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
Osteosarcoma is the most common cancer of bone. It osurs most frequently in childhood (teenage years) and current therapy is limited to surgery and chemotherapy. We have developed a new model of osteosarcoma that displays a high degree of similarity to human osteosarcoma. We aim to further understand this model and apply these findings to help treat human osteosarcoma.
Role Of A DNA Helicase, Recql4, In Haematopoiesis, Skeletal Biology And Malignancy
Funder
National Health and Medical Research Council
Funding Amount
$750,701.00
Summary
We are interested in understanding how a gene involved in familial cancer works. Mutations in this gene cause patients to develop a range of cancers in their blood and skeleton. We are seeking to understand how this gene functions so that we can understand how the cancers form in these families and also how sporadic cancer forms.
Manipulation Of Haematopoietic Stem Cell Niches To Improve Therapeutic Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$451,716.00
Summary
My aim is to understand how stem cells are naturally regulated by the body. My central hypothesis is that local environment (niche) factors largely govern stem cell behaviour. Identification and manipulation of these factors will offer a novel therapeutic opportunity to improve the clinical use of normal haematopoietic stem cells to improve transplantation success, as well as sensitise leukaemia cells to chemotherapy.
Effects Of Ephrin-Eph And PTHrP Signalling On Osteosarcoma.
Funder
National Health and Medical Research Council
Funding Amount
$646,486.00
Summary
Osteosarcoma (OS) is the most common bone cancer in children, with ~170 cases per year in Australia. We used genetic mutation of mice to induce OS that is very similar to human OS. The OS produces parathyroid hormone-related protein and ephrins and responds to both proteins. We will study how the cancer develops and spreads, and how this is affected by these two pathways, both of which are implicated in cancer development, and could be targets for treatment.
Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. ....Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. OCs are formed from white blood cells that are present in the bone marrow and the blood. The recent discovery of a family of new factors that control the formation of OCs has enabled the generation of human OCs in the laboratory so now we can investigate the genes that control the process of conversion of white blood cells to OCs. An important advance in this project involves the use of cord blood that contains stem cells. These very na ve cells will enable us to study the very earliest genes that control differentiation of precursors to OC. We have found a number of genes that are regulated by these new bone-forming factors. In white blood cells the activation of particular genes can regulate OC formation. One example is vitamin D-upregulated gene, VDUP. This gene is of particular interest as it causes inhibition of the mechanism that leads to OC formation in the bone. Obviously, the ability to control a 'switch' that regulates OC formation may enable us to control the progress of bone loss in diseases such as osteoporosis. In this project, we intend to investigate how and why the genes that lead to OC formation are regulated and what influence the various bone cell factors have on the formation of bone-resorbing OCs. These studies will lead to the development of treatments for osteoporosis and other bone diseases.Read moreRead less
Identification Of Novel PTH Anabolic Targets In Osteoblasts
Funder
National Health and Medical Research Council
Funding Amount
$547,216.00
Summary
Osteoporosis is a major disease affecting Australians. Whilst there are a number of drugs available that will reduce bone loss, there are few drugs available that build new bone, and little is known of the action of these drugs. New targets have been identified that modulate bone formation, and this project aims to validate these in appropriate models and determine their mechanism of action.
Novel Strategies For The Treatment Of Bone Disease By Nutrient Activators Of Calcium-sensing Receptors
Funder
National Health and Medical Research Council
Funding Amount
$467,432.00
Summary
Osteoporosis is a major health problem in the Australian community and will worsen with an ageing population. This work aims to develop new strategies for the treatment of osteoporosis and associated fractures based on the nutritional and/or pharmacological activation of calcium-sensing receptors.