Investigation Of The Role Of Type II PI 3-kinases In Platelet Function
Funder
National Health and Medical Research Council
Funding Amount
$444,973.00
Summary
Inappropriate blood clot formation is the cause of most heart attacks and strokes, and platelets are the blood cells which form these clots. Current therapies that interfere with platelet function are used to prevent heart attack and stroke but are frequently ineffective. We will study the signals which control platelet incorporation into clots in order to discover improved therapeutic strategies for heart attack and stroke prevention.
Influence Of Flavonoid Structure And Function On Cardiovascular Protection
Funder
National Health and Medical Research Council
Funding Amount
$571,447.00
Summary
The proposed research will further explore the hypothesis that dietary flavonoids can protect against cardiovascular disease. The importance of flavonoid structure for bioactivity needs further study. In addition, metabolic changes to flavonoid structure could have a profound effect on their bioactivity. Therefore, our overall aim is to investigate the effects of individual flavonoids and their metabolites on bioactivity relevant to cardiovascular disease.
Seminal findings within our laboratory have demonstrated that disturbances of blood flow are an important trigger for blood clot formation, promoting heart attacks and stroke. Our studies have demonstrated that specialised blood cells, termed platelets, respond rapidly to local changes in blood flow in diseased blood vessels. In the present proposal we aim to identify the mechanisms by which platelets sense and respond to blood flow disturbances with the aim of identifying new approaches to prev ....Seminal findings within our laboratory have demonstrated that disturbances of blood flow are an important trigger for blood clot formation, promoting heart attacks and stroke. Our studies have demonstrated that specialised blood cells, termed platelets, respond rapidly to local changes in blood flow in diseased blood vessels. In the present proposal we aim to identify the mechanisms by which platelets sense and respond to blood flow disturbances with the aim of identifying new approaches to prevent disease-causing blood clots.Read moreRead less
(a) Pathogenesis Of Aortic Stenosis : Relationship To Valvular Endothelial Function.
Funder
National Health and Medical Research Council
Funding Amount
$254,995.00
Summary
In the 21st century, heart disease will continue to be a major cause of disability and death in Western society. However, the relative decline in the frequency of premature death due to coronary disease (such as heart attacks) combined with increases in longevity, will see the emergence of new disease states. Aortic stenosis (AS) is likely to be one of the most important of these: progressive aortic valvular narrowing, culminating in the development of heart failure, and cardiac death. To date, ....In the 21st century, heart disease will continue to be a major cause of disability and death in Western society. However, the relative decline in the frequency of premature death due to coronary disease (such as heart attacks) combined with increases in longevity, will see the emergence of new disease states. Aortic stenosis (AS) is likely to be one of the most important of these: progressive aortic valvular narrowing, culminating in the development of heart failure, and cardiac death. To date, the only established treatment for severe AS is valve replacement. The incidence of AS increases with age: approximately 40% of individuals over the age of 80 have some AS, while 4% have severe AS. Studies to date have revealed that AS is more likely to occur (and to progress rapidly) in patients with impaired kidney function, and that some coronary risk factors (high cholesterol levels and diabetes, for example) also predispose to AS. The planned research will examine the potential role of the (endothelial) cells lining the aortic valve in protecting against the development of AS. In particular, we will try to identify which chemicals interfere with endothelial function, and how this leads to thickening of the valve. The ulitmate objective of this research is to delineate the chemical factors causing AS, in order to help in the development of preventative strategies for this disease.Read moreRead less
Ligand Interactions Of Platelet Glycoprotein Ib-IX-V In Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$363,098.00
Summary
The transition of circulating blood platelets from a fluid-phase, non-adherent state to an adherent, activated and aggregated state (thrombus formation) is critical in the normal haemostatic response to blood vessel injury and in thrombotic diseases such as heart attack and stroke. One unique platelet receptor, the glycoprotein Ib-IX-V complex, is of particular interest, because it initiates platelet aggregate or thrombus formation at high fluid shear stress in flowing blood, including the patho ....The transition of circulating blood platelets from a fluid-phase, non-adherent state to an adherent, activated and aggregated state (thrombus formation) is critical in the normal haemostatic response to blood vessel injury and in thrombotic diseases such as heart attack and stroke. One unique platelet receptor, the glycoprotein Ib-IX-V complex, is of particular interest, because it initiates platelet aggregate or thrombus formation at high fluid shear stress in flowing blood, including the pathological shear stress that occurs in a sclerotic coronary artery. Our published and preliminary results show how GPIb-dependent interaction of platelets with von Willebrand factor, the major adhesive ligand for GPIb-IX-V, is dependent on the level of shear stress. Using a cross-species (human to canine) homology-swap approach, where human sequence is replaced by the corresponding canine sequence within discrete structural domains, a sequence of GPIb has been identified which becomes increasingly important as hydrodynamic shear stress increases. It is proposed to further define the interactive surface of GPIb that recognizes von Willebrand factor at increasing shear, and to define the relationship between the shear-dependent alteration of GPIb conformation and its ability to interact with other pro-thrombotic or pro-inflammatory binding partners.Read moreRead less
The Role Of The Platelet Glycoprotein Ib Alpha Cytoplasmic Domain In Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$600,230.00
Summary
Our studies aim to provide a better understanding of the factors that make platelets sticky, because this is important not only for normal blood clot formation but also in the development of harmful blood clots (thrombosis). Improving our understanding of these processes will add significantly to our knowledge of how blood clotting is controlled. This information is relevant to many human diseases including heart attack and stroke and will help us to develop drugs to prevent these diseases.
The Anti-thrombotic Potential Of Immunoreceptors In Platelet Thrombus Formation
Funder
National Health and Medical Research Council
Funding Amount
$522,773.00
Summary
Platelets are small cells in the blood stream that 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, two of the biggest killers of humans in the western world. In this proposal, we will seek to understand how immunoreceptors expressed on the surface of platelets modulate th ....Platelets are small cells in the blood stream that 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, two of the biggest killers of humans in the western world. In this proposal, we will seek to understand how immunoreceptors expressed on the surface of platelets modulate the function of platelet collagen interactions involving collagen GPVI receptor, the low affinity IgG receptor, FcgammaRIIa and the major platelet integrin, integrin alphaIIbbeta3. The aims of this work will define the role of these receptors in platelet aggregation both in cell-based assays and in mouse models of thrombosis. This work could lead to new strategies for therapeutic management of thrombotic disorders.Read moreRead less
Investigation Of Activating Signals Transmitted During Platelet Aggregation
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
The blood platelet is a specialized adhesive cell that plays a critical role in the normal blood clotting process through its ability to rapidly adhere to sites of vascular damage. Upon injury to a blood vessel, platelets undergo a number of internal signalling process and strucural changes that allow them to rapidly adhere to the area of damage. Following this initial adhesion process, platelet-platelet interactions occur leading to the development of a stable blood clot. Our research studies a ....The blood platelet is a specialized adhesive cell that plays a critical role in the normal blood clotting process through its ability to rapidly adhere to sites of vascular damage. Upon injury to a blood vessel, platelets undergo a number of internal signalling process and strucural changes that allow them to rapidly adhere to the area of damage. Following this initial adhesion process, platelet-platelet interactions occur leading to the development of a stable blood clot. Our research studies are aimed at understanding more closely the factors that regulate platelet-platelet interactions during the course of blood clot formation, since this is an important determinant not only of normal clot formation, but also in the development of harmful blood clots (thrombi) associated with the onset of diseases such as heart attack and stroke. Our particular focus is on the way in which platelets communicate to one another during the course of platelet thrombus development. Particulary, we are interested in the role of calcium as a signal mediating platelet-platelet communication. We believe that the transmission of these calcium signals may be the key signaling mediator of blood clot formation and normal haemostasis.Read moreRead less