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Characterisation Of Human Embryonic Stem Cell Differentiation To Haematopoietic Progenitors And Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$638,856.00
Summary
Blood stem cells, which are found in the bone marrow, are currently used for treating human blood disorders including leukemia and lymphoma. However, for the majority of bone marrow transplant candidates, suitable donors cannot be found. Using embryonic stem cells, this project aims to define the conditions required to generate blood stem cells in the laboratory. The aim of the work is to provide a new source of blood stem cells that could be used in place of donor derived bone marrow.
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
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 Beta-catenin And Its Regulator FAM In Haemopoietic Stem Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$506,500.00
Summary
Haemopoietic stem cells (HSC) are currently the best characterised adult stem cell (SC) population and currently the only SC population used in cellular therapy. Adult HSC reside in the bone marrow and it is generally accepted that these rare cells cycle slowly and maintain themselves by a process involving self renewal. The cellular physiology that underlies HSC self renewal is still to be defined and no single factor has been described which is able to induce substantial proliferation and expa ....Haemopoietic stem cells (HSC) are currently the best characterised adult stem cell (SC) population and currently the only SC population used in cellular therapy. Adult HSC reside in the bone marrow and it is generally accepted that these rare cells cycle slowly and maintain themselves by a process involving self renewal. The cellular physiology that underlies HSC self renewal is still to be defined and no single factor has been described which is able to induce substantial proliferation and expansion of HSC in a defined system while maintaining critical stem cell properties. Like other SC, a critical characteristic of the rare HSC population of cells is their ability to maintain their unique stem cell properties in vivo (the process of self-renewal) while generating more committed cells which will form large numbers of differentiated and specialized mature blood cells. Recent evidence that HSC can repair other organs under some circumstances raises the possibility that this adult SC population could provide an alternative to embryonic stem cells for many stem cell therapies. If this is the case the therapeutic application of HSC becomes significantly broader. Critical to development of such applications will be an understanding of HSC self renewal and development and new approaches to expand this limited cell population. Major progress in this area will require the definition of both the intrinsic and extrinsic mechanisms that control HSC maintenance and self-renewal. Any findings in this area will have major clinical significance and be of enormous benefit to the community. Here we focus on the role of a known intrinsic regulator of SC behaviour (beta-catenin) with the aim of establishing its role in the maintenance of HSC and its regulation by a novel cofactor (FAM). We will determine if the level of beta-catenin is critical in the maintenance and-or differentiation of haemopoietic stem cells and what role FAM plays in this regulation.Read moreRead less
Role Of The Ets Family Transcription Factor Erg In Stem Cell Function And Hematopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$413,775.00
Summary
The cells responsible for producing blood are called hematopoietic stem cells (HSCs). Our research is focused on the genes that control HSC growth and development. We have discovered that a gene known to cause cancer, Erg, plays a critical role in regulating this process. This Project will tease apart the mechanism by which it does so, provide insights into how Erg can trigger cancer, and help us understand the molecular network of regulators that control blood cell production.
Transcriptional Regulation Of Haematopoietic Stem Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$566,470.00
Summary
Cancer initiating cells acquire stem cell characteristics and self renew within a supportive environment that helps maintain and propagate malignant tumours. Identifying the normal hierarchy of gene regulation within blood stem cells and designing therapies that target key transcription factors (proteins that control other genes) that are over expressed in cancer stem cells is the ultimate goal.
Interactions Between Transcription Factor Networks And Cell Signaling Pathways During Early Blood Development
Funder
National Health and Medical Research Council
Funding Amount
$589,338.00
Summary
Cancer initiating cells acquire stem cell characteristics and self renew within a supportive environment that helps maintain and propagate malignant tumours. Identifying the normal hierarchy of gene regulation within blood stem cells and designing therapies that target key transcription factors (proteins that control other genes) that are over expressed in cancer stem cells is the ultimate goal.
Role Of The Hypoxia-inducible Transcription Factor HIF-1a In Controlling Haematopoietic Stem Cell Fate
Funder
National Health and Medical Research Council
Funding Amount
$586,428.00
Summary
Haematopoietic stem cells (HSCs) reside in the bone marrow (BM) and make all immune and blood cells. We have found that, in the areas of the BM where HSC normally live, the level of oxygen is very low (hypoxia) and decreases even further when HSC are forced to move into the blood in order to be collected for transplantation. This project is to better understand how oxygenation of the BM controls HSC behaviour and properties, and to evaluate its impact on HSC transplantation.
Dissecting The Embryonic Blood-endothelial Regulatory Code And Investigating Its Role In Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$646,389.00
Summary
Cancer initiating cells acquire stem cell characteristics and multiply within a supportive environment that helps maintain and propagate malignant cells. Identifying the normal hierarchy of gene control within blood stem cells and designing therapies that target cancer cells is the ultimate goal of this body of work.
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