The future of cancer therapy lies in the tailoring of treatment to the characteristic of individual tumour. We have previously identified a subset of breast tumours that are characterised by the presence of large excess of proteins called D-type cyclins. Similar overexpression of cyclin D1 has been shown to lead to the development of cancer in mammary gland in animal models. In normal cells, D-type cyclins are degraded rapidly, therefore the regulation of protein degradation, or proteolysis, is ....The future of cancer therapy lies in the tailoring of treatment to the characteristic of individual tumour. We have previously identified a subset of breast tumours that are characterised by the presence of large excess of proteins called D-type cyclins. Similar overexpression of cyclin D1 has been shown to lead to the development of cancer in mammary gland in animal models. In normal cells, D-type cyclins are degraded rapidly, therefore the regulation of protein degradation, or proteolysis, is crucial in preventing the accumulation of D-type cyclins. In the subset of breast cancers we have identified, D-type cyclin proteolysis is defective. We, and others, have obtained evidence for the involvement of the SKP2 gene in the proteolysis of D-type cyclins. SKP2 has also been shown to be required for the proteolysis of another important protein, called p27. In the clinic, accumulation of p27 in tumours is used as a good prognostic indicator. However, some exceptions have been found where the accumulation of p27 correlates with aggressive tumours. As D-type cyclins are able to counteract the effect of p27, we hypothesise that the aggressive behaviour of these tumours is due to the simultaneous accumulation of D-type cyclins and that this is due to a mutation in the SKP2 gene. The experiments described in this proposal are designed to test this hypothesis. As the choice of treatment is affected by the interpretation of p27 levels, the results obtained from this study may have a direct impact in the clinic.Read moreRead less
Investigating The Role Of The Notch4 Receptor In Blood Vessel Formation And Remodelling In Mammals
Funder
National Health and Medical Research Council
Funding Amount
$653,086.00
Summary
We aim to understand how blood vessels form. This process is crucial for foetal development, and for injury repair in adults. When there is too much or too little blood vessel formation, diseases such as arthritis, blindness and osteoporosis can result. Also many tumours grow and spread by growing new blood vessels. We will study a signal that occurs between cells (Notch signalling) that is important in controlling the amount of blood vessel formation, by analysing in detail one component (Notch ....We aim to understand how blood vessels form. This process is crucial for foetal development, and for injury repair in adults. When there is too much or too little blood vessel formation, diseases such as arthritis, blindness and osteoporosis can result. Also many tumours grow and spread by growing new blood vessels. We will study a signal that occurs between cells (Notch signalling) that is important in controlling the amount of blood vessel formation, by analysing in detail one component (Notch4)Read moreRead less
Functional Analysis Of The Notch Signalling Pathway In The Differentiation And Maintenance Of Pituitary Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$421,320.00
Summary
Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development, metabolism and milk production, are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow ....Many of the processes that are essential for normal bodily function such as growth, the ability to cope with stress, sexual organ development, metabolism and milk production, are controlled by the pituitary gland. This organ is located at the base of the brain and regulates these bodily functions through the release of six different hormones. Formation of the pituitary gland occurs during development of the foetus. This process requires a specific set of genes that shape the pituitary and allow the hormone secreting cells to arise. Changes in these pituitary formation genes results in underdevelopment of the pituitary in newborn babies. In severe cases, where the pituitary has failed to form completely (panhypopituitarism), these babies are extremely ill and in some instances do not survive. We are studying the genes that belong to the Notch signalling pathway. These genes are important regulators of cell differentiation during the development of the brain, skin, bone and many other tissues. However, the role of the Notch signalling genes in pituitary development is not known. We have shown for the first time that these genes are active during pituitary development. To test the function of these genes in the pituitary, we will generate mouse models that either lack or inappropriately activate these genes. Our results will provide insight into the role of Notch Signalling genes in pituitary development in mice and humans. In this project, we also hope to identify cells in the pituitary that are able to give rise to multiple hormone secreting cell types. These stem cells are of significant clinical importance as they provide an avenue for the development of novel therapies for pituitary disorders in humans, based on the replacement of defective pituitary tissue with functional stem cell derived tissue.Read moreRead less
The Intersection Between Hedgehog And Notch Signalling In Medulloblastoma.
Funder
National Health and Medical Research Council
Funding Amount
$620,647.00
Summary
Brain tumours are the second most common malignancy of childhood and the leading cause of cancer related death and disability in children. Medulloblastoma is the most frequent malignant childhood brain tumour, arising in the cerebellum. This application looks at the relationship between two genetic pathways responsible for medulloblastoma which are also drug targets. Understanding this interaction will lead to better treatment options for the disease.
Some bacteria can cause inflammation of the brain (bacterial meningitis). This leads to 170,000 deaths annually in the world. Many patients who survive after antibiotic treatment have lifelong disabilities like deafness, and problems of memory and learning. We aim to show that a certain biochemical pathway in the brain contributes to death and disability, with a view to identifying new drug treatments that can be used alongside antibiotics to improve disease outcomes.
The Contribution Of Gp130-Stat3 During Wnt-beta-catenin Induced Intestinal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$396,275.00
Summary
There is growing evidence that cancer is initiated and develops not by the deregulation of a single gene or signaling pathway, but by multiple events. We will study the co-operation between two pathways - gp130-Stat and Wnt. These signaling pathways are frequently deregulated in many types of cancer, however their interaction remains poorly understood. We shall explore their mechanism of interaction during intestinal cancer in order to develop a novel therapeutic target for this disease.
Colorectal cancer is a common malignancy in Australia and the mutation of one gene (Apc) is implicated in >80% of the cases. We aim to understand Apc biochemistry in normal and colon cancer cells by integrating mathematics with our experimental biology program. The main outcomes for this project will be a better understanding of the regulatory systems perturbed in colon cancer. We believe that the insights gained by our research will point the way to more effective treatments of colon cancer.