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Allergen-sensitzation And Environmental Exposures In Early Life Interact Synergistically To Alter Lung Growth
Funder
National Health and Medical Research Council
Funding Amount
$425,088.00
Summary
Asthma develops as the result of complex interactions between genetic susceptibilities and environmental exposures. Approximately 40% of 6-year-old children in Perth are sensitized to inhaled allergens, however, only half of these have asthma. Allergic sensitization per se is therefore insufficient for the development of persistent asthma. A second hit, associated with lung inflammation in early life, increases this risk several fold. This second hit could come from viral infection or from other ....Asthma develops as the result of complex interactions between genetic susceptibilities and environmental exposures. Approximately 40% of 6-year-old children in Perth are sensitized to inhaled allergens, however, only half of these have asthma. Allergic sensitization per se is therefore insufficient for the development of persistent asthma. A second hit, associated with lung inflammation in early life, increases this risk several fold. This second hit could come from viral infection or from other inflammatory stimuli such as exposure to cigarette smoke, air pollutants and vehicle exhaust emissions. The timing of this second hit may well be important, particularly if it is early while the lungs are still growing and developing. The aim of this project is to examine interactions between allergen sensitization and exposure to environmental hazards in early life using a mouse model of allergic inflammation. We will test the hypothesis that the combination of allergic sensitization and viral infections in early life alter lung growth, airway function and airway hyperresponsiveness, however, exposure to air pollutants can not provide the 'second hit required to induce persistent asthma. Determining the role viral infection and environmental pollution have early in life may provide us with a strategy for intervention that could prevent life-long changes in respiratory function and airway hyperresponsiveness.Read moreRead less
Flavivirus Replication - Biogenesis, Ultrastructure And Roles Of Induced Membranes
Funder
National Health and Medical Research Council
Funding Amount
$334,880.00
Summary
Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue, and hepatitis C virus is a member of the same virus family. During virus multiplication in cells, new membrane structures are induced and these represent regions where the replication events occur. Using Kunjin virus, an agent of Australian encephalitis, as a model, and advanced techniques in biochemistry and electron microscopy, we have previously identified these membranes as the site of synthe ....Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue, and hepatitis C virus is a member of the same virus family. During virus multiplication in cells, new membrane structures are induced and these represent regions where the replication events occur. Using Kunjin virus, an agent of Australian encephalitis, as a model, and advanced techniques in biochemistry and electron microscopy, we have previously identified these membranes as the site of synthesis of the viral RNA or genetic material, and the viral proteins involved. These comprise the viral replication complex. The research will define the origin of these membranes, and how the components of the associated replication complex are assembled. Assembly of the virus particles in cells is also being analysed using similar technology. Hepatitis C virus cannot be reliably grown at present for research purposes in cultured cells, and we will attempt to develop a helper system to overcome the problem. An understanding of these processes, and how the viral RNA is copied into progeny RNA for new virus particles, may assist in the development of antiviral drugs for treatment of slow or persistent virus infections such as hepatitis C.Read moreRead less
Improving engagement in learning and transition to mainstream schooling for newly-arrived Sudanese youth in the middle years of schooling. The 'new wave' of Sudanese refugees (48.3% of 2003 intake) with disrupted educational and social/emotional backgrounds is currently challenging Australian schools' expertise and resources. Using frameworks that draw on cultural theory, identity and language, the study will explore the social capital needs (skills and capacities, and resource needs) of Sudanes ....Improving engagement in learning and transition to mainstream schooling for newly-arrived Sudanese youth in the middle years of schooling. The 'new wave' of Sudanese refugees (48.3% of 2003 intake) with disrupted educational and social/emotional backgrounds is currently challenging Australian schools' expertise and resources. Using frameworks that draw on cultural theory, identity and language, the study will explore the social capital needs (skills and capacities, and resource needs) of Sudanese middle-schooling students enabling successful, productive and engaged transition from their on-arrival program into mainstream secondary schooling. The resulting model and web-based materials will provide a framework for educating other groups likely to follow from Africa/elsewhere, and meet the National Priority Goal: strengthening Australia's social fabric.Read moreRead less
Glucose, Glucose Transporters And Blastocyst Formation In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$281,650.00
Summary
Embryo-based biotechnologies have the potential to improve human reproductive health, notably in treating infertility by In vitro fertilisation (IVF). They are also central to the future use of embryonic stem cells for human tissue replacement. This project investigates the molecular mechanisms controlling one of the earliest differentiations in the growth of the embryo. Using the mouse as an experimental model it will investigate the importance of several factors in the changes which set up the ....Embryo-based biotechnologies have the potential to improve human reproductive health, notably in treating infertility by In vitro fertilisation (IVF). They are also central to the future use of embryonic stem cells for human tissue replacement. This project investigates the molecular mechanisms controlling one of the earliest differentiations in the growth of the embryo. Using the mouse as an experimental model it will investigate the importance of several factors in the changes which set up the placenta and fetus as seperate tissues in the very early embryo. A key focus is the supply of glucose to the newly fertilised embryo and how important this glucose supply is for the survival of the embryo. Moreover there is great interest in the possibility that metabolic events in utero can contribute to the development of diseases in later life, notably, coronary heart diease, stroke, high blood pressure and non-insulin dependent diabetes. The results from these studies will contribute to our understanding of why some couples are infertile, lead to improved management of infertility by diet and invitro fertilisation procedures. It will also be of benefit in dietary advice to women with diabetes mellitus, seeking to have children. The adenoviral strategy for gene delivery into early mouse embryos may in the long term also find wide clinical application in the treatment of genetic defects at the very earliest stages in development and as such is of enormous potential benefit in the management of both animal and human reproduction.Read moreRead less
The measurement of primary traits in second language oral proficiency in second language acquisition research. The proposed research will help to inform high-quality learning outcomes for international ESL (English as a Second Language) students and students who study Japanese or Spanish as a second language in Australian universities. Improved effectiveness in current second language teaching pedagogy will result from a deeper understanding of the role that the key language traits (syntactic co ....The measurement of primary traits in second language oral proficiency in second language acquisition research. The proposed research will help to inform high-quality learning outcomes for international ESL (English as a Second Language) students and students who study Japanese or Spanish as a second language in Australian universities. Improved effectiveness in current second language teaching pedagogy will result from a deeper understanding of the role that the key language traits (syntactic complexity, lexical range, accuracy and fluency) play in the attainment of advanced proficiency. Read moreRead less
Fungal Phospholipases: A Novel Drug Discovery Platform
Funder
National Health and Medical Research Council
Funding Amount
$588,679.00
Summary
Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to thes ....Invasive fungal infections are a serious and escalating health issue. They cause severe disease with a high death rate and are very costly to the health system. This is especially the case in immunocompromised patients, such as those with blood malignancies, organ transplant recipients and AIDS. The number of currently available drugs for the treatment of fungal infections is limited and they are, in general, either not very effective or toxic. The development of fungal strains resistant to these drugs is also becoming problematic. There is an urgent need to discover and develop new drugs effective against fungal infections through identifying new targets in the fungal cell and-or targets that prevent the spread of infection in the human host. We were the first to describe an enzyme, phospholipase B (PLB1), which is secreted by the medically important fungus, Cryptococcus neoformans, and is important in invasion of human tissue by the fungus. It is also important in remodelling of membranes in the fungal cell. This enzyme is sufficiently different from human phospholipases to be a good target for antifungal drugs. In this project, we aim to synthesise and test molecules which should inhibit the activity of PLB and in this way block its harmful effects. We will test the effects of such drugs to make sure they do not interfere with human enzyme systems. Inhibitory compounds may also be used to kill the fungal cells, especially if administered together with currently used therapies. The design and development of new antifungal drugs with a novel mode of action represents a major advance in the treatment of fungal disease, and a saving of some A$60000 per affected patient (estimated from a recent US study).Read moreRead less
In the asthmatic lung structural changes or remodelling occur, which are thought to contribute to the abnormal functioning of the airways. These remodelling events which occur in the asthmatic airway include increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix ECM proteins), and an increased mass of bronchial smooth muscle cells. Many of these critical structural changes are not reversed or prevented with current asthma therapy. Remodelling is an i ....In the asthmatic lung structural changes or remodelling occur, which are thought to contribute to the abnormal functioning of the airways. These remodelling events which occur in the asthmatic airway include increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix ECM proteins), and an increased mass of bronchial smooth muscle cells. Many of these critical structural changes are not reversed or prevented with current asthma therapy. Remodelling is an important process in both the development and progression of asthma. The reason why remodelling occurs in the lungs of people with asthma is not known. It is thought that persistent inflammation drives the remodelling process; however remodelling can perpetuate inflammation, thereby creating a cyclic series of events. Furthermore we have shown that cells from non-asthmatic volunteers which are grown on asthmatic ECM change to become more like cells from asthmatic subjects. Viruses which infect the lungs may play a role in the development of asthma, and in the increased remodelling which is observed. Many common respiratory viruses are capable of infecting lung cells, eg epithelial cells, which evokes an inflammatory response. I will investigate if viral infection can alter the remodelling process, using lung cells isolated from asthmatic and non-asthmatic volunteers. Furthermore, I will assess if current and novel treatments are effective in reducing the remodelling process. We have preliminary evidence that infection of lung epithelial cells with rhinovirus (the common cold virus) alters the amount of ECM deposited by these cells. I hypothesise that this process will be increased in cells from volunteers with asthma compared to non-asthma. As current therapeutics are unlikely to be able to reverse these remodelling events these experiments will enable the development of new therapeutics which can target this important aspect of airway disease.Read moreRead less
Airway Virus Infection, Protease-activated Receptors And Microvascular Permeability
Funder
National Health and Medical Research Council
Funding Amount
$421,527.00
Summary
Asthma is an inflammatory airway disease which kills about 800 Australians each year and otherwise afflicts millions of children and adults in all age groups. Respiratory tract viral infections trigger inflammation and asthma. We believe that this is caused by the loss of naturally protective, bronchodilator and anti-inflammatory substances such as prostaglandin E2 and increased production of asthma promoting substances such as endothelins. Both of these substances are made by the epithelial lin ....Asthma is an inflammatory airway disease which kills about 800 Australians each year and otherwise afflicts millions of children and adults in all age groups. Respiratory tract viral infections trigger inflammation and asthma. We believe that this is caused by the loss of naturally protective, bronchodilator and anti-inflammatory substances such as prostaglandin E2 and increased production of asthma promoting substances such as endothelins. Both of these substances are made by the epithelial lining cells of the bronchi where viruses grow. This project will assess the influence of respiratory tract virus infection on epithelial mechanisms for the production of PGE2 and endothelins. Respiratory viral infections are accompanied by airway inflammation and thus by elevated microvascular permeability and oedema which exacerbates obstruction in asthma. We will measure airway microvascular permeability changes during viral infection and assess the protective effect of stimulating protease-activated receptors which increases PGE2 production. The impact of the PAR system on the integrity of microvascular tissue and on epithelial endothelin production has not been previously investigated. In addition, the influence of respiratory tract viral infection on PAR function in this system is also unknown, but is potentially of great importance to our understanding of the behaviour and regulation of this natural bronchoprotective pathway. This work may lead to the use of novel PAR activators as combined bronchodilator-anti-inflammatory therapies in asthma.Read moreRead less
Key indicators of development in adolescent writing. The project aims to identify significant indicators of development in the writing of adolescents at various stages of secondary education. There are a number of students who struggle with the demands of secondary schooling because they have not developed control over the more abstract, technical, and metaphorical language required in written assignments and examinations. This study will map the development of those linguistic resources critica ....Key indicators of development in adolescent writing. The project aims to identify significant indicators of development in the writing of adolescents at various stages of secondary education. There are a number of students who struggle with the demands of secondary schooling because they have not developed control over the more abstract, technical, and metaphorical language required in written assignments and examinations. This study will map the development of those linguistic resources critical to success in secondary learning, drawing on and extending Halliday's functional theory of language. An understanding of typical patterns of development will enable teachers to productively intervene in those cases where students' academic progress is impeded.
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