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Overcoming Immunosenescence For Effective Stem Cell Therapies
Funder
National Health and Medical Research Council
Funding Amount
$419,180.00
Summary
An established treatment for blood cancers involves a stem cell transplant to replace the blood stem cells that are damaged by radiation and chemotherapy. However, treatment success is limited with advancing age due to multiple defects in the immune system. We will use new technologies to investigate how the ageing immune system copes with stem cell transplantation and explore new methods for improving recovery and immunity after HSCT.
Manipulation Of Haematopoietic Stem Cell Niches To Improve Their Clinical Use
Funder
National Health and Medical Research Council
Funding Amount
$434,883.00
Summary
Haematopoietic stem cells (HSC) reside in adult bone marrow (BM) and make all blood and immune cells. HSCs can be damaged by chemotherapy leading to blood and BM failure. We have identified an adhesion molecule in the BM which regulates HSC behaviour. We anticipate that inhibiting this molecule will i) help minimise HSC damage during chemotherapy and ii) enhance the success of BM transplantation.
Recipient Bone Marrow Macrophages Contribute To Haematopoietic Stem Cell Transplantation Success
Funder
National Health and Medical Research Council
Funding Amount
$608,906.00
Summary
We propose an innovative approach to reduce risk and increase success of blood stem cell transplantation. We will determine whether a specialized cell within the transplant patient is required for donor stem cells to successfully take up residence and recreate the blood and immune system. We will test whether fortifying these specialized cells will improve transplantation outcomes, consequently increasing the number of transplants that can proceed and reducing potentially fatal complications.
Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inf ....Macrophages are a key component of the immune system; thier functions include killing of pathogens as well as cancerous cells. Macrophage lineage cells are derived from stem cells within the bone marrow and thier differentiation, proliferation and survival is mediated by a particular growth factor termed colony stimulating factor-1 (CSF-1). The understanding of how macrophage lineage cells develop will help us to treat many diseases including certain cancers (such as leukemia), arthritis and inflammation, and disorders of the immune system. The action of CSF-1 is mediated by the CSF-1 receptor (CSF-1R) which, when activated, controls gene regulation. In this proposal we will study CSF-1R activation and identify the genes regulated by CSF-1 with a view to characterize genes critical for macrophage development. These genes may provide potential targets for new pharmacological agents.Read moreRead less
Targeting The Hypoxia Sensing Pathway To Improve Hematopoietic Stem Cell Mobilisation And Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$653,313.00
Summary
Transplantation of patients’ own blood stem cells is used to treat many blood cancers. It increases the chance of cure. However the damage caused by chemotherapies used to combat the cancer can compromise stem cell collection and transplantation. Without transplant, these patients are less likely to survive cancer. This project is to test new drugs that enhance the harvest of blood stem cells for transplantation. These will increase the success rates of transplants and cure in these cancer patie ....Transplantation of patients’ own blood stem cells is used to treat many blood cancers. It increases the chance of cure. However the damage caused by chemotherapies used to combat the cancer can compromise stem cell collection and transplantation. Without transplant, these patients are less likely to survive cancer. This project is to test new drugs that enhance the harvest of blood stem cells for transplantation. These will increase the success rates of transplants and cure in these cancer patients.Read moreRead less
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.
Gene Therapy, Stress Haematopoiesis And The Risk Of Malignancy
Funder
National Health and Medical Research Council
Funding Amount
$617,354.00
Summary
The immense potential of gene therapy has been confirmed by the successful treatment of immune deficiencies disorders. A key issue that has emerged however is the need to avoid potentially cancer-causing genetic damage to cells undergoing repair. Some of this risk can be linked to the gene repair technology used, but we have identified and propose to investigate another potentially important mechanism involving the unusually high levels of replication imposed on cells during disease correction.
The Developmental Hierarchy Of Haemopoietic Lineage Relationships
Funder
National Health and Medical Research Council
Funding Amount
$192,000.00
Summary
The blood cells are all the progeny of a very rare stem cell, that is thought to reside in the bone marrow. The stem cell maintains itself throughout the life span of the individual as well as generating the billions of more mature cell types required in the blood. However the processes and stages that immature cells pass through from the stem cell to ultimately a mature functional blood cell such as a lymphocyte remain disputed. This study aims to determine to relationship of the various blood ....The blood cells are all the progeny of a very rare stem cell, that is thought to reside in the bone marrow. The stem cell maintains itself throughout the life span of the individual as well as generating the billions of more mature cell types required in the blood. However the processes and stages that immature cells pass through from the stem cell to ultimately a mature functional blood cell such as a lymphocyte remain disputed. This study aims to determine to relationship of the various blood cell progeny with each other and thus to provide a lineage map of the system. To do this we will isolate precursors at various stages along the developmental pathways and determine their capabilities to produce the normal range of progeny. We will then use a number of genetically altered mouse strains to assess the genes involved in this process. These studies will help provide an underlying scientific basis to the attempts to development a number of stem cell therapies that are aimed at boosting or directing stem cell production in procedures such as bone marrow transplantation for leukemia and immune deficiency. In addition a number of characterized human blood malignancies seem to have developed along aberrant pathways indicating that inappropriate lineage specification may be a factor in cancer.Read moreRead less
Approaches To Allogeneic Chimerism For The Induction Of Transplantation Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
All patients with organ failure who receive a transplant require lifelong immunosuppressive medications to prevent the body from rejecting the foreign tissue. Indefinite immunosuppressive therapy is associated with significant side-effects which include infections and cancers. In addition, long-term loss of the transplants due to slow rejection (chronic rejection) remains high. Achieving a state of immunological tolerance in which transplanted tissue is regarded as self, but reactivity to all ot ....All patients with organ failure who receive a transplant require lifelong immunosuppressive medications to prevent the body from rejecting the foreign tissue. Indefinite immunosuppressive therapy is associated with significant side-effects which include infections and cancers. In addition, long-term loss of the transplants due to slow rejection (chronic rejection) remains high. Achieving a state of immunological tolerance in which transplanted tissue is regarded as self, but reactivity to all other foreign tissues (e.g. harmful viruses, bacteria) remain normal, would solve all these problems. Tolerance would eliminate the need for immunosuppressive medications and prevent rejection of transplanted organs. The production of mixed bone marrow chimerism is a potent method of inducing tolerance. Chimerism is a state in which bone marrow tissue from two genetically different individuals coexists in one person. This can be achieved by bone marrow transplantation from a specific donor, and if chimerism is achieved, the recipient will accept all tissues from the bone marrow donor without the need for ongoing immunosuppressive therapy. This study will attempt to examine the use of different therapeutic reagents (e.g. antibodies alone or antibodies linked to idarubicin, a drug which prevent cells dividing) to develop safe protocols for the production of bone marrow chimerism and tolerance for routine clinical use in humans. The study will also examine different cellular components of the donor bone marrow which may induce tolerance.Read moreRead less
All cells in the blood are the descendants of a single cell type, the stem cell. Stem cells are found in the bone marrow and throughout life have the unique ability to generate more of themselves (termed self-renewal) as well as to produce the functional cell types of the blood, ie. red and white blood cells. This project concentrates on the processes by which these stem cells can achieve these two functions. What are the genes that enable a stem cell to have this self-renewal characteristic and ....All cells in the blood are the descendants of a single cell type, the stem cell. Stem cells are found in the bone marrow and throughout life have the unique ability to generate more of themselves (termed self-renewal) as well as to produce the functional cell types of the blood, ie. red and white blood cells. This project concentrates on the processes by which these stem cells can achieve these two functions. What are the genes that enable a stem cell to have this self-renewal characteristic and conversely what are the genes that are activated when a cell becomes committed to become, for example, a white blood cell ? We have identified a gene, Pax5, which is essential in the process whereby a stem cell commits to become a lymphocyte . Our aim is to understand the function of Pax5 as a model for understanding how the commitment process as a whole works in the blood. These studies, as well as having an underlying fundamental scientific importance, are relevant to the clinical development of a number of stem cell therapies which rely on boosting stem cell production in procedures such as bone marrow transplantation for leukaemia and immune deficiency. In addition a number of characterised human blood malignancies indicate that inappropriate lineage commitment may be a factor in cancer.Read moreRead less