The Role Of 'Orphan' Transporters In Bone Homeostasis And Disease
Funder
National Health and Medical Research Council
Funding Amount
$675,668.00
Summary
Osteoclasts (OCs) are giant multinucleated cells exclusively responsible for physiological bone degradation (resorption). Excessive OC activity leads to localised bone destruction (osteolysis) as observed in patients with osteoarthritis and underlies decreased bone mass and fragility fractures that are a hallmark of osteoporosis. This project examines the role of an orphan solute carrier transporter in OC function and its potential involvement in bone disease.
Structural And Functional Analyses Of Rat Receptor Activator Of NF-kb Ligand
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Rat RANKL (Xu and Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fra ....Rat RANKL (Xu and Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fractures. This proposal addresses the important and fundamental issue of RANKL regarding the role of molecular structure on its biological function. We have established that the TNF-like core domain is the functional domain, important for osteoclastogenesis, osteoclast polarisation and protecting against Fas-triggered apoptosis. This proposal will further characterise the mutant forms of the TNF-like core domain of RANKL using site directed mutagenesis and protein truncation analysis, and assess their respective binding activities to OPG and RANK, and their biological activities both in vitro and in vivo. It will lead us into better understanding of the structure-function relationship of RANKL. Ideally, we would like to develop a relative agent for the suppression of osteolysis in orthopaedic related diseases including osteoporosis. Such an optimized molecule could become a potent therapeutic agent that selectively inhibits osteoclast formation and bone resorption.Read moreRead less
Molecular Characterization Of V-ATPase V0 Domain Subunits E1 And E2 In Osteoclast
Funder
National Health and Medical Research Council
Funding Amount
$558,909.00
Summary
Osteoporotic fractures in the elderly are often linked to increased mortality rates. Excess bone resorption is a major contributor to the onset of the disease. The proposed project focuses on the investigation of the molecular mechanisms of acid secretion that is required for the bone degradation in body. The project will examine the role of the proton pump in bone resorption and seek potential targets for the treatment of osteoporosis.
gp130 is a protein expressed in all cells in the body; this project will analyse the influence of gp130 within the cells that form bone, the cells that destroy bone, and the cells that form a communication network within the bone matrix. Understanding the way this protein works will help us to understand how current therapies for osteoporosis work, and will help us to design new therapies.
Myo1b Bridges The Actin-membrane Interface During Osteoclastic Bone Resorption
Funder
National Health and Medical Research Council
Funding Amount
$429,387.00
Summary
Osteoporosis is a debilitating bone disease which features progressive bone loss. Bone loss (resorption) is driven by the bone resident cell the osteoclast. Identifying molecules that regulate bone resorption by osteoclasts is a crucial first step towards developing new targets for theraputic intervention. This proposal explores the role of Myo1b, a novel protein that appears to facilitate osteoclastic bone resorption and thus represents an attractive new candidate to target bone loss.
Molecular Mechanisms And Therapeutic Effects Of Novel Parthenolide Analogs On Osteolysis
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Rheumatoid arthritis and osteoporosis are common bone diseases with features of bone loss. Drugs that inhibit bone loss are needed for the prevention and treatment of bone diseases. The proposed research explores the potential use of novel herbal inhibitors for the suppression of bone resorbing cells, and their potential as treatments for bone loss.
Furin: Carving-up Vital Substrates For Bone Remodelling And Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$815,972.00
Summary
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. It is caused by an imbalance between the cells that are constantly reabsorbing and reforming bone. The proposed project will address furin as a novel regulator of bone remodelling.
Relationship Of The Anabolic And Catabolic Responses In Healing A Critical Sized Defect In Rats
Funder
National Health and Medical Research Council
Funding Amount
$329,750.00
Summary
Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In some other situations, the body's bon ....Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In some other situations, the body's bone resorbing response, the catabolic response, may be too high and prevent healing from occurring. In normal bone healing, there is a balance between the anabolic and catabolic response. In disordered bone healing, these responses are out of balance. Several reasonably new treatments are available which can increase the anabolic response or decrease the catabolic response. We have preliminary results showing that with these agents we can bring these elements into better control, and thus drive bone healing. We have optimised an animal model where both the anabolic and catabolic responses can be controlled. In this project, we explore the optimisation of the timing and magnitude of anabolic and catabolic responses in bone healing.Read moreRead less
Paget's Disease Of Bone Associated Sequestosome 1/p62 Mutations In Autophagy-mediated Processes And Bone Resorption
Funder
National Health and Medical Research Council
Funding Amount
$474,892.00
Summary
Paget’s disease of bone (PDB) is a common, chronic bone disorder characterized by focal lesions of increased bone degradation initiated by giant overactive osteoclasts. Subsequent bone formation is irregular, resulting in bones that are structurally weak. Genetic mutations are a common cause of PDB in Caucasians. Understanding the genetic mutations and their regulation on bone cells may lead to the discovery of a new drug target for the treatment of PDB.