V-ATPases Subunit D2 Is Critical For Acdification And Bone Resorption.
Funder
National Health and Medical Research Council
Funding Amount
$531,264.00
Summary
Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, aci ....Overproduction and excessive activity of osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone loss. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is critical for osteoclastic bone resorption and, therefore represents a potential molecular target for the discovery of novel bone anti-resorptive agents. The proposed project addresses the fundamental role of the V-ATPase in osteoclast differentiation, acidification and bone resorption. Understanding the molecular and cellular mechanisms by which V-ATPases regulate osteoclast function and bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone disordersRead moreRead less
Characterisation And Therapeutic Targeting Of Molecular Pathways That Promote Breast Cancer Metastasis To Bone
Funder
National Health and Medical Research Council
Funding Amount
$442,573.00
Summary
Breast cancer that has spread to bone cannot be cured. Using the most clinically relevant model of breast cancer available we have identified that tumour cells growing in bone need to suppress immune elimination (by suppressing the Type I interferons) and invade through the bone tissue (by activation of cysteine cathepsins). Studying the functional role of these pathways will provide novel insight into the mechanisms of breast cancer spread to bone that can be augmented therapeutically.
How Do Bone-active Drugs Increase Patient Survival?
Funder
National Health and Medical Research Council
Funding Amount
$613,952.00
Summary
Bisphosphonates are a class of drugs used to prevent bone destruction in diseases such as osteoporosis. Evidence is emerging that these drugs also act on cells outside the skeleton to have additional beneficial effects, for example prolonging patient survival. This project will identify the cells affected and the mechanisms involved. With this knowledge, these drugs could be used more effectively and in different ways for the prevention or treatment of cancer and chronic human illnesses.
Bone Marrow Macrophages: “Resident Evil” In The Establishment And Progression Of Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$570,585.00
Summary
Multiple myeloma (MM) is a cancer that develops within the bone marrow (BM). To date, which cells of the BM stroma are required for the support of MM growth remains unknown. Our preliminary data suggest BM resident macrophages, expressing CD169 and CX3CR1, are essential for MM growth. Using innovative and elegant animal models of MM, we will define the role of these macrophages in MM growth and determine if macrophage-targeted therapies can delay MM growth in the relapsed disease setting.
The Role Of P62/A170 In Pathological Bone Destruction
Funder
National Health and Medical Research Council
Funding Amount
$276,000.00
Summary
Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the involvement of P62 in RANKL-induced NF-Kb signaling, we propose ....Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the involvement of P62 in RANKL-induced NF-Kb signaling, we propose that intracellular molecule P62-A172 may play an important part in the switch off-on signals necessary for bone resorbing cells to resorb bone. To this end, we will study the molecular mechanism of P62 in action, and the interaction with its possible partners for the facilitation of abnormal bone resorption. The clinical significance of this project is to: 1) enhance understanding of abnormal bone resorption in Orthopaedic related diseases and conditions. 2) provide a strategy of drug development for the treatment of these disease and conditions.Read moreRead less
The Role Of TNF Family Members TWEAK And TNF-alpha In Bone Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$566,946.00
Summary
Bone remodelling, or turnover, is the process by which bone is broken down by osteoclasts and replaced by osteoblasts. Disruption of this process is the cause of many bone-related diseases that affect millions of Australians and countless others worldwide. It is controlled by the complex interactions of a large number of systemic factors (hormones) and locally acting agents, such as chemokines and cytokines, the details of which are not fully understood. Each of these factors, however, is a pote ....Bone remodelling, or turnover, is the process by which bone is broken down by osteoclasts and replaced by osteoblasts. Disruption of this process is the cause of many bone-related diseases that affect millions of Australians and countless others worldwide. It is controlled by the complex interactions of a large number of systemic factors (hormones) and locally acting agents, such as chemokines and cytokines, the details of which are not fully understood. Each of these factors, however, is a potential therapeutic target. Pro-inflammatory cytokines, those that are associated with inflammatory diseases such as Rheumatoid Arthritis (RA), are known to have key roles in both the physiology and pathology of bone. TWEAK is a recently described member of the TNF family of cytokines. We have shown that TWEAK is a novel mediator of inflammatory arthritis in mouse model systems and is therefore a likely candidate as a therapeutic target. We now have extensive preliminary data to suggest that TWEAK is involved in human RA, and also in the regulation of normal bone remodelling. TWEAK therefore may be implicated in a wide spread of bone diseases, including osteoporosis. We believe it is of great importance to perform a thorough analysis of TWEAK in bone biology, and we propose to do so.Read moreRead less
Inhibiting Tumour Growth By Targeting EphA3 And Disrupting Tumour Stromal And Vascular Microenvironment
Funder
National Health and Medical Research Council
Funding Amount
$645,136.00
Summary
Tumours consist of cancer cells, tumour blood vessels and connective tissue, all of which are different to normal tissues. Many of the cells making up tumour vessels and connective tissue are recruited, during initial growth and subsequent spreading of tumours, from the bone marrow. Our research will examine the presence and function of the EphA3 receptor on these cells during tumour development and assess how our anti-EphA3 antibody inhibits tumour growth by targeting stroma and vasculature.
Monitoring Bone Loss And Response To Therapy Through Bone Material And Structural Composition
Funder
National Health and Medical Research Council
Funding Amount
$696,111.00
Summary
Millions of scripts are filled for treatment of osteoporosis. However, there is no way of knowing if these drugs are right for these individuals, if it improves bone strength or are actually doing harm. Bone density measurement is of limited value. We have developed a new analysis method that measures changes in bone structure that tell us if the treatment is or is not working so alternative treatment can be used. The aim of this study is to test this new method.
BMP4 - A Metastasis Suppressor Gene In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$454,220.00
Summary
Breast cancer is the most common cause of cancer death in western women. Whilst the primary tumour can often be eradicated successfully, in many cases, it may have already spread to other organs, including lungs, liver and bone, causing severe morbidity. Current treatments are largely palliative and new therapies that specifically prevent to spread of breast cancer are urgently required. However, little is known about the molecular pathways regulating the spread of cancer cells. We have shown th ....Breast cancer is the most common cause of cancer death in western women. Whilst the primary tumour can often be eradicated successfully, in many cases, it may have already spread to other organs, including lungs, liver and bone, causing severe morbidity. Current treatments are largely palliative and new therapies that specifically prevent to spread of breast cancer are urgently required. However, little is known about the molecular pathways regulating the spread of cancer cells. We have shown that expression of a gene called BMP4 in tumours blocks the spread of breast cancer in a mouse model. The aim of this project is to develop the application of BMP4 as a therapy for advanced breast cancer using our mouse model. We will measure the expression of BMP4 in human breast cancer and test whether treatment with purified BMP4 protein can protect mice from the spread of breast cancer. If successful, this study will offer a new therapy for women with currently incurable breast cancer.Read moreRead less