| Research Interests|
||Receptor activation mechanism |
| ||We have developed a new model for hormone-induced receptor activation involving relative rotation of subunits within a preexisting dimer.|
We continue to develop small molecule antagonist candidates for the GH receptor together with Protagonist Pty Ltd.
We have created a number of "super" potency GH mutants, in this case of porcine GH, and have also mapped the epitope for one of the three known agonist antibodies to the GH receptor (MAb 263).
We have created the first knockin mice mutants.
"Top panel shows 60 day old mice carring different knockin constructs of GH receptor. Bottom panel shows signalling elements associated with mutant receptor cytoplasmic domains
These are providing information about the requirements for promotion of somatic growth in vivo and about the genes promoting longevity in mammals as GH receptor knockout mice live around 50% longer than wild type littermates. They are being studies with gene microarrays. We previously published the first gene array study on peptide hormone activation of transcription.
"Docked complex of GH receptor with agonist MAb 263, showing predicted conformational change between antibody and hormone bound forms
We have shown that the GH receptor in the endoplasmic reticulum traffics to the nucleus in response to the hormone binding at the surface. The extracellular domain is a transcriptional activator, and binds to identified coactivators. Nuclear localized receptor provides hormone independent growth and survival, and regulates a novel set of genes. We are seeking the DNA sequences which bind directly to the GH receptor extracellular domain.
We have proposed important roles for suppressors of cytokine signalling in the breast response to milk engorgement and in the process of luteolysis (in collaboration with Jonathon Curlewis SBMS). These are involved in neuronal differentiation and modulate the actions of GH which alters the ratio of astrocytes to neurons, hence brain structure.
60 day old mice carring different knockin constructs of GH receptor
Docked complex of GH receptor with agonist MAb 263, showing predicted conformational change between antibody and hormone bound forms
Signalling elements associated with mutant receptor cytoplasmic domains
|Links: ||Neuroscience at UQ|