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
The Role Of Hyaluronic Acid, CD44 And Osteopontin In Haemopoietic Stem Cell Biology
Funder
National Health and Medical Research Council
Funding Amount
$472,062.00
Summary
Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules. This project is based upon the unique observations made in the applicants laboratory demonstrating that the three molecules hyaluronic acid (HA), CD44 and osteopontin play key roles in the localisation of HSC with ....Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules. This project is based upon the unique observations made in the applicants laboratory demonstrating that the three molecules hyaluronic acid (HA), CD44 and osteopontin play key roles in the localisation of HSC within the BM following transplantation and in regulating their development into mature blood cells. Encapsulating the concept of highly specific, local interactions regulating blood cells is the 'niche' hypothesis in which MC form a specific 'niche'. The current inability to identify HSC in situ makes it impossible to analyse either their distribution or molecules that regulate this process. Circumstantial evidence suggests the presence of HSC 'niches' in close association with the bone. Using a novel approach based on BM transplantation to track cells lodging in the BM, we were the first to report that the lodgement of a transplanted HSC is not a random process, but results in cells of donor origin migrating to the bone-marrow interface. The presence of HA and CD44 on the HSC and CD44 and ostepontin in the marrow microenvironment are critical for this pattern of lodgement. In addition, we now have evidence that HA and osteopontin are important in the maintenance of HSC in their primitive state. This proposal aims to confirm the critical roles and interactions of these three molecules in HSC biology.Read moreRead less
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.
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
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.
Osteal Macrophages: Novel Regulators Of Osteoblast Function And The Endosteal Stem Cell Niche
Funder
National Health and Medical Research Council
Funding Amount
$406,125.00
Summary
Bone diseases are a major health problem and current treatments are inadequate. We are investigating a novel role for macrophages (cells important in tissue maintenance and immune responses) in bone growth, repair and disease. Greater understanding of this will provide new ways to treat bone disease. We will also determine if these macrophages help support stem cells that reside near bone surfaces, which may provide new treatment strategies to improve bone marrow transplantation in cancer.
Cell Cycle Regulation, Haemopoietic Stem Cells And Myeloproliferation.
Funder
National Health and Medical Research Council
Funding Amount
$579,138.00
Summary
My research has focused on understanding how the process of cell division can result in different outcomes for adult blood stem cells. I am interested in determining the role of bone and blood vessels in the regulation of blood stem cells and in the development of blood diseases (myeloprolifertive disease). I will also determine the effects of changing the cell cycle with drugs to improve transplantation of blood stem cells.
Acute myeloid leukaemia (AML) is a major health problem with only about one third of patients being cured. In addition therapies have changed little over the last 20 years. However there is optimism that with greater knowledge of the biochemical changes in AML that are caused by genetic mutations, more effective treatments will be developed. This project therefore aims to increase understanding of the biochemical interplay between two proteins called c-Cbl and Flt3 that are altered in AML.