Apical Membrane Proteins As Targets For A Schistosomiasis Vaccine
Funder
National Health and Medical Research Council
Funding Amount
$480,459.00
Summary
Schsitosomiasis is a chronic neglected tropical disease for which there is currently no vaccine. A vaccine is sorely needed to control this parasite. This proposal seeks to identify molecules from the outer surface of the parasite which are recognised by the immune system of people from Brazil who are resistant to schistosomiasis. Molecules identified in this manner will be tested as vaccines in an animal model of schistosomiasis, and ranked based on their performances to enter human trials.
Translational Control Of Gene Expression And The Choice Between Cell Death And Proliferation
Funder
National Health and Medical Research Council
Funding Amount
$378,000.00
Summary
Proteins carry out most enzymatic and structural functions in a cell. Thus, the kinds of protein molecules that are found in a given cell determine its characteristics and cells respond to changes in their environment by adjusting the abundance of some or many proteins in their collection. The instructions for the assembly of proteins are encoded in the genes and this information is expressed via intermediary molecules called messenger (m)RNA. Both, transcription of the genes into mRNA molecules ....Proteins carry out most enzymatic and structural functions in a cell. Thus, the kinds of protein molecules that are found in a given cell determine its characteristics and cells respond to changes in their environment by adjusting the abundance of some or many proteins in their collection. The instructions for the assembly of proteins are encoded in the genes and this information is expressed via intermediary molecules called messenger (m)RNA. Both, transcription of the genes into mRNA molecules and their subsequent translation by the ribosomes into protein are tightly controlled steps in the gene expression pathway. Erroneous gene expression is a major factor in human disease and dysregulation of translation is linked to a growing spectrum of illnesses such as cancer and cardiovascular disease, viral infection, and less frequent hereditary syndromes. The project proposed here is prompted by emerging evidence for a role of translational regulation in controlling the balance between cell death and survival. Tipping this balance has disastrous consequences for an organism as evidenced by its involvement in many major disorders (e. g. stroke, heart failure, neurodegeneration, AIDS, cancer, autoimmunity). Our aim is to test the hypothesis that a putative translational regulator termed p97-DAP5-NAT1, and a specialised mechanism of translation initiation by internal ribosome entry are important for the maintenance of this balance. To investigate this, we will employ DNA chips, a novel tool from Genomics research that allows the measurement of the levels of thousands of mRNA molecules in a single experiment. It is conceivable that knowledge of these special mechanisms of translation will lead to novel targets for therapeutic intervention, and this work will contribute some of the experimental tools to explore these avenues in the future.Read moreRead less
CHAPERONES IN BREAST CANCER AND ESTROGEN RECEPTOR FUNCTION
Funder
National Health and Medical Research Council
Funding Amount
$256,573.00
Summary
Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor res ....Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor responses to hormone. Through a novel mode of action, coumarin-based Hsp90 inhibitors disrupt Hsp90 dimerization causing receptor release and subsequent depletion. We will confirm this novel mechanism for new, high affinity Hsp90 inhibitors and determine which can best interfere with estrogen signalling, either alone or in combination with antiestrogen therapies in the treatment of hormone-dependent cancers. Our study has the potential to pin point the site of action of the immunophilins in ERa to a proline in a region critical for ligand-induced receptoractivation. We will determine the role of the immunophilins and this active-site proline residue in modulating receptor stability and function. Aberrant expression of receptor-associated immunophilins appears linked to endocrine resistance and metastasis in breast cancer. Our study will profile the expression of these chaperones in well defined breast cancer tissue microarrays, and has the potential to identify them as informative biomarkers in the treatment of the disease.Read moreRead less
Developmental And Cellular Mechanisms Involved In The Pathological Changes To The Epithelium In Asthma.
Funder
National Health and Medical Research Council
Funding Amount
$263,500.00
Summary
A consensus has developed in recent years that asthma involves chronic airway inflammation superimposed upon a background of airway remodelling. If untreated, these processes result in increased airway responsiveness, variable airflow obstruction and ultimately a progressive decline in lung function). Recently the role of the epithelium in the pathogenesis of asthma has been emphasised based upon observations indicating that the epithelium can play an important role in airway inflammation and re ....A consensus has developed in recent years that asthma involves chronic airway inflammation superimposed upon a background of airway remodelling. If untreated, these processes result in increased airway responsiveness, variable airflow obstruction and ultimately a progressive decline in lung function). Recently the role of the epithelium in the pathogenesis of asthma has been emphasised based upon observations indicating that the epithelium can play an important role in airway inflammation and remodelling. However, this paradigm has been developed using data accumulated almost exclusively from studies in adults. Epidemiological studies suggest that airway remodelling might play a less significant role in the majority of childhood asthma since most children with asthma have relatively minor symptoms, minimal disruption of lung function and tend not to have symptoms that persist into adulthood. Clearly the relative importance of inflammation and remodelling and the regulatory mechanisms involved are important factors to understand particularly if new, effective prevention and therapeutic strategies are to be developed. For the first time in children, the proposed project will allow the study of asthma mechanisms using target organ tissue (airway epithelium) from a large unselected population. Primary cell samples recovered by bronchial brushing will be analysed separately and also cultured in order to investigate critical elements of the pathogenesis of asthma. Data collected from symptomatic children can be easily compared with that from healthy controls and also with data from adults to determine age related factors that contribute to asthma. Furthermore, the establishment of a repository of cultured epithelial cells from these children will provide a unique resource that will allow future collaborations with scientists studying a variety of mechanisms in asthma and with the pharmaceutical industry.Read moreRead less
Array-based Comparative Genomic Hybridisation In Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$314,773.00
Summary
Lung cancer is the most frequent cause of cancer deaths in many Western countries, including ours. Lung cancer is the third leading cause of death of Australians and the fifth leading cause of burden of disease in Australia. In many cases, even with the best treatment available, the lung cancer spreads from where it starts, to other parts of the lung, chest and throughout the body. This eventually leads to death. We are interested in the factors that influence when and how lung cancer spreads. W ....Lung cancer is the most frequent cause of cancer deaths in many Western countries, including ours. Lung cancer is the third leading cause of death of Australians and the fifth leading cause of burden of disease in Australia. In many cases, even with the best treatment available, the lung cancer spreads from where it starts, to other parts of the lung, chest and throughout the body. This eventually leads to death. We are interested in the factors that influence when and how lung cancer spreads. With exposure to cancer-causing agents such as cigarette smoke, parts of the lung may suffer permanent damage that increases the risk of lung cancer. Many of these changes include the genes in air passages and lung tissue. In this study, we will use the latest technology in genetics called gene chips to study changes in genes that affect the spread of lung cancer. These gene chips can study a vast number of genes at once. In particular, we will whether there is an abnormal number of copies of genes in the lung cancer. We hope that this research study will provide new information about the diagnosis and treatment of lung cancer.Read moreRead less
Molecular Characterisation And Diagnosis Of Malignant Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$421,250.00
Summary
Malignant mesothelioma (MM) is an aggressive, asbestos-related tumour of increasing incidence throughout the world that is estimated to be cause approximately 20,000 deaths per annum . MM was rare until approximately 20-30 years ago but it is now more, or as, common a cause of death in Australia as cancers of the bone, liver, cervix, bladder and ovary. Although asbestos use has declined to virtually zero across most of the developed world, due to 30 to 40 year latency of the disease, the peak in ....Malignant mesothelioma (MM) is an aggressive, asbestos-related tumour of increasing incidence throughout the world that is estimated to be cause approximately 20,000 deaths per annum . MM was rare until approximately 20-30 years ago but it is now more, or as, common a cause of death in Australia as cancers of the bone, liver, cervix, bladder and ovary. Although asbestos use has declined to virtually zero across most of the developed world, due to 30 to 40 year latency of the disease, the peak in cases of mesothelioma is not expected until 2010. MM is one of the most aggressive and debilitating tumours known, with a median survival of 7-10 months and a clinical pattern that usually involves substantial pain and dyspnea. Advances in therapy-prevention of mesothelioma will have not only have a major health impact, but potentially an extraordinary economic impact. MM is predicted to cost the Australian economy around $5 billion in compensation over the next 35-40 years. Government, insurance companies and industry will share that cost. The significance of this disease therefore extends beyond its actual incidence. There is growing evidence in many tumour types that the best diagnostics and treatments for cancer will come about as a result of understanding the molecular logic that underpins carcinogenesis, and designing therapies and diagnostics accordingly. We will carry out a project using the most comprehensive microarrays available to profile gene expression in malignant mesothelioma. We will use the expression data we obtain to fulfil three aims. Firstly, we will use patient outcome information to search for genes whose expression is indicative of response to therapy. Secondly, we will search the data to identify candidate secreted molecules which may be useful in the early detection of MM. Finally, we will develop a molecular assay to unequivocally diagnose MM from cells collected from pleural effusions.Read moreRead less
Genomic Profiling To Predict Lung Cancer Metastases
Funder
National Health and Medical Research Council
Funding Amount
$323,500.00
Summary
Lung cancer is the most frequent cause of cancer deaths in many Western countries, including ours. Lung cancer is the third leading cause of death of Australians and the fifth leading cause of burden of disease in Australia. In many cases, even with the best treatment available, the lung cancer spreads from where it starts, to other parts of the lung, chest and throughout the body. This eventually leads to death. We are interested in the factors that influence when and how lung cancer spreads. W ....Lung cancer is the most frequent cause of cancer deaths in many Western countries, including ours. Lung cancer is the third leading cause of death of Australians and the fifth leading cause of burden of disease in Australia. In many cases, even with the best treatment available, the lung cancer spreads from where it starts, to other parts of the lung, chest and throughout the body. This eventually leads to death. We are interested in the factors that influence when and how lung cancer spreads. With exposure to cancer-causing agents such as cigarette smoke, parts of the lung may suffer permanent damage that increases the risk of lung cancer. Many of these changes include the genes in air passages and lung tissue. In this study, we will use the latest technology in genetics called gene chips to study changes in genes that affect the spread of lung cancer. These gene chips can study a vast number of genes at once. We hope that this research study will provide new information about the diagnosis and treatment of lung cancer.Read moreRead less
Mechanism Of Interaction Of VWC Domains And Consequence For Protein Function
Funder
National Health and Medical Research Council
Funding Amount
$516,803.00
Summary
More than 1000 proteins contain a type of module known as the VWC domain. These domains are discreet sections of the protein that are very important for how the protein works. Proteins containing this domain are involved in normal functioning of the human body and in diseases of the nervous system and blood, among others. The main function of the VWC domain is to link proteins together in complexes. How this is achieved is not known and is what we aim to discover.