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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
Cell-targeted Gene Delivery Into Human Haematopoietic Stem Cells For The Treatment Of Thalassaemia
Funder
National Health and Medical Research Council
Funding Amount
$171,208.00
Summary
Thalassaemia is the most common inherited single gene disorder affecting haemoglobin synthesis in red blood cells. It mainly affects people of Mediterranean, Middle Eastern, African, South East Asian, Chinese, and Indian origin. However, large numbers of thalassaemia patients are found nowadays in Australia and other developed countries, due to large population movements in the twentieth century. Approximately 300,000 severely affected children are born each year with thalassaemia and various ot ....Thalassaemia is the most common inherited single gene disorder affecting haemoglobin synthesis in red blood cells. It mainly affects people of Mediterranean, Middle Eastern, African, South East Asian, Chinese, and Indian origin. However, large numbers of thalassaemia patients are found nowadays in Australia and other developed countries, due to large population movements in the twentieth century. Approximately 300,000 severely affected children are born each year with thalassaemia and various other abnormalities of haemoglobin synthesis. If untreated, most thalassaemia patients will die within the first few years of life. The vast majority of thalassaemia patients depend on regular blood transfusions every two to three weeks, and on nightly infusions of an iron chelator (a drug for removing excess iron from the blood). These procedures place considerable burden on thalassaemia patients, their families and society, and expose them to blood transmitted infections. The only curative treatment for thalassaemia is bone marrow transplantation from a matching donor. However, the vast majority of patients do not have matching donors and thus the only prospect for them to receive such therapy is to replace in their bone marrow cells a copy of the normal set of genes for the synthesis of haemoglobin. The studies in this proposal are therefore designed to test gene therapy protocols on bone marrow stem cells derived from thalassaemia patients. A normal set of globin genes will be delivered to the bone marrow stem cells via non-viral delivery systems and examined for function in an immunodeficient mouse strain that can accept human bone marrow. This research may enable bone marrow transplantation to be applied for the therapy of most patients with thalassaemia, while it may also have a major impact on therapeutic approaches for other haematological anomalies.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
Mechanisms Underlying The Effects Of Retinoic Acid Receptor Gamma In Haemopoiesis And Bone Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$366,801.00
Summary
My recent studies have demonstrated that a model of vitamin A deficiency results in impaired blood cell production and contributes to a blood cell disorder that can progress to leukaemia. There are also reduced numbers of blood stem cells (which give rise to all blood cells) and bone (which helps to regulate blood cell production) in this mouse model. In these studies I seek to understand more on how vitamin A deficiency causes these defects, which may lead to better treatment of such diseases.
Characterization Of Haemopoietic Lineage Determining Genes
Funder
National Health and Medical Research Council
Funding Amount
$631,021.00
Summary
Haemopoiesis is the process by which blood cells develop from stem cells. This process is tightly regulated and is dependant upon the appropriate expression of genes at each developmental stage within various lineages. Our work focuses on two genes (Mlf1 and Hls5) that are involved in determining lineage commitment and affect the expression of key hemopoietic regulators. If these genes are aberrantly expressed leukemias and other blood disorders can develop.
Hematopoietic Effects Of Activating The Hedgehog Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$410,551.00
Summary
The hedgehog proteins are important for normal human development. They are expressed on cells of the brain and developing limbs and provide important signals to neighbouring cells so that development of the brain and limbs can occur normally. Mutations in genes within the hedgehog signalling pathway lead to congenital abnormalities such as failure of the brain to fold properly and shortened limbs or extra digits. Hedgehog proteins also stimulate the growth of adult stem cells that are responsibl ....The hedgehog proteins are important for normal human development. They are expressed on cells of the brain and developing limbs and provide important signals to neighbouring cells so that development of the brain and limbs can occur normally. Mutations in genes within the hedgehog signalling pathway lead to congenital abnormalities such as failure of the brain to fold properly and shortened limbs or extra digits. Hedgehog proteins also stimulate the growth of adult stem cells that are responsible for the maintenance of many adult tissues such as the skin, bone and hair. Excessive hedgehog signalling however can lead to cancers, particularly of the brain and skin. The ability of hedgehog proteins to stimulate the growth of stem cells raises their use for expansion of stem cells. This would be particularly useful for umbilical cord blood stem cells, which could be used to treat patients with leukemia if there were sufficient numbers. This project will examine the potential use of hedgehog proteins for stimulating blood stem cells.Read moreRead less
Production Of Large Scale Erythroid Progenitor Cultures From Human Embryonic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$396,718.00
Summary
Transfusion of fresh red blood cell units of the correct blood type into patients can be life saving. However, access to units of the correct blood type is often limited due to limited supply of donor blood and its short shelf life creating the need for a constant donor blood supply. We propose to develop a system that allows us to generate unlimited numbers of human red blood cells in a culture dish which we will derive from differentiating human embryonic stem cell lines.
We want to understand more about the control of blood cell formation and the development of leukemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukemia, and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to take these observations further so that we can ultimately understand how a gene important in blood cell formati ....We want to understand more about the control of blood cell formation and the development of leukemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukemia, and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to take these observations further so that we can ultimately understand how a gene important in blood cell formation can also be important in causing leukemia. Here we propose to use genetic engineering approaches to generate mice in which the function of this gene is ablated or removed in a controlled and regulated fashion.Read moreRead less
Analysis Of The Hematopoietic Function Of Endophilin And MASH Proteins
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
We want to understand more about the control of blood cell formation and the development of leukaemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukaemia and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to understand how a gene important in blood cell formation can also be important in causing leukaemia. To address ....We want to understand more about the control of blood cell formation and the development of leukaemia. We have discovered one gene that is very important in both these processes. It is the most common genetic abnormality involved in causing human T-cell leukaemia and we have recently shown that it is absolutely required for the development of all blood cells within an animal. We wish to understand how a gene important in blood cell formation can also be important in causing leukaemia. To address this we will study a new molecule with which it partners, and two molecules via which it exerts its actions.Read moreRead less