2012

Associate Professor Yuben Moodley, Professor Peter Henry and Dr Graeme Zosky

Project title:  Stem cell therapy for asthma.

Project description:  Asthma is a major cause of morbidity in Australia and is responsible for a reduction in quality of life in all age groups. Current therapies (inhaled bronchodilators and corticosteroids) treat symptoms and do not cure the disease. There is a cohort of patients that respond poorly to these treatments. We have shown that Mesenchymal Stem Cells derived from the umbilical cord (uMSCs) reduce lung inflammation and fibrosis. We therefore propose to investigate the use of uMSCs in a mouse model of asthma. Beneficial outcomes would potentially add a new therapeutic arm in the treatment of this common and complex disease.  uMSCs are potentially capable of reducing bronchial hyper-responsiveness, inflammation and remodelling. Therefore in a clinical setting, uMSCs may be curative in patients with mild asthma, or improve asthma control in patients with severe asthma that is difficult to control. Furthermore, uMSCs may reduce the need for corticosteroid treatment, as well as exacerbations in patients who present regularly to hospital with severe exacerbations. As proof of concept we need to demonstrate that uMSCs show therapeutic effectiveness in a mouse model of asthma.

Professor Prue Hart and Dr Deborah Strickland

Project title:  Can tolerogenic bone marrow-derived dendritic cells be boosted in inflammatory airways disease?

Project description: We have recently characterised tolerogenic dendritic cells expanded from the bone marrow of mice with inflammation in the airways. Their tolerogenic properties were tested in vivo by loading with a chemical hapten and injection into the ears of naïve mice. A week later the injected ears were exposed to the same hapten and a memory response analysed. In the absence of inflammation of the bone marrow donor mice, bone marrow derived dendritic cells induced a strong antigen-specific contact hypersensitivity response (significant ear swelling) in the recipient mice. For the ears of mice injected with dendritic cells from the bone marrow of mice with inflammatory airways disease, there was minimal ear swelling. In Aim 1, this study will use a different assay to test the regulatory properties of the bone marrow derived dendritic cells from mice with inflammatory airways disease. The cells will be loaded with the allergen, ovalbumin, and their ability to regulate upon intranasal delivery airway inflammation in mice with established ovalbumin-driven airways disease will be investigated. In Aim 2, the bone marrow cells from control mice and mice with inflammatory airways disease will be expanded in naïve, gamma-irradiated recipient mice (chimeric mice), and not in vitro. After bone marrow cell engraftment in these recipient mice, we will induce models of allergic asthma and test the proposal that immune responses are reduced in those mice that received bone marrow cells from mice with inflammatory airways disease.

This project should tell us more about the signals from inflammatory airways to bone marrow and the production of dendritic cells for subsequent seeding out to the peripheral tissues. We propose that we have identified an important homeostatic process that can be harnessed for therapeutic use.

Associate Professor Graham Hall and Dr Shannon Simpson

Project title:  Measurement of bronchial hyper-responsiveness in young children: Mannitol and exercise challenge testing.

Project description:  The addition of objective measures of bronchial hyper-responsiveness (BHR) to current clinical practice may result in improved diagnosis and management of young children with exercise related symptoms. This project aims to determine the feasibility of BHR testing using the forced oscillation technique (FOT) as a primary outcome of the mannitol challenge test in pre-school children with exercise induced symptoms. In addition we aim to determine the agreement of the mannitol challenge test and exercise challenge test in these children.

2012 New Investigator Grant

Dr Jasminka Murdzoska and Associate Professor Sunalene Devadason

Project title:  Is there an association between parental and infant GSTP1 sequence variation and promoter methylation, with effects on infant lung health outcomes in early life?

Project description:  In utero exposure to tobacco smoke has been associated with epigenetic alterations such as higher levels of DNA methylation and, in combination with genetic variations in detoxification genes, has been associated with reduced lung function, increased airway responsiveness (AR) and asthma in childhood and beyond. Enzymes including the Glutathione S-transferases (GSTs) play important roles in detoxifying constituents of tobacco smoke, and GSTP1 is the isoenzyme predominantly expressed in the lungs. The aim of this project is to assess the influence of DNA methylation and genetic variations in the GSTP1 gene on associations with lung function and AR in infants exposed to maternal tobacco smoke in utero compared to those not exposed. There is also increasing evidence that epigenetic regulation of genes, in particular DNA methylation, may be transmitted through the germline. The rapid increase in the incidence of allergic diseases, including asthma, towards the end of the last century is likely to be associated with environmental influences and epigenetic factors, as the genetic makeup of individuals alone would not have changed sufficiently in such a short period of time to account for the marked increase in disease prevalence. As the burden of exposure to environmental toxins (industrial, occupational, diesel, wood smoke) increases, it is vital to understand how such exposures alter expression of detoxification genes, whose role is to facilitate elimination of these toxic compounds from the body thereby reducing the impact on lung health specifically and overall health in general.

Miss Esther Cheah, University of Western Australia

Supervisor:  Professor Peter Henry

Project title:  Characterisation of a novel airway explant system.

Project description:  Our laboratory has recently developed a novel system for investigating the direct effects of pathogenic substances on the structure and function of small airways.  To date, we have used the system to investigate the effects of respiratory tract viruses on airway function, but are looking at expanding our approach to look at the effects of other known triggers of asthma exacerbations, such as cigarette smoke constituents.  In this system, airways are removed from the respiratory tract and perfused with sterile physiologic media at 37°C for selected periods of time.  Preliminary studies indicate that the structural and functional integrity of the airway epithelium and smooth muscle can be maintained for at least 4 days in the absence of any pathogenic stimuli.  In contrast, exposure of the tracheal explant to influenza A virus for 5 minutes at the start of the perfusion results in the propagation of influenza virus during the ensuing 2 days (determined using immunohistochemical detection of virus) and significant damage to the airway epithelium by 4 days (determined using histological examination of H&E stained sections).  During the development phase, we have tested the system using tracheal preparations obtained from laboratory mice, but during the next year we intend to expand this to include examinations of small airways obtained from asthmatic and non-asthmatic human subjects.  The principal aim of this Vi Watson Scholarship Application is to further characterise this novel explant perfusion system.  These studies will be conducted by Ms Esther Cheah who is in the process of completing her Bachelor of Science at UWA.  Esther has a truly outstanding academic record (Weighted Average Mark 93.85) and has applied to enrol in the Honours Pharmacology program in 2012 to undertake a project using this novel system.

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Miss Laura Coleman, Telethon Institute for Child Health Research

Supervisor:  Dr Graeme Zosky

Project title:  The development of airway hyper-responsiveness in asthma.

Project description:  Asthma is a chronic allergic airways disease that is characterised clinically by increased airway reactivity to bronchoconstricting agents.  This airway hyper-responsiveness (AHR) is the primary reason for the morbidity and mortality associated with asthma and yet is poorly understood.  One of the primary risk factors for the development of asthma is allergic status.  It is thought that “atopic” (allergic) responses in the airway to inhaled allergens result in the recruitment of inflammatory cells to the airway wall.  Over time repeated inflammatory events lead to changes in airway wall structure which results in an increased response to bronchoconstricting stimuli.  One of the key elements of this hypothesis is that atopic individuals are born with otherwise normal lungs (i.e. no AHR) and develop abnormal bronchoconstriction responses over time as airway remodelling progresses.  However, recent data suggest that asthmatic airways are remodelled very early in life (perhaps in utero) and the level of remodelling remains constant throughout life despite persistent inflammation.

We have available two strains of rat that have very different innate AHR responses i.e. the “atopic” BN rat has AHR compared to the “non-atopic” PVG rat.  This project is aimed at understanding the development of AHR utilising these strain related differences.  Laura will be comparing the structure of the airway between the two strains using histological techniques to determine if there is an association between airway wall structure (including inflammation) in these and AHR phenotype.  This experience will provide Laura with an ideal introduction to lab-based research into asthma.

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Mr Alex Kaye, Sir Charles Gairdner Hospital

Supervisor:  Professor Alan James

Project title:  Airway smooth muscle remodelling in asthma: distribution and relation to inflammation.

Project description:  Asthma is a significant public health problem worldwide and within Australia.  It is characterised by excessive airway smooth muscle (ASM) and airway inflammation. Eosinophilic (EA) and non-eosinophilic (NEA) inflammatory phenotypes have been described in asthma. Their relation with airway remodelling, particularly to ASM hypertrophy and hyperplasia and their distribution in large and small airways, is unknown.  Aim: To compare mean ASM cell volume (VC), total number of cells per mm of airway (NL) in large and small airways and relate them to eosinophil and neutrophil numerical density in the same airways. Methods: Post-mortem tissues from control subjects and cases of nonfatal and fatal asthma will be used. The numerical density (NV) of ASM cell nuclei will be estimated on 30μm sections and VC will be calculated, correcting for the fraction smooth muscle within the layer of ASM. Airway dimensions (area of ASM, basement membrane perimeter - Pbm) will be measured on 5μm sections (H&E). Eosinophils and neutrophils within the inner airway will be counted.  Relevance: Increasingly it is recognised that different phenotypes of asthma exist, most notably in the type of inflammation that is present in the airways. One previous study has shown that variations in the distribution of remodelling of the ASM may also exist and be related to the type of inflammation. This has important implications for the prevention and effective treatment of asthma.  Since severe asthma remains difficult to treat and is related to ASM remodelling, this project will address an important, current question regarding asthma pathophysiology.

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