Regulation Of Bone Resorption And Formation In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$5,596,183.00
Summary
Bone is continually being formed and broken down, and these two processes are critical forthe maintenance of a normal skeleton. These processes are dependent upon communication between the bone building and degrading cells, and the hormones growth factors and cytokines that are present in the circulation or produced in bone. The tightly regulated processes of bone formation and degradation need to remain equal, and are essential for the achievement and maintenance of skeletal strength and form. ....Bone is continually being formed and broken down, and these two processes are critical forthe maintenance of a normal skeleton. These processes are dependent upon communication between the bone building and degrading cells, and the hormones growth factors and cytokines that are present in the circulation or produced in bone. The tightly regulated processes of bone formation and degradation need to remain equal, and are essential for the achievement and maintenance of skeletal strength and form. Osteoporosis results from an excess of bone breakdown over formation, and our Program aims to identify the factors that regulate these processes, and develop new therapies that can modify them. We will also determine what it is about bone cell properties that make some cancers, especially those of breast and prostate, particularly prone to spread to bone.Read moreRead less
My work focuses on cells of the immune system that act as sentinels on the lookout for invading pathogens and danger. These cells are called dendritic cells. I am particularly interested in understanding how these cells function within the bone marrow environment and how they may sense viral infection or cancerous cells within this tissue. We aim to understand their function in specific diseases including Lupus and in pre-leukemia conditions, and also in infectious and parasitic diseases.
Regulation Of T Follicular Helper Cell Development And Effector Function In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,197.00
Summary
Immune cells mature into distinct populations with specialized functions. One subsets are T follicular helper (TFH) cells which are important for instructing B cells to produce antibodies following infection or vaccination. The means by which TFH cells are generated are unknown. We will determine mechanisms whereby TFH cells are produced and how they function. We hope to design approaches that will modulate the function of TFH cells in cases of immunodeficiencies, autoimmunity or vaccination.
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
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
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
Pain associated with bone cancer, fractures, osteoporosis, osteoarthritis, osteomyelitis (and other bone infections) often presents the clinician with a difficult problem of treatment as the pain can be debilitating and intractable. Most current treatments for bone pain are based on the assumption that the neural mechanisms underlying pain from different sources, whether it be visceral, cutaneous, muscular or bony, are the same, and can therefore be targeted with similar therapies. However, litt ....Pain associated with bone cancer, fractures, osteoporosis, osteoarthritis, osteomyelitis (and other bone infections) often presents the clinician with a difficult problem of treatment as the pain can be debilitating and intractable. Most current treatments for bone pain are based on the assumption that the neural mechanisms underlying pain from different sources, whether it be visceral, cutaneous, muscular or bony, are the same, and can therefore be targeted with similar therapies. However, little is known of the response properties, structure and organization of receptors and neurones responding to, and relaying information about painful stimuli, from bone to the brain. The objectives of this project are to reveal the fundamental neural mechanisms that account for the perception of bone pain. The project will test a series of specific hypotheses in order to explain why bone pain is often poorly controlled by standard pharmacological or surgical approaches. It is expected that this study will reveal the neural mechanisms responsible for relaying sensory information, in particular, that regarding painful stimuli, from bone to the brain. It will lead to a better understanding of the mechanisms of bone pain and form the template for future studies of its treatment.Read moreRead less
Twist-1 Inhibits MSC Osteoblast Differentiation During Osteoporosis Via Direct Regulation Of The Wnt Signalling Pathway
Funder
National Health and Medical Research Council
Funding Amount
$482,704.00
Summary
There is a predicted dramatic increase in the number of orthopaedic related problems that require surgical intervention and rehabilitation therapy in the coming decade associated with higher incidences of bone diseases as a consequence of an aging population. This proposal seeks to determine whether the transcription factor, Twist-1 plays a central role in regulating the growth and differentiation of skeletal progenitors during bone loss following the onset of osteoporosis.
The Role Of The Dendritic Cell Surface Molecule Clec9A In Dendritic Cell Subset Function And Dead Cell Recognition
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Dendritic cells (DC) are sentinels of the immune system. DC monitor the environment and regulate tolerance to self versus immunity to dangerous material. Different types of DC perform different jobs. We have identified a new surface molecule, Clec9A, on some mouse and human DC. We will investigate the function of Clec9A in the immune response. We will also use Clec9A to help unite mouse and human DC biology, since until now there have been few useful marker molecules common to both species.
Smart Synthetic Biomaterial Provides An Appropriate Microenvironment For Bone Tissue Regeneration
Funder
National Health and Medical Research Council
Funding Amount
$337,946.00
Summary
The demand for synthetic biomaterials to repair lost or diseased bone is rapidly growing and placing a major burden on national health budgets. But the synthetic scaffolds currently in use are far from optimal. My aim is to determine the underlying mechanisms by which synthetic biomaterials promote bone regeneration, in order to develop better scaffolds. This would improve health outcomes for recipients of bone graft substitutes as well as reduce individual and national healthcare costs.