the presence of complex aortic plaque alone, and as many again with simple plaque (40% in total). Using the NHMRC estimated cost of $40,000 per stroke (and assuming that recurrent stroke costs are similar to initial stroke costs) and the estimated recurrent stroke rates of 11.9-100 person-years for plaque > 4 mm, the national cost of recurrent ischaemic stroke attributable to complex aortic plaque alone is about $3 million in the first year. This estimate does not include patients with incident TIA and atherosclerotic plaque or the resources spent on evaluating recurrent stroke and TIA attributable to aortic plaque, the cost of lost wages, or the negative impact on the quality of life of the victims. The economic and public health burden to our society could be greatly reduced by successful efforts at secondary stroke prevention in individuals with aortic plaque and TIA or ischaemic stroke. If just 25% of recurrent ischaemic strokes associated with aortic arch debris could be prevented by treatment interventions, the annual savings to society for recurrent ischaemic stroke alone would be considerable.Read moreRead less
Novel Selective Anti-platelet And Clot-specific Anticoagulant Strategies Targeting Conformational States Of GPIIb/IIIa
Funder
National Health and Medical Research Council
Funding Amount
$496,517.00
Summary
The inhibition of platelets and the inhibition of coagulation factors are among the most widely used drugs in medicine and provide major benefits for numerous patients. Prevention and treatment of thrombosis, emboli, stroke and heart attack are examples of the many diseases where anti-platelet and anticoagulant drugs are administered. However, the downsides of these drugs are bleeding complications, which can result in death or disability. The consequences of these drug-associated bleeding compl ....The inhibition of platelets and the inhibition of coagulation factors are among the most widely used drugs in medicine and provide major benefits for numerous patients. Prevention and treatment of thrombosis, emboli, stroke and heart attack are examples of the many diseases where anti-platelet and anticoagulant drugs are administered. However, the downsides of these drugs are bleeding complications, which can result in death or disability. The consequences of these drug-associated bleeding complications are also a major financal burden for our health care system. Thus, progress towards therapeutic strategies with less bleeding complications is highly sought-after. The proposed project aims to generate new antibody-based agents for platelet inhibition. One group of these agents do only block platelets when they are activated. Furthermore, these agents allow an enrichment of potent inhibitors of coagulation factors at the site of the clot. Thus, these inhibitors should predominatly act at the site where they are needed. At the same time the overall concentration of inhibitors of coagulation factors can be kept low and the functions of non-activated platelet can be left intact. Overall, the proposed project aims for the development of novel anti-platelet and anticoagulant strategies with high anti-thrombotic efficacy and low bleeding risks.Read moreRead less
A Case Control Study Investigating Factors Contributing To The Risk Of Bleeding In Patients Receiving Warfarin Therapy
Funder
National Health and Medical Research Council
Funding Amount
$572,242.00
Summary
Warfarin is a drug commonly used in the elderly to prevent blood clots. Blood clots can lead to stroke. While a very effective drug, it is also a dangerous drug because it can lead to thin blood which makes it more likely that they will bleed. For this reason, the drug should be closely monitored. We know that many people do suffer catastrophic bleeds because the blood is too thin directly as a result of taking warfarin. Some of the reasons for these bleeds are well known; they may be taking dru ....Warfarin is a drug commonly used in the elderly to prevent blood clots. Blood clots can lead to stroke. While a very effective drug, it is also a dangerous drug because it can lead to thin blood which makes it more likely that they will bleed. For this reason, the drug should be closely monitored. We know that many people do suffer catastrophic bleeds because the blood is too thin directly as a result of taking warfarin. Some of the reasons for these bleeds are well known; they may be taking drugs that interact with warfarin, they may have problems with their liver or kidney which affects the body's ability to get rid of it, they may have suffered a fall, to name a few. Studies done overseas have suggested that people are more likely to have a bleed if they do not know how to properly manage their tablets, if they are depressed, if they have no helpers to support them or if their care is not well organised. In Australia, we do not know what impact the organisation of care has on whether a person's warfarin is well managed. We do not know the impact that depression has on their care, or whether people are more likely to have pooorly controlled warfarin if they have few community ties. These are importnat questions to answer, so that we can make significant inroads into preventing death and disability from warfarin.Read moreRead less
Modulating Interactions Between TNFalpha And IGF-1 Signaling Pathways To Reduce Necrosis Of Dystrophic Muscle
Funder
National Health and Medical Research Council
Funding Amount
$476,515.00
Summary
Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attracti ....Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attractive options for treatment of DMD patients due to their high specificity of action and relatively few side effects. We have shown that both of these drugs have a striking protective effect and reduce necrosis of dystrophic muscle in the mdx mouse. The benefits of these drugs (and the mouse equivalent cVIq) is due to blocking the action of the key pro-inflammatory cytokine Tumour Necrosis Factor-alpha (TNFa). However, the precise mechanism by which high levels of TNFa increase necrosis of dystrophic muscle is not clear. There are many possible pathways. Identifying which is the key pathway(s), is of central importance to design and target new drugs to treat such lethal muscle diseases. Such modulation of signalling is a major therapeutic goal. To determine which mechanism of TNFa action is responsible for muscle necrosis, experiments will investigate several signalling pathways using specific inhibitors: the drug Pifithrin to inhibit p53; soluble RAGE to block RAGE (Receptor for Advanced Glycation Endproducts); and specific inhibitory peptides to block JNK (c-Jun N-terminal kinase). The application of these inhibitors (drugs), in mice, as future therapies for muscle diseases is novel. These studies will provide much new information on TNFa related signalling that is highly relevant to the potential treatment of many diseases, including muscle wasting that is a major problem in the ageing population and in disuse atrophy and cachexia.Read moreRead less
I am an infectious diseases physician and basic scientist interested in the immunopathogenesis of HIV and hepatitis B virus. My work focuses on HIV viral reservoirs and immune reconstitution and the adaptive immune response to hepatitis B virus.
Investigating The Link Between Oxidative Stress And Biomechanical Integrin Activation In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$653,742.00
Summary
Diabetes represents a serious healthcare problem globally. A large proportion of deaths associated with diabetes can be attributed to the development of blood clots in the circulation of the heart and brain (heart attack/stroke). The blood clotting mechanism is ‘hyperactive’ in diabetes, although the reason for this is not well defined. In this proposal we will investigate a new mechanism promoting blood clots, and will investigate innovative approaches to reduce this clotting mechanism.
Regulation Of Receptors That Control Platelet Function Under Shear Stress
Funder
National Health and Medical Research Council
Funding Amount
$507,273.00
Summary
Specialized human blood cells that control blood loss and clotting (platelets) are currently difficult to test in the clinical laboratory, meaning patients are at risk of excessive bleeding or serious clot formation during disease or treatment. The aim of this proposal is to use our new reagents and assays to develop more reliable methods for evaluating relative bleeding or clotting risk in individuals.
Cancer is now the number one killer of Australians and there is an unmet medical need to develop new therapies that are safe and maximize anti-cancer efficacy. Cancer immunotherapy now represents a new fourth pillar in cancer treatment to complement surgery, radiotherapy and chemo-/targeted therapies. This application aims to develop new therapeutic approaches to broaden the effectiveness of cancer immunotherapy and potentially allow the treatment of a broader range of cancers and patients.
Identification Of A Novel Adhesion Mechanism Regulating Platelet-endothelial Interactions.
Funder
National Health and Medical Research Council
Funding Amount
$501,691.00
Summary
Platelets are important blood cells, stopping bleeding in the event of blood vessel injury. However, platelets can also interact with the blood vessel lining (endothelium) to regulate and in some cases promote inflammation. We have identified a new structure platelets use to stick to endothelium, which under disease states (enhanced oxidative stress), can promote inflammation. We will investigate how tractopods form, and examine their role in the setting of elevated oxidative stress and inflamma ....Platelets are important blood cells, stopping bleeding in the event of blood vessel injury. However, platelets can also interact with the blood vessel lining (endothelium) to regulate and in some cases promote inflammation. We have identified a new structure platelets use to stick to endothelium, which under disease states (enhanced oxidative stress), can promote inflammation. We will investigate how tractopods form, and examine their role in the setting of elevated oxidative stress and inflammatory disease.Read moreRead less
A Transgenic Approach To Rationale Drug Design In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
Malaria is a disease caused by parasites of the genus Plasmodium. It is responsible for more than 2 million deaths per year predominately in Sub-Saharan Africa. Many of the currently used drugs to combat this disease are failing through drug resistance in the parasite population. New and novel drugs are urgently required. This project uses state of the art techniques to identify and validate new and novel targets within the parasite that can be used for rational drug design