Antitumour Efficacy Of TRAIL: An Immunotherapeutic Approach For The Treatment Of Skeletal Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$459,034.00
Summary
The most serious clinical problem with patients with solid tumours is metastasis to bone, which leads to complications that can cause erosion of the patient's quality of life, and eventually death. TRAIL is a new cancer therapeutic that selectively kills cancer cells while sparing normal cells. The use of TRAIL agonistic antibodies that do not bind OPG and have increased serum half life offers an exciting approach for the treatment of skeletal malignancies that is non toxic and safe.
The Role Of Muscle And The Application Of Muscle-cell Therapies In Bone Repair
Funder
National Health and Medical Research Council
Funding Amount
$438,936.00
Summary
Muscle is often close to bone and we have found that muscle cells can directly contribute to bone repair. We are examining importance of muscle cells in orthopaedic repair and whether new methods for mobilizing muscle cells can improve healing.
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
Histone Deacetylase Inhibitors (HDIs) With Antineoplastic And Antiosteolytic Properties
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
Metastatic bone disease is very common in patients with many forms of solid tumours. Our approach to use Histone Deacetylase Inhibitors (HDIs), to target bone metastases offers an exciting therapeutic potential. Treatment with HDIs will have the potential to suppress cancer-induced bone destruction by integrating the cytotoxic and osteotropic properties that reside within the same compound. Our preclinical data will facilitate the translation of HDIs to clinical trials for bone cancer.
Novel Therapeutic Interventions For The Orthopaedic Complications Of Neurofibromatosis Type 1 (NF1).
Funder
National Health and Medical Research Council
Funding Amount
$628,422.00
Summary
Children with the genetic disease NF1 can develop fractures that fail to unite and this can lead to amputation. We have advanced models of NF1-deficient bone cells and fracture healing that we will use to test new pharmaceutical treatments for NF1.
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
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
Cartilage Destruction In Joint Disease: Studies With ADAMTS-4 And ADAMTS-5 Deficient Mice
Funder
National Health and Medical Research Council
Funding Amount
$540,600.00
Summary
In healthy joints the proteoglycan, aggrecan, gives cartilage compressive resilience to permit weight bearing, but in disease aggrecan is degraded by ADAMTS enzymes. The challenges to the field are to determine which ADAMTS is involved, when these enzymes are active and precisely where they come from. We hypothesise that ADAMTS-4 and-or ADAMTS-5 is involved in cartilage pathology. To test this hypothesis we aim to [1] Generate mice containing mutant ADAMTS-4 and-or -5 in all cells, or [2] in car ....In healthy joints the proteoglycan, aggrecan, gives cartilage compressive resilience to permit weight bearing, but in disease aggrecan is degraded by ADAMTS enzymes. The challenges to the field are to determine which ADAMTS is involved, when these enzymes are active and precisely where they come from. We hypothesise that ADAMTS-4 and-or ADAMTS-5 is involved in cartilage pathology. To test this hypothesis we aim to [1] Generate mice containing mutant ADAMTS-4 and-or -5 in all cells, or [2] in cartilage cells only. [3] Analyse mutant mice for changes in skeletal architecture, changes in ADAMTS mRNA and protein, and changes in aggrecan breakdown products. [4] Assess disease severity in mutant mice in in vivo models of joint disease. We already have mice with ADAMTS-4, or -5, mutated in all tissues and we are generating the double mutants now. We will also generate single and double mutants with dysfunctional enzymes in cartilage only. We will examine skeletal structure by histology and X-ray at all ages and monitor for expression of ADAMTS-1 and -9 to detect any compensatory over-production of other potential 'aggrecanases'. We will also do co-culture experiments in which cartilage and synovial cells from combinations of mutant and control mice will be incubated together to determine whether synovial ADAMTS can penetrate and degrade aggrecan in cartilage. Finally we will induce arthritis in mutant and control mice and monitor them to detect differences in the time of disease onset, the rate of disease progression and overall disease severity. A comparison of whole-mouse with cartilage only mutants in the in vivo models will complement the in vitro co-culture studies and determine whether other joint tissues such as synovium and joint capsule can also produce ADAMTS enzymes that destroy cartilage. This is not known. Together these experiments will reveal if, where and when ADAMTS-4 and-or -5 are active, and whether indeed they are the best targets for drug development.Read moreRead less