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Mesenchymal Stem Cell Maintenance And Recruitment During Skeletal Repair Are Dependent On EphB-ephrinB Signalling
Funder
National Health and Medical Research Council
Funding Amount
$611,827.00
Summary
There is currently a steady increase in surgical intervention and rehabilitation therapy for bone related fractures due to trauma or osteoporosis as a consequence of an aging population. Bone regeneration involves the coordinated participation of skeletal precursor cells, blood vessels and immune cells recruited from the surrounding tissues. This proposal examines the mechanisms mediating the maintenance and recruitment of skeletal precursor cells to sites of bone damage.
Regulation Of Astrocytic Gliosis And Axonal Regeneration In EAE By EphA4
Funder
National Health and Medical Research Council
Funding Amount
$532,352.00
Summary
Multiple Sclerosis (MS) is a debilitating disease with currently no effective cure. Apart from losing the protective insulating sheath called myelin, nerve cells are damaged and a scar forms. If this could be prevented then MS may be better treated. Using a model of MS called EAE, the role of a molecule, EphA4, will be examined for its ability to induce nerve loss and scar formation and to determine whether blocking it will promote repair, leading to a therapy for MS.
Molecular And Cellular Changes Following A Cortical Injury: What Role Do They Play In Regeneration?
Funder
National Health and Medical Research Council
Funding Amount
$499,625.00
Summary
Damage to the visual areas of the brain is common after, for example stroke, neurotrauma or hypoxia. The injury often manifests in the form of a scar caused by a specific type of brain cell (astrocyte). This scar acts as a barrier to the cells which transmit information (neurones), preventing re-establishment of connectivity, thus functional recovery. We will see if we can reduce this scar and enhance re-connectivity after injury by blocking some of the molecules that brain cells express.
Targeting Eph Receptors As Anti-cancer Therapy In Malignant Glioma.
Funder
National Health and Medical Research Council
Funding Amount
$403,639.00
Summary
Malignant gliomas are the commonest form of brain cancer and are characterised by a high degree of morbidity and mortality. Present treatment involves surgery and adjuvant chemoradiotherapy but despite best care the outlook for patients with this disease is poor. The increasing understanding of the biology of glioma offers the prospect of improved therapies. This proposal seeks to investigate a therapy target in this disease in animal models of human malignant glioma.
Defining The Role Of EphA5 In Olfactory Axon Growth, Guidance And Fasciculation
Funder
National Health and Medical Research Council
Funding Amount
$256,320.00
Summary
The olfactory (smell) system is a unique part of the nervous system; nerve cells are generated throughout life and it can regenerate even after injury. It therefore provides an excellent model for examining the growth, development and maintenance of nerve cells. This project will examine the effects on the organisation of the olfactory system when some guidance signals are altered. Information we obtain about how this system develops and regenerates may be useful in treating brain disorders and ....The olfactory (smell) system is a unique part of the nervous system; nerve cells are generated throughout life and it can regenerate even after injury. It therefore provides an excellent model for examining the growth, development and maintenance of nerve cells. This project will examine the effects on the organisation of the olfactory system when some guidance signals are altered. Information we obtain about how this system develops and regenerates may be useful in treating brain disorders and spinal injuries In the current project we will examine the effects of specific nerve cell guidance molecules by generating transgenic mice that produce these molecules only in the olfactory system. We can then determine what changes occur to the nerve cells when these extra molecules are produced. In addition, we will also examine the behaviour of live cells as they are growing. In the past all attempts to understand how nerve cell connections are formed in the olfactory system have used dead tissue that has been permanently preserved. In this project we have the unique opportunity to visualise living nerve cells to enable us to determine how the cells react to the guidance signals. The advantage of this approach is that it allows us to identify important interactions as they occur, rather than attempting to decipher them after they have occurred. An analogy would be watching a football game live and observing how goals were scored and appreciating the performance of individual players versus trying to guess from the final score how the game was played and who the key performers were. The results of these experiments will provide important information on the regeneration of olfactory nerve cells, as well as on the initial growth and targeting of these nerve cells.Read moreRead less
The Role Of Eph/ephrin Clustering And Trafficking In Control Of Tumour Cell Invasion
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
Eph and ephrin proteins are important for normal development of the embryo by controlling cell positioning. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where their presence is thought to promote aggressive tumours. We wish to understand how these proteins control cell movement and contribute to cancer progression so that we can develop new cancer therapies.
Functional Analysis Of The Molecular Switch That Regulates ADAM10-mediated Cleavage Of RTK Ligands In Tumour Cells.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of th ....We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of the ephrin by ADAM10 which also functions in other cancer promoting events by cleaving growth factors. Our structure reveals how Eph-bound ephrin is specifically targeted by ADAM. We will now determine the relevance of this mechanism for other ADAM10 targets, and design drugs to bind this region and inhibit ADAM function, which we will test in assays measuring tumour cell movement and growth, with the aim of developing therapies to block cancer progression.Read moreRead less
The Role Of Eph-ephrin Interactions In Mediating Mesenchymal Stem Cell Commitment, Migration And Bone Fracture Repair
Funder
National Health and Medical Research Council
Funding Amount
$579,138.00
Summary
In Australia, there is an increasing incidence of fractures that require surgical intervention and rehabilitation therapy. Fracture healing is a complex process that involves the coordination of different bone and immune cells. Our proposal will identify which cell-cell contact molecules mediate bone cell recruitment and development during normal skeletal growth and bone fracture repair. This study will help advance therapies for fracture repair and diseases of bone loss.
The Role Of Protein Tyrosine Phosphatases Regulating Eph RTK-signalling And Modulating Invasive Tumour Cell Properties.
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
The Ephs and interacting ephrins are proteins on the cell surface, which enable orientation of cells that move within the body tissues and organs, but also in tumours. Eph proteins have tyrosine kinase enzyme activity that becomes active after binding ephrins on neighbouring cells. Once active, they instruct these cells to change their shape and their adhesion to the substratum or between each other, and to become more motile. In adult organisms Ephs and ephrins are low in most cells, but they r ....The Ephs and interacting ephrins are proteins on the cell surface, which enable orientation of cells that move within the body tissues and organs, but also in tumours. Eph proteins have tyrosine kinase enzyme activity that becomes active after binding ephrins on neighbouring cells. Once active, they instruct these cells to change their shape and their adhesion to the substratum or between each other, and to become more motile. In adult organisms Ephs and ephrins are low in most cells, but they re-appear in many tumors. For example, when normal cells in the skin (melanocytes) become tumor cells, they often will have Ephs and ephrins on their surface. It is believed that these proteins will now affect if these melanoma cells will migrate and to which locations within the body. In our studies we will examine what controls the activity of Eph proteins. In particular, a class of enzymes called tyrosine phosphatases are known to regulate the function of tyrosine kinase receptors, however it is not clear which particular phosphatase regulates EphA3, the focus of our studies. We will find out, which set of phosphatases regulates EphA3 function and whether exposure to oxidative conditions, such as UV radiation, also activates Ephs and instructs tumour cells to become more motile and to invade other areas of the body. The understanding of this mechanism will help to understand the cause of cancers such as melanoma and might offer possibilities to optimise new strategies for its treatment.Read moreRead less