Hormones are essential chemical messengers that regulate the normal functions of the body. Reproduction in particular is widely influenced by hormones. The development of the very early embryo and its implantation into the uterus is not well understood. A new class of hormone has been implicated in this process. This hormone, known as platelet-activating factor (or PAF) is special among hormones since it belongs to a class of chemicals known as phospholipids. This is quite uncommon. This hormone ....Hormones are essential chemical messengers that regulate the normal functions of the body. Reproduction in particular is widely influenced by hormones. The development of the very early embryo and its implantation into the uterus is not well understood. A new class of hormone has been implicated in this process. This hormone, known as platelet-activating factor (or PAF) is special among hormones since it belongs to a class of chemicals known as phospholipids. This is quite uncommon. This hormone can act in an apparently contradictory fashion. Its production by the embryo allows it to act back on the embryo to stimulate embryo growth and survival. The embryo (of some species) then releases other hormones which prevents the PAF from acting on the uterus. If this repression of the uterine response to PAF does not occur then PAF acts on the uterus to stop further progression of the pregnancy (luteolysis). Hormones act on cells via special cell proteins known as receptors. It seems that the receptor for PAF in the embryo and the uterus are different and may therefore result in triggering different cellular responses by these 2 tissues. We have available to us mice with mutations that stop the functioning of these two likely classes of receptors. The progress of pregnancy and the development of embryos in mice with these mutations will be studied as a means of defining how PAF acts in pregnancy. The embryo will be studied in detail to determine the nature of the changes induced within the embryo by PAF acting via its receptor. One of these receptors is an entirely new class of molecules not previously understood to be able to act as a cell signalling devise. This study will describe if and how this potential new receptor acts in the embryo, allowing future detailed investigation of its role in normal cell function. It will show how this single hormone can regulate both the uterus and embryo to have contradictory roles in the establishment of pregnancy.Read moreRead less
Investigate The Role Of Platelet Von Willebrand Factor In Initiating Platelet Aggregation Under Flow
Funder
National Health and Medical Research Council
Funding Amount
$307,165.00
Summary
Platelets are small specialised blood cells that are essential for normal blood clotting and repair of damaged blood vessels following injury. We are studying the processes that enable platelets to stick to each other and to other cells to form a stable blood clot at the site of injury. The same processes, unchecked, are involved in the formation of harmful blood clots in the bloodstream that may block blood vessels in the heart or brain and result in a heart attack or stroke. Platelets stick to ....Platelets are small specialised blood cells that are essential for normal blood clotting and repair of damaged blood vessels following injury. We are studying the processes that enable platelets to stick to each other and to other cells to form a stable blood clot at the site of injury. The same processes, unchecked, are involved in the formation of harmful blood clots in the bloodstream that may block blood vessels in the heart or brain and result in a heart attack or stroke. Platelets stick to the blood vessel wall through specialised adhesive proteins. These adhesion proteins are stored within the platelet and expressed on the cell surface when the platelets stick to the blood vessel wall. In conditions such as Gray Platelet Syndrome, the platelets are unable to store adhesion receptors, resulting in impaired blood clot formation. A clearer understanding of how platelets stick to the blood vessel wall will not only increase our knowledge of blood clot formation in health and disease, but also with the potential development of new therapies for the prevention of heart disease and stroke.Read moreRead less
Investigation Of A Novel Role For Factor XIII In Regulating The Adhesive Function Of Platelets
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
Platelets are small specialised blood cells that are extremely important for the normal formation of blood clots and for the repair of injured blood vessels. We are studying the processes that allow platelets to stick to the site of vessel injury and to each other to form stable blood clots. If this process proceeds unchecked, harmful blood clots can form which block blood vessels and cause heart attacks and strokes. There are many factors, both inside and outside platelets, which control how bi ....Platelets are small specialised blood cells that are extremely important for the normal formation of blood clots and for the repair of injured blood vessels. We are studying the processes that allow platelets to stick to the site of vessel injury and to each other to form stable blood clots. If this process proceeds unchecked, harmful blood clots can form which block blood vessels and cause heart attacks and strokes. There are many factors, both inside and outside platelets, which control how big and how fast a blood clot grows and whether it becomes harmful enough to cause a blood vessel blockage. One of these factors is the level of platelet 'stickiness' or 'reactivity'. We are working towards a better understanding of how platelet reactivity is regulated. Specifically, we believe we have identified a new factor which keeps blood clots at a size that is not harmful to cause blood vessel blockade. This information will not only increase our knowledge of blood clot formation in health and disease but also may help in the development of new therapies for the prevention of heart attack and stroke.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
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
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 Shear-sensitive Signalling Pathways In Human Platelets
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Platelets are extremely important cells that control bleeding by sticking to injured blood vessels to form a blood clot. Excessive clotting can lead to fatal vascular events such as heart attacks and strokes. On the other hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to the wall of a blood vessel when receptors on the surface of these cells interact with materials (ligands) that are exposed when the vessel wall is injured. The stickiness or adh ....Platelets are extremely important cells that control bleeding by sticking to injured blood vessels to form a blood clot. Excessive clotting can lead to fatal vascular events such as heart attacks and strokes. On the other hand, defects in blood clotting can result in life threatening bleeding problems. Platelets stick to the wall of a blood vessel when receptors on the surface of these cells interact with materials (ligands) that are exposed when the vessel wall is injured. The stickiness or adhesive behaviour of platelets is controlled by many proteins (enzymes) which are contained inside these cells. These enzymes 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 enzymes which are responsible for controlling platelet stickiness. Our research will provide a better understanding of the complicated pathways regulating platelet stickiness and clot formation. The knowledge gained from these studies may ultimately asssist in the design of specific drugs for the prevention and-or treatment of heart attacks and strokes.Read moreRead less
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.