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
Investigation And Modulation Of RANKL-induced Osteoclastogensis, Bone Resorption And Signaling Pathways
Funder
National Health and Medical Research Council
Funding Amount
$33,825.00
Summary
Osteoclasts are exclusively responsible for the degradation of bone matrix. RANKL is a member of a ligand-receptor system which directly regulates osteoclast differentiation and bone resorption. New treatment regime for various bone diseases have been highly sought after for many years. The identification of potential natural compounds that inhibit the formation and function of osteoclasts might serve as a useful tool for such treatment.
Artificial joint implants are widely used to replace diseased or damaged joints. Despite the impressive success of joint replacement many artificial joints do not last indefinitely. In many patients joints last for 25 years or more but in about 15% the artificial joints will fail prematurely. Artificial joints need to be replaced because of loosening resulting from the loss of bone from around the artificial joint. The bone loss is caused by large numbers of small particles generated by excessiv ....Artificial joint implants are widely used to replace diseased or damaged joints. Despite the impressive success of joint replacement many artificial joints do not last indefinitely. In many patients joints last for 25 years or more but in about 15% the artificial joints will fail prematurely. Artificial joints need to be replaced because of loosening resulting from the loss of bone from around the artificial joint. The bone loss is caused by large numbers of small particles generated by excessive wear of the artificial joint. We now know that specialised cells in the body react to the wear particles and try to destroy them. During this process they produce molecules which lead to bone destruction. This project seeks to investigate the way particles cause bone loss and to develop drug treatments that will either prevent the loss of bone or promote new bone to replace that which has been lost. The increasing use of joint replacement and an aging population means that the number of patients with artificial joint failure will increase. This will mean that an increasing amount of medical recourses will be needed to replace failed and painful artificial joints. It is planned that the findings obtained from this project will eventually result in drug treatments which can reduce the need for the replacement of artificial joints.Read moreRead less
De-differentiation Of Committed Cells Into Haematopoietic Stem Cells By The Instructive Role Of The Transcription Factor HOXB4
Funder
National Health and Medical Research Council
Funding Amount
$683,040.00
Summary
Blood stem cells are long-lived and can give rise to every cell type of the blood system and due to these properties they are currently used in the clinics. Despite their importance, our knowledge of the mechanisms the control the multiplication of these rare cells is very scarce. This proposal aims to identify key factors that have the potential to convert mature, easy available blood cells into stem cells. This knowledge has to potential to lead to novel system that allow the expansion of stem ....Blood stem cells are long-lived and can give rise to every cell type of the blood system and due to these properties they are currently used in the clinics. Despite their importance, our knowledge of the mechanisms the control the multiplication of these rare cells is very scarce. This proposal aims to identify key factors that have the potential to convert mature, easy available blood cells into stem cells. This knowledge has to potential to lead to novel system that allow the expansion of stem cells for transplantations in the future.Read moreRead less
‘Transcriptional Tumour Suppression’ By Pax5 And Ikaros In B Progenitor Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$558,927.00
Summary
B-progenitor acute lymphoblastic leukaemia (B-ALL) is the most common cancer in children. The genes Pax5 and Ikaros are frequently mutated in B-ALL, but how this contributes to leukaemia development and treatment resistance remains unclear. We have recently produced new B-ALL models driven by reversible suppression of Pax5 or Ikaros activity, and propose to use these models to uncover how these genes control leukaemia differentiation and regression.
Transcriptional Effectors Of Oncogenic ERK Signaling In Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$820,776.00
Summary
This project aims to unravel how one of the most frequently deregulated molecular pathways in colorectal cancer controls the expression of genes required for these tumours to grow and spread. We expect this work to uncover novel therapeutic targets to effectively inactivate this pathway and biomarkers to select patients most likely to benefit from existing therapies.
Deciphering The Transcriptional Program That Instructs Lymphatic Endothelial Cell Fate.
Funder
National Health and Medical Research Council
Funding Amount
$541,950.00
Summary
Lymphatic vessels are essential to maintain fluid balance in most tissues of the human body. Further the lymphatic vasculature plays a central role during cancer and contributes to tumour metastasis. Despite this integral function in health and disease little is known about the molecular programs that coordinate gene expression to build a functional vasculature. This research project will address this gap in our knowledge and will open up new therapeutic avenues for lymphatic vascular disorders