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.
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.
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
Investigation Of The Role Of The GPIb/V/IX-filamin-1 Interaction In Regulating Platelet Function In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
Platelets play an essential role in blood clotting and blod vessel repair. Upon injury to a blood vessel, platelets rapidly adhere to the area of damage where they undergo dramatic changes in their shape and internal structure that facilitates spreading over the area of injury and subsequent formation of a stable blood clot. Our research studies are aimed at understanding more closely the factors that regulate the adhesiveness of platelets, since this is an important determinant not only in norm ....Platelets play an essential role in blood clotting and blod vessel repair. Upon injury to a blood vessel, platelets rapidly adhere to the area of damage where they undergo dramatic changes in their shape and internal structure that facilitates spreading over the area of injury and subsequent formation of a stable blood clot. Our research studies are aimed at understanding more closely the factors that regulate the adhesiveness of platelets, since this is an important determinant not only in normal blood clot formation but also in the development of harmful blood clots (thrombosis) associated with the development of diseases such as heart attack and stroke. Our particular focus is on the interaction between adhesion receptors on the surface of the platelet and components of the intracellular platelet structure referred to as the cytoskeleton and how this interaction might regulate the reactivity of platelets and their ability to adhere to blood vessels. We believe this may be an important mechanism that regulates platelet adhesion and notmal blood clotting.Read moreRead less
Tetraspanins Serve As Molecular Facilitators To Regulate Platelet Thrombus Formation
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Platelets are small fragments of megakaryocytes that circulate in the blood stream. They 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. We have discovered that tetraspanins serve to regulate platelet glycoproteins including integrin alphaIIbbeta, P2Y12 and thrombosis.