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
Regionalisation And Differentiation Of EPL-derived Neurectoderm: Directed Formation Of Dopaminergic Neurons In Vitro.
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Neurodegenerative diseases result from the loss, damage or dysfunction of neural populations. For example, dopaminergic neurons are lost progressively in Parkinson's Disease. A potential method of treatment is 'cell therapy' which envisages transplantation of cells back to the site of cell loss, and restoration of function. Application of the cell therapy approach is limited by the unavailability of cells for transplantation. Embryonic stem (ES) cells provide a potential solution to this problem ....Neurodegenerative diseases result from the loss, damage or dysfunction of neural populations. For example, dopaminergic neurons are lost progressively in Parkinson's Disease. A potential method of treatment is 'cell therapy' which envisages transplantation of cells back to the site of cell loss, and restoration of function. Application of the cell therapy approach is limited by the unavailability of cells for transplantation. Embryonic stem (ES) cells provide a potential solution to this problem because they can be grown in unlimited numbers and differentiated to any kind of cell that is found in the embryo or adult. In this application we propose to continue our work on controlling the differentiation of ES cells to neural lineages. Production of dopaminergic neurons will be a particular focus. We will establish conditions that enable the production of these cells in a manner that is therapeutically relevant and predicted to be acceptable to regulatory authorities. Cells will be tested by transplantation into adult rats to assess their therapeutic potential, in particular persistence, integration and differentiation within the brain environment. Research required to achieve the production of transplantable cells will also provide basic information about the mechanisms by which the mammalian embryo allocates cells, specifically cells of the nervous system, to specific lineages during embryogenesis. This information will be important for the production of other neural cell types, which have therapeutic potential for treatment of diseases like stroke, motor neuron disease and spinal cord injury.Read moreRead less
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.
The Molecular Mechanisms Controlling Maintenance Of Osteogenic Precursor Cells And Skeletal Tissue Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$234,750.00
Summary
Within human bone marrow there exists a rare population of bone marrow stromal stem cells (BMSSCs) able to develop into the different cell types that form haematopoietic supportive stroma and surrounding skeletal tissue. There has been alot of interest of late in the potential of BMSSCs as a cellular based therapy to treat and manage bone fractures or bone loss caused by disease. Increasing evidence suggests that decreased bone mass due to osteoporosis dos not purely result in an increase of bon ....Within human bone marrow there exists a rare population of bone marrow stromal stem cells (BMSSCs) able to develop into the different cell types that form haematopoietic supportive stroma and surrounding skeletal tissue. There has been alot of interest of late in the potential of BMSSCs as a cellular based therapy to treat and manage bone fractures or bone loss caused by disease. Increasing evidence suggests that decreased bone mass due to osteoporosis dos not purely result in an increase of bone resorption by osteoclasts, but may also occur through a decline in the number of bone forming cells called osteoblasts or their progenitors. Fracture non-union, prosthetic loosening and the replacement of large defects in bone are common and difficult problems. The use of autologous bone cells generated from isolated BMSSCs in combination with bio-compatible implant materials would provide a novel solution for the treatment of these problems, avoiding the use of autografts and allografts of bone with all their associated difficulties. However, large numbers of ex vivo expanded BMSSCs are currently required to heal even small bone defects in animal models. This is compounded by the decline in proliferation rates and bone forming capacity of BMSSCs during prolonged expansion in culture. An improved understanding of the genes that regulate the proliferation and differentiation of BMSSCs in vitro is therefore an essential prerequisite for the effective management of bone fracture and bone loss. We propose to genetically manipulate the expression of genes in BMSSCs, that are known to regulate cellular growth and development inorder to maintain the growth of stem cell populations in vitro and to extend their capacity to form bone when transplanted in vivo.Read moreRead less
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
Isolation And Characterisation Of Novel Progenitor Cells In The Mammary Epithelium And Their Role During Carcinogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$470,346.00
Summary
Stem and progenitor cells in the breast are the immature cells from which mature cells are derived. Their are long-lived, resistant to death and can produce multiple types of mature cells, implicating them as cells from which breast cancer may originate. We aim to search for novel cell surface markers that define the progenitor cells in the mouse mammary gland. The data gathered from this project may facilitate the development of targeted therapies to the cells of origin in breast cancer.