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Factors Determining Collapsibility Of The Human Upper Airway During Sleep And General Anaesthesia
Funder
National Health and Medical Research Council
Funding Amount
$259,625.00
Summary
Obstructive sleep apnoea (OSA) is common, affecting between 2-4% of middle-aged adults. It is characterised by repetitive partial or complete collapse of the upper airway during sleep. Each episode is accompanied by transient hypoxemia, hypertension and arousal. The repetitive arousals disrupt sleep resulting in excessive daytime tiredness and lethargy, which have major consequences for social well-being and productivity in our community. OSA is an independent risk factor for vascular disease. C ....Obstructive sleep apnoea (OSA) is common, affecting between 2-4% of middle-aged adults. It is characterised by repetitive partial or complete collapse of the upper airway during sleep. Each episode is accompanied by transient hypoxemia, hypertension and arousal. The repetitive arousals disrupt sleep resulting in excessive daytime tiredness and lethargy, which have major consequences for social well-being and productivity in our community. OSA is an independent risk factor for vascular disease. Central to understanding OSA is knowledge of the mechanisms responsible for vulnerability to upper airway collapse. It remains unclear to what extent this vulnerability relates to abnormalities in the underlying structure and passive physical characteristics of the upper airway, versus abnormalities in activity of upper airway muscles. Making this distinction has been problematic because current methods of testing upper airway collapsibility in sleeping humans tend to result in changes in muscle activity and-or sleep state, affecting the measurements. It is, however, possible to suppress upper airway muscle activity and eliminate measurement-related changes in muscle activity and state with general anaesthesia, while maintaining normal spontaneous breathing. We have developed and refined this method and propose to use it in novel investigations to (a) relate the behaviour of the flaccid airway (no muscle activity) under anaesthesia to its behaviour during sleep (when muscle activity is variable but quantifiable), and (b) determine the effect of changes in body habitus (posture and lung volume) on airway collapsibility. These studies will allow examination of the exciting possibility that measurements made under brief general anaesthesia could be used to define propensity to obstruction during sleep. They will also allow examination of the contribution of common changes in body habitus toward vulnerability to upper airway collapse.Read moreRead less
Functional Significance Of Subcellular Localisation Of Viral 3C Protease In Rhinovirus Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$613,513.00
Summary
Rhinovirus (RV) infections are the major cause of virus induced asthma attacks and common colds, causing significant morbidity and mortality. The incidence of asthma is increasing worldwide with new strategies urgently needed to reduce RV-associated disease. We have observed RV 3C protease in the nuclear compartment of infected host cells and propose to determine its significance in RV pathogenesis with relevance to asthma therapies.
Antiviral Defects Of The Airway Epithelium Associated With Wheeze And Atopy In Children
Funder
National Health and Medical Research Council
Funding Amount
$658,571.00
Summary
Asthma affects 10-15% of Australian. Repeated respiratory viral infections increase the risk of developing asthma, and are also the principal cause of asthma attacks. Asthmatics may be more susceptible to respiratory viral infections due to a defect in the innate antiviral response to infection. Here we aim to identify defects in the antiviral response of children who are at risk of developing asthma, and understand how they occur so that future therapies may be developed.
Development Of New Therapies For Respiratory Diseases And Infection
Funder
National Health and Medical Research Council
Funding Amount
$847,490.00
Summary
Prof Hansbro’s group have developed world 1st experimental models of emphysema, severe asthma infection and lung cancer. He uses them to further our understanding of these untreatable diseases. This has led to the development of new potential therapeutic approaches. Now, in discovery programs he will expand studies of pathogenesis to identify new therapeutic targets these diseases. In development and translational programs he will progress new therapies towards clinical application.
Influence Of Early-life Viral Infection On Severity Of Murine Chronic Asthma And Acute Exacerbations
Funder
National Health and Medical Research Council
Funding Amount
$508,528.00
Summary
This project examines the relationship between certain childhood infections with respiratory viruses and the progression of asthma later in life. The experimental work will use mouse models of mild chronic asthma and of an acute exacerbation of the illness -- these unique models have been developed in the laboratories of the chief investigators. It will employ the most appropriate mouse models of infection by the relevant group of viruses. We expect to obtain new information about mechanisms of ....This project examines the relationship between certain childhood infections with respiratory viruses and the progression of asthma later in life. The experimental work will use mouse models of mild chronic asthma and of an acute exacerbation of the illness -- these unique models have been developed in the laboratories of the chief investigators. It will employ the most appropriate mouse models of infection by the relevant group of viruses. We expect to obtain new information about mechanisms of airway inflammation and airway hyper-reactivity, which are characteristic features of chronic asthma and of acute exacerbations. This could help to identify candidate signalling molecules and pathways that could be targeted by new treatments. The findings might also provide a basis for development of ways to modify the immune response after respiratory viral infection in childhood.Read moreRead less
Mechanisms Of Induction And Progression Of Childhood Asthma: Investigations In A Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$517,586.00
Summary
This project investigates how certain respiratory viral infections in very young children might predispose to developing asthma, and how inflammation in the airways in asthma might then worsen. The experimental work, which will use unique mouse models developed in the laboratories of the chief investigators, will focus on changes in genes that control the pattern of immune response to allergens and that regulate the progression of inflammation.
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
The Mechanisms Underlying Pneumoviral-induced Angiogenesis Of The Lung And Its Impact On The Asthmatic Response.
Funder
National Health and Medical Research Council
Funding Amount
$564,625.00
Summary
Asthma, is a serious respiratory disease resulting in structural changes to the lung and breathing difficulties, and is often compounded by respiratory viruses. We have shown that viral infection of newborn mice causes the growth of new blood vessels in the lungs (a feature seen in human asthmatics). This project will investigate the mechanisms involved and determine the potential of this feature as a therapeutic target.