In Vivo Modelling Of WIF1 In Bone Development And Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$402,796.00
Summary
Osteosarcoma is the most common primary cancer of the bone. We identified Wnt inhibitory factor 1 (WIF1), a secreted protein that inhibits the Wnt cell growth pathway, to be silenced in osteosarcoma. We propose to investigate the role of WIF1 in normal development, how its loss contributes to cancer progression, and whether treatment with WIF1 protein can inhibit tumour growth. Our overall aim is to discover key molecules, which can be targeted therapeutically to inhibit osteosarcoma growth..
E2F Inhibitors As Anticancer Agents For Squamous Cell Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Squamous cell carcinoma of the head and neck is one of the six most frequent causes of cancer death worldwide. these tumours are currently treated with surgery, radiotherapy and chemotherapy. Although these treatments are associated with a five year survival rate of between 40% and 60% there is a critical need for more effective and less destructive treatments. In this application we will extend on our earlier work in which we identified the protein E2F1 as being a major contributor to tumour de ....Squamous cell carcinoma of the head and neck is one of the six most frequent causes of cancer death worldwide. these tumours are currently treated with surgery, radiotherapy and chemotherapy. Although these treatments are associated with a five year survival rate of between 40% and 60% there is a critical need for more effective and less destructive treatments. In this application we will extend on our earlier work in which we identified the protein E2F1 as being a major contributor to tumour development. In normal cells, E2F1 is required for the regulated growth of head and neck cells. However, we found that in head and neck tumours, E2F1 is overactive and contributes to the dergulated growth of the tumour. In this project we will test our newly developed inhibitors of E2F1 on various tumour cells derived from head and neck cancers to see how effective they are at stopping tumour cell growth. Furthermore we will test these compounds in animal models of head and neck cancer to determine whether they will be useful therapeutic agents for treatment of human cancer. Early results on tumour cell lines look very promising.Read moreRead less
Barrett's Oesophagus And Reflux Oesophagitis : Efficacy Of Medical Vs Surgical Management
Funder
National Health and Medical Research Council
Funding Amount
$510,750.00
Summary
Gastro-oesophageal reflux disease is very common. In some people it leads to oesophageal cancer, which is increasing in incidence more rapidly than any other cancer in the developed world. Significant resources are required for its diagnosis, surveillance and treatment. There are two main forms of treatment, acid suppressing drugs which may be required for the rest of the person's life, or surgery. The goal of treatment is the control of the symptoms such as heartburn, and the prevention of canc ....Gastro-oesophageal reflux disease is very common. In some people it leads to oesophageal cancer, which is increasing in incidence more rapidly than any other cancer in the developed world. Significant resources are required for its diagnosis, surveillance and treatment. There are two main forms of treatment, acid suppressing drugs which may be required for the rest of the person's life, or surgery. The goal of treatment is the control of the symptoms such as heartburn, and the prevention of cancer. It is relatively easy to determine if the symptoms are controlled, and both medical and surgical treatments do this. It is not as easy to measure if a treatment will reduce the risk of cancer, because it takes so long to develop. We will compare a group of patients with reflux disease treated with drugs with a group treated by surgery. In each group we will take oesophageal tissue before treatment and compare it with similar tissue taken after treatment. We will look for reductions in abnormal cells and genes that are in diseased tissue and are important in the development of cancer. This study will help us understand the mechanisms by which reflux causes damage to the oesophagus and how it ultimately leads to cancer. We will learn if medical or surgical treatment is better in healing the underlying damage in the oesophagus, and which treatment is more likely to prevent cancer developing. It may result in more effective management of reflux in our community and help reduce the number of cases of oesophageal cancer.Read moreRead less
C-Kit Signalling And Cellular Responses In Haemopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$731,115.00
Summary
Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biolo ....Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biology approaches to determine the role of different signalling pathways in cellular responses mediated by the growth factor receptor c-Kit. The c-Kit receptor has essential functions in blood cell development, skin and hair pigmentation, gut function and the reproductive system. It is also essential for the development and function of mast cells which trigger allergic responses such as asthma and eczema. Mutant forms of the receptor have been identified in certain leukaemias and colon cancers. Many new drugs that target specific intracellular signalling pathways have recently been developed and are beginning to be evaluated in clinical trials. Better understanding of how individual pathways contribute to the function of c-Kit and other receptors is essential for optimal use of these new drugs. For example, it may enable the choice of drugs to block c-Kit dependent cancer cell growth or allergic reactions without affecting the growth of normal blood cells.Read moreRead less
Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian c ....Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian cancer cases, that affect 1 in 8000 Australian women, are due to the inheritance of a faulty gene. An understanding of the way gene expression and hence tissue differentiation is altered after sex reversal will inform us about the causes and consequences of normal and abnormal sexual development, gonadal malignancies and infertility. The gonad is unusual in that two completely different organs can arise from an essentially identical primordium, so that errors in development lead to intersexual phenotypes. We will use our new experimental animal model to clarify these processes.Read moreRead less
Dissecting The Role Of Hedgehog Signalling In Chondrogenesis And Skeletal Disease
Funder
National Health and Medical Research Council
Funding Amount
$408,739.00
Summary
There are close to 400 inherited disorders that affect how the skeleton develops, as well as a range of injury and age-related skeletal defects. There is much interest in treating such abnormalities with artificial bone grown outside the body. In order to achieve this aim we must understand all of the processes involved in producing and maintaining bone within the body. We are using both mouse and cell culture models of skeletal development to increase our understanding of these processes.
THE ROLE OF UBIQUITIN LIGASE ADAPTOR PROTEIN NDFIP1 IN NEURONAL DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$581,813.00
Summary
Many brain diseases are characterized by faulty connections between nerve cells (neurons), in some cases caused by the inability to remove unwanted proteins from the neuron. This function is carried out by the ubiquitin-proteasome system (UPS). We have evidence that a UPS protein called Ndfip1 is important for forming functional brain circuits. We aim to discover whether neuron growth, branching and connectivity is promoted by Ndfip1 targeting of PTEN (phosphatase with tensin homology) to the UP ....Many brain diseases are characterized by faulty connections between nerve cells (neurons), in some cases caused by the inability to remove unwanted proteins from the neuron. This function is carried out by the ubiquitin-proteasome system (UPS). We have evidence that a UPS protein called Ndfip1 is important for forming functional brain circuits. We aim to discover whether neuron growth, branching and connectivity is promoted by Ndfip1 targeting of PTEN (phosphatase with tensin homology) to the UPS.Read moreRead less
Body Segment Identity Specification By The Transcription Regulator, Moz
Funder
National Health and Medical Research Council
Funding Amount
$366,301.00
Summary
One in 28 newborns have birth defects. Cleft palate and aortic arch defects are among the most common, always requiring surgery and often causing lethality. We propose to study a protein, Moz, which is essential for palate and aortic arch development. Moz (Monocytic leukaemia zinc finger protein) was first identified in human chromosomal abnormalities causing particularly aggressive forms of childhood and adult leukaemia. We have shown previously that Moz is essential for the formation of blood ....One in 28 newborns have birth defects. Cleft palate and aortic arch defects are among the most common, always requiring surgery and often causing lethality. We propose to study a protein, Moz, which is essential for palate and aortic arch development. Moz (Monocytic leukaemia zinc finger protein) was first identified in human chromosomal abnormalities causing particularly aggressive forms of childhood and adult leukaemia. We have shown previously that Moz is essential for the formation of blood stem cells. Moz can regulate the activity of genes, but which genes it regulates in vivo is unknown. In the absence of Moz, mice are born with a cleft palate, lack the thymus, where immune cells are instructed, and fail to form the lung blood circulation, so that they are unable to supply their blood with oxygen after birth. Moz deficiency also causes defects of the vertebrate column, such that individual vertebrae acquire the appearance of their neighbours. These symptoms are typical for a general defect in positional information of individual body segments with respect to their location along the body axis. We will investigate the molecular mechanisms that require Moz in patterning of the body axis. This project will characterize a genetic mechanism that is crucial for normal development of the palate, the aorta and the vertebrate column.Read moreRead less
Molecular Genetics Of Sex Determination And Gonad Development
Funder
National Health and Medical Research Council
Funding Amount
$539,000.00
Summary
Disorders of sexual development are among the most common forms of birth defects in humans (1 in 4,000 births). Many other childhood conditions with this incidence warrant prenatal diagnosis or neonatal screening. These disorders often result in infertility, genital abnormalities and gender mis-assignment. Uncertainty about a child s gender at birth can be very traumatic physically and psychologically for the individual and family concerned. There are profound consequences in later life for the ....Disorders of sexual development are among the most common forms of birth defects in humans (1 in 4,000 births). Many other childhood conditions with this incidence warrant prenatal diagnosis or neonatal screening. These disorders often result in infertility, genital abnormalities and gender mis-assignment. Uncertainty about a child s gender at birth can be very traumatic physically and psychologically for the individual and family concerned. There are profound consequences in later life for the affected individual. The cause of these problems is most often the failure of the delicate network of gene regulation that is responsible for proper development of testes or ovaries in the embryo. This research project will identify genes important for sex determination and development of the gonads, find out how these genes function and interact, and discover how they contribute to cases of aberrant sexual development in humans.Read moreRead less
The Role Of Scube Genes In Hedgehog Signal Transduction
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
Cancer often results form the miss-regulation and-or mutation of genes that control tissue formation in the developing embryo. Particular sets of genes combine to form a signal transduction pathway that coordinates the cell's response to its environment during the course of normal fetal growth. One such pathway is called the Hedgehog signal transduction pathway which has been shown to coordinated cell division and patterning within malignant and normal tissues. Genes encoding components of this ....Cancer often results form the miss-regulation and-or mutation of genes that control tissue formation in the developing embryo. Particular sets of genes combine to form a signal transduction pathway that coordinates the cell's response to its environment during the course of normal fetal growth. One such pathway is called the Hedgehog signal transduction pathway which has been shown to coordinated cell division and patterning within malignant and normal tissues. Genes encoding components of this pathway are mutated in the most common forms of human cancers. Understanding how this pathway is regulated is critical to designing strategies to treat the onset and progression of these cancers. The studies outlined in this grant plan to study a new component of this pathway that we have identified in our laboratory, in an easy to study vertebrate model, the zebrafish embryo. We plan to study how this class of proteins, termed scube proteins, acts to control activation of the pathway. We hope this will lead to a fuller understanding of this process, and at the same time help understand the nature of the end result of the patterning process within the muscle cells that we are studyingRead moreRead less