Structural and functional analyses of rat receptor activator of NF-kb ligand

Funding Activity

Website
http://purl.org/au-research/grants/nhmrc/212027

Funding Status
Closed

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Funded Activity 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 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.

Funded Activity Details

Start Date: 01-01-2002

End Date: 01-01-2004

Funding Scheme: NHMRC Project Grants

Funding Amount: $226,320.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Orthopaedics

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

Age related skeletal disorders | Aseptic bone loosening | Bone destruction | Bone resorption | Osteoclast biology | Osteoclast differentiation factor | Osteoporosis | Osteoprotegerin ligand

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