Regulation Of Cytokine Signalling: Structure And Biophysical Characterisation Of Key Protiens
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
Cells are informed when to grow, divide, migrate or die by protein molecules called cytokines. The cellular response to cytokines needs to be carefully regulated or else inflammation and other disorders will result. The SOCS (Suppressors Of Cytokine Signalling) family of proteins are a major regulator of cytokine signalling. This work will examine the structure and interactions of this important protein class.
Investigation Of Novel Mechanisms Regulating Platelet Reactivity During Haemostasis And Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$221,210.00
Summary
Platelets are small specialised blood cells that are critical for normal blood clotting and blood vessel repair following injury. We are studying the processes that enable platelets to stick to the site of vessel injury and to each other to form a stable blood clot. These very processes, when unchecked, are responsible for 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. Many factors control how big ....Platelets are small specialised blood cells that are critical for normal blood clotting and blood vessel repair following injury. We are studying the processes that enable platelets to stick to the site of vessel injury and to each other to form a stable blood clot. These very processes, when unchecked, are responsible for 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. Many factors control how big and how rapidly a blood clot grows and whether it becomes harmful enough to lead to a heart attack or stroke. One of these factors is the level of platelet 'reactivity' or 'stickiness' . We are working towards a better understanding of how platelet reactivity is regulated and how this dictates the potential of a blood clot to become harmful. This knowledge will not only increase our knowledge of blood clot formation in health and disease, but also help in the development of new therapies for the prevention of heart attack and stroke.Read moreRead less
Interactions Between Haematopoietic, Bone, Vascular And Endocrine Systems Control Stem Cell Fate And Mobilization
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
Haemopoietic stem cells (HSC) normally reside in the bone marrow (BM) where they make blood and immune cells. We can force HSC to move from the BM into the blood, a process called mobilisation, used to collect large numbers of HSC for transplantation into cancer patients. My research involves identifying factors that control HSC fate within the BM (that is survival, growth, differentiation) and what happens during mobilisation to force them to leave with the aim of improving transplant success.
Role Of Selectins And Their Receptors In The Regulation Of The Haemopoietic System
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
The production of blood cells occurs in the bone marrow. This process depends on the controlled proliferation and development of rare and multipotent precursors called haemopoietic stem cells, and involves a subtle balance between the positive regulation of proliferation and growth inhibition necessary to prevent blood cell overproduction and leukaemia. We have recently shown that two related proteins expressed at the surface of cells of the bone marrow vasculature negatively regulate blood cell ....The production of blood cells occurs in the bone marrow. This process depends on the controlled proliferation and development of rare and multipotent precursors called haemopoietic stem cells, and involves a subtle balance between the positive regulation of proliferation and growth inhibition necessary to prevent blood cell overproduction and leukaemia. We have recently shown that two related proteins expressed at the surface of cells of the bone marrow vasculature negatively regulate blood cell formation. These proteins, called P-selectin and E-selectin, are essential to regulate the migration of immune cells into lymphoid organs and inflamed tissues. We have found that these selectins also mediate the adhesion of haemopoietic stem cells in the bone marrow vasculature, inhibit their proliferation and kill some of their progeny. This project includes three specific aims to: 1) characterise the role of P-selectin and E-selectin in vivo in the regulation of blood cell formation, 2) understand the molecular mechanisms inside haemopoietic stem cells which are responsible for the growth inhibition and cell death in response to selectins, and 3) identify the receptors which are responsible for these effects of selectins on haematopoietic stem cells. These findings will give us a better understanding of how blood formation is regulated in vivo and how these interactions are perturbed during the emergence of leukaemia.Read moreRead less
Role Of Neutrophil Proteases In The Mobilisation Of Haemopoietic Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$318,279.00
Summary
Mobilisation is a procedure consisting in inducing the egress of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent to induce mobilisation of haemopoietic stem cell is a cytokine called granulocyte - colony stimulating factor (G-CSF). In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow. Elements contributing to this success have be ....Mobilisation is a procedure consisting in inducing the egress of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent to induce mobilisation of haemopoietic stem cell is a cytokine called granulocyte - colony stimulating factor (G-CSF). In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow. Elements contributing to this success have been the simplicity of the procedure (daily injections of a mobilising cytokines such as G-CSF), a more rapid recovery following high dose chemotherapy and transplantation, and lower costs. Despite its common use in clinics, the molecular mechanisms responsible for haemopoietic stem mobilisation following injection of cytokines are still unknown. A large body of experimental data demonstrate the critical role of adhesive interactions between blood forming cells and the bone marrow microenvironment These interactions control the lodgement of blood forming cells in the bone marrow, where they normally reside, and their egress into the blood during mobilisation. Experiments from this laboratory have shown that the mobilisation of blood forming cells that follows the administration of G-CSF, may be the consequence of the accumulation in the bone marrow of a class of leukocytes called neutrophils. These neutrophils subsequently release within the bone marrow a set of enzymes that specifically cleave a cell adhesion molecule expressed in the bone marrow, and therefore disrupt the adhesive interactions between the bone marrow and the blood forming cells resulting in their egress in the blood. This proposal aims to demonstrate this hypothesis and to provide tools to predict and improve the levels of mobilisation that can be achieved with healthy donors and cancer patients.Read moreRead less
Role Of Neutrophil Proteases And Their Inhibitors In Haematopoietic Stem Cell Mobilisation
Funder
National Health and Medical Research Council
Funding Amount
$472,750.00
Summary
Mobilisation is the enforced migration of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent used to induce mobilisation of haemopoietic stem cells is a cytokine called G-CSF. In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow aspirates. The simplicity of the procedure (daily injections of G-CSF, absence of bone marrow aspiration) ....Mobilisation is the enforced migration of blood forming cells (haemopoietic stem cells) from the bone marrow, where they normally reside, into the blood. The most common agent used to induce mobilisation of haemopoietic stem cells is a cytokine called G-CSF. In recent years, the number of transplantations performed with mobilised blood stem cells has exceeded those performed with bone marrow aspirates. The simplicity of the procedure (daily injections of G-CSF, absence of bone marrow aspiration), better patient recovery and survival, lower costs have all contributed to the success of this procedure. Despite its common use in clinics to rescue cancer patients undergoing high-dose chemotherapy, the reasons why haemopoietic stem cells mobilise are still not fully understood. It is known that haemopoietic stem cells stay in the bone marrow because they express 'adhesive' molecules on their surface. In pioneering work, this laboratory has shown that cytokines such as G-CSF increases the number of neutrophils (a type of white blood cell) in the bone marrow. These neutrophils release enzymes (known as proteases) which cut into pieces the 'adhesive' molecules and other proteins responsible for the retention of blood forming cells within the bone marrow. This project aims to further these investigations to include both the role of proteases and their naturally-occurring inhibitors in the mobilisation of blood forming cells. Particularly, we will investigate how the expression of serpins and TIMPs, two families of protease inhibitors, is regulated in the bone marrow during mobilisation and how these inhibitors control the activity of proteases responsible for the mobilisation of blood forming cells. This knowledge may lead to the design of new treatments that induce more efficient mobilisation and ultimately improve the success of haemopoietic stem cell transplantation.Read moreRead less
Mechanisms Of Haemopoietic Stem Cell Mobilisation: Role Of The Cross-talk Between Bone Marrow And Bone.
Funder
National Health and Medical Research Council
Funding Amount
$461,196.00
Summary
Blood or Haematopoietic stem cells (HSCs) are found in the bone marrow and make all the blood cells we require life-long. This process must be carefully regulated. The production of too many blood cells leads to leukaemia while too little means anaemia. However we still have much to learn on how this regulation occurs. Scientists have recently found that osteoblasts (the cells that normally form bone) are responsible for some of this regulation. In fact osteoblasts create a type of 'home' for HS ....Blood or Haematopoietic stem cells (HSCs) are found in the bone marrow and make all the blood cells we require life-long. This process must be carefully regulated. The production of too many blood cells leads to leukaemia while too little means anaemia. However we still have much to learn on how this regulation occurs. Scientists have recently found that osteoblasts (the cells that normally form bone) are responsible for some of this regulation. In fact osteoblasts create a type of 'home' for HSCs. Our laboratory has recently found that this relationship also works the other way around. That is bone marrow cells themselves regulate osteoblast numbers and thus bone formation. To show this, we used a therapy that forces haematopoietic stem cells to leave the bone marrow and migrate into the blood (a process called mobilisation). Mobilisation is used clinically to harvest large numbers of HSCs for transplantation into cancer patients to prevent bone marrow failure following chemotherapy. To our surprise, we found that when we mobilise HSCs, the rate of bone formation dropped. As osteoblasts (the bone forming cells) are also involved in creating the HSC 'home', we aim to test whether treatments which increase bone formation boost the number of HSCs that are available to be mobilised and collected for transplantation. Thus, by manipulating bone formation we may ultimately be able to improve the long-term survival rates of cancer patients that require high dose chemotherapy and subsequent transplantation. This proposal also aims to better understand (i) how blood-forming cells control bone formation, and reciprocally (ii) how bone-forming cells regulate haematopoietic stem cells in the bone marrow.Read moreRead less
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