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.
Investigate Novel Functional Roles For PI 3-kinases In Platelets.
Funder
National Health and Medical Research Council
Funding Amount
$537,215.00
Summary
Platelets are small blood cells which have a well defined role in blood clotting. There is a growing body of evidence that platelets play an important role in a broad range of inflammatory diseases, and we have identified a key role for the platelet PI3K enzyme in controlling the pro-inflammatory function of platelets. This grant will examine the importance of PI3K in health and disease, and examine the potential therapeutic benefits of inhibiting platelet PI3K.
Investigation Of Mechanotransduction Mechanisms In Platelets
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Platelets are extremely important cells that stop bleeding by sticking to injured blood vessel walls, forming blood clots. Excessive clotting can lead to fatal vascular events such as heart attack and stroke. On the other hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to sites of vessel wall injury through the interaction between cell surface receptors and sticky materials (proteins) that become exposed to the blood flow when the vessel wall is ....Platelets are extremely important cells that stop bleeding by sticking to injured blood vessel walls, forming blood clots. Excessive clotting can lead to fatal vascular events such as heart attack and stroke. On the other hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to sites of vessel wall injury through the interaction between cell surface receptors and sticky materials (proteins) that become exposed to the blood flow when the vessel wall is damaged. The stickiness of platelets is controlled by many proteins (and-or enzymes) inside these blood cells. These proteins transmit messages from platelet receptors on the surface into the cell interior, thereby controlling platelet behaviour. We are in the process of identifying several types of proteins-enzymes which are responsible for controlling platelet stickiness. The studies proposed in this application will provide better understanding of the complicated pathways regulating platelet stickiness and clot formation. The knowledge gained may utimately assist in the design of specific drugs for the prevention and-or treatment of heart attacks and strokes.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.
The Role Of The Inositol Polyphosphate 4-phosphatase In Cellular Signalling
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell growth, cell division and other specialized functions. These cellular responses are dependent on the generation of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane compartments are called phosphoinositides. We plan to i ....Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell growth, cell division and other specialized functions. These cellular responses are dependent on the generation of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane compartments are called phosphoinositides. We plan to investigate the role of a specific lipid called PtdIns(3,4)P2 that recruits signalling proteins to specific cellular membranes including the inner wall of the plasma membrane and vesicles found within the cell. We have identified and are currently characterizing a novel enzyme called the inositol polyphosphate 4-phosphatase that terminates the signals generated by PtdIns(3,4)P2. We are characterizing mice which lack this enzyme. 4-phosphatase deficient mice demonstrate significant abnormalities in the brain and bone marrow. These mice appear unable to make circulating platelets, small anucleate cells which are vital in preventing bleeding. We will determine how the 4-phosphatase functions in regulating platelet production, by examining the bone marrow and blood of these mice. These studies are significant as platelet production is essential for prevention of blood loss following trauma and also is of vital importance in conditions associated with blood clotting including heart attack and stroke. Secondly we have identified a related enzyme to the 4-phosphatase designated P-Rex-1 which is highly expressed in brain and nerve cells. This proposal aims to determine if P-Rex-1 promotes nerve development.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
CHARACTERISATION OF A NOVEL REGULATOR OF PHOSPHOINOSITIDE 3-KINASE-MEDIATED CELL PROLIFERATION AND PLATELET SIGNALLING
Funder
National Health and Medical Research Council
Funding Amount
$500,091.00
Summary
Critical functions such as cell growth, cell death and metabolism, are tightly controlled by key proteins which respond to specific stimuli. Perturbation of this process may lead to uncontrolled growth and cancer. This project proposes to examine the potential of a novel protein (an enzyme) as a physiological regulator of cell growth. It is proposed that this enzyme may function as a brake in preventing the evolution of a cancerous state. We will also study the ability of the novel enzyme to inf ....Critical functions such as cell growth, cell death and metabolism, are tightly controlled by key proteins which respond to specific stimuli. Perturbation of this process may lead to uncontrolled growth and cancer. This project proposes to examine the potential of a novel protein (an enzyme) as a physiological regulator of cell growth. It is proposed that this enzyme may function as a brake in preventing the evolution of a cancerous state. We will also study the ability of the novel enzyme to influence other diverse functions, such as uptake of glucose, and blood clot initiation.Read moreRead less