AAIR Charity awards applications (2015) – Funded projects
Title: Research Equipment: Centrifuge Heraeus Megafuge 40r
Awarded to: Rosie Mackay, A. Postle, A. Walls, J. Madsen, H. Clark and P. Howarth, S Pender and R. Salib
Lay summary: As our understanding of the development of airway disease, such as asthma, advances we are becoming increasingly aware of the complexity of disease processes. Previously people were treated according to disease status (e.g. mild, moderate or severe asthma) and unsurprisingly the treatment did not work for all patients. We are now more aware for the need of more individual approaches to the treatment of such disease (stratified medicine), as such the need for more precise repeatable detection of symptoms and development of reliable laboratory tests for identifying who is at particular risk of more severe disease. Critical to the development of new tests, as well as selection of drug targets, is an understanding of the underlying mechanisms of such disease and the molecules involved. Important advances have come from studies performed in Southampton on proteases and other proteins. Therefore, developing tests to measure levels of these molecules, or elucidation of their function requires their isolation from tissue or fluids. The equipment sought will permit safe, efficient and standardized sample processing. This will allow development of new laboratory tests for diagnosis and provide an understanding of disease processes that should underpin new approaches to treatment of asthma, allergies and inflammatory diseases.
Title: Could exposure to widely found fibrous dust particles cause scarring of the airways?
Awarded to: Richard Latouche and D. Smart
Lay summary: Air pollution is a toxic mixture of gases and dust particles. To understand how the pollution particles can affect our airways, we need to relate their chemical composition and properties such as size and shape, to their effects on our cells. When inhaled, these particles settle on airway lining cells (epithelial cells), and can be enveloped and removed by other cells (macrophages). During my PhD, I have studied the effects of Afghan desert dust, thought to cause asthma and structural changes to the airways, as has been seen in soldiers. Using analytical chemistry and ultra-high powered microscopes, I studied the composition and structure of this dust, discovering that it contains long, thin fibres of a mineral, which is also used industrially and in some home products. Fibrous structures are important in the toxicity of asbestos, so although the desert dust mineral is chemically different to asbestos, we need to understand whether these fibrous structures might make it harmful. I then grew epithelial cells and macrophages in the laboratory, representing the surface of the lower airways, and discovered that they respond to mineral particles by releasing chemicals involved in inflammation. However, to better understand how structural changes might be caused by the dust, we need to grow structural cells (fibroblasts), which underlie and support the epithelial cells, and expose them to the chemicals released by the epithelial cells and macrophages. This will help us to better understand how our airways might respond to this dust, and how such effects might be mitigated.
Title: Understanding Loss or Persistence of Asthma using Bronchial Challenge Testing in the lsle of Wight Birth Cohort
Awarded to: Ramesh Kurukulaaratchy
Lay summary: Long-term research following populations over time has identified different types of asthma. These may appear at different ages, varying in nature and severity, with some forms of asthma proving long-lasting while others are outgrown. A key area for future research is why some people outgrow their asthma and whether that provides clues on how to combat this common disease. To answer that question ideally requires a well characterised study population that is followed over many years plus accurate information that reliably proves loss of asthma. One tool to support that process is measurement of a key feature of asthma called bronchial hyper-responsiveness which reflects the twitchiness of the airways in asthmatics.
The lsle of Wight Cohort (containing 1456 subjects) was established in 1989 to study the natural history of asthma, has been followed regularly in the 1” 1B-years, and is now being re-assessed at 26-years. This proposal is for a sub-study at 26-years to assess bronchial hyper-responsiveness via bronchial challenge tests in a subset of these subjects (250). These will be undertaken in subjects at 26-yearswhointhel’t18-years had early persistent asthma, loss of asthma, or never had asthma. These findings will help assess the later outcomes of asthma patterns in the 1st 1B years with the aim of better understanding what is associated with loss or persistence of asthma. Understanding how people outgrow asthma could help direct future treatment development with potential to hugely benefit the 5 million asthma sufferers in the UK.
Title: Research equipment: Meso QuickplexSQ120
Awarded to: Laure Lau, P. Howarth, H. Arshad, A. Walls and H. M. Haitchi
Lay Summary: Asthma and other allergic conditions are mediated by a range of chemicals in the tissues. Their accurate measurement in blood or other fluids can yield important information on the type of disease and how it may be modulated by treatment, on underlying mechanisms and on new targets for drug development. We seek funds for the purchase of Meso Quickplex SQ 120 equipment. This allows accurately detection of extremely low levels of chemicals in small amounts of blood or other sample from people with disease. Access to this equipment will allow our research to proceed efficiently and open up new avenues to advance understanding of asthma and allergic disease and for improving diagnosis and treatment.
Title: Quality of life measures for patients with primary ciliary dyskinesia
Awarded to: Laura Behan and J. Lucas
Lay summary: Primary ciliary dyskinesia is a rare, inherited, progressive respiratory disease, characterised by recurrent infections of the upper and lower airways, nasal congestion, sinusitis, hearing impairment and sub-fertility. It is caused by impaired mucociliary clearance as a consequence of abnormal function of motile cilia. Until now there is no disease specific outcome measure to monitor PCD patients clinically, document the progression of their illness or to assess the effect of therapeutic interventions in clinical trials.
A research team from the University of Southampton is leading a large multinational study to develop and validate age specific, cross-cultural, multilingual, health related quality of life (HRQoL) measures for patients with PCD. HRQoL measures assess the impact of a disease from the patient’s perspective and capture at least four core domains: symptoms, physical, social and emotional functioning. Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) support and advocate the development and use of patient-reported outcome measures for evaluation of new medications and treatments.
Development of these PCD specific HRQoL measures has been completed through consultation with expert panels and in-depth semi-structured and cognitive interviews with >150 PCD patients across the UK, Ireland and the US. A senior research assistant working at the University Hospital Southampton will conduct a multi-national, psychometric field-study to assess these measures for several forms of reliability (e.g., internal consistency, test-retest) and validity and enable them to be used for clinical purposes as well as for national and international studies.
Title: Travel fellowship for training in gene analysis of large data from ADAM33 mouse lungs in order to understand how ADAM33 causes airway remodelling in asthma
Awarded to: Joanne Kelly and H. M. Haitchi
Lay Summary: ADAM33 is an asthma susceptibility gene that is associated with wheezing and ‘twitchy’ airways. It is unusual that the soluble ADAM33 protein (sADAM33) can be found in lung fluids from asthma patients, and we think that its presence contributes to abnormal changes (remodelling) in the thickness of the airways (the tubes that carry air into the lungs). To determine whether sADAM33 can cause airway remodelling, we have developed a novel research model (collaboration with Jeff Whitsett in Cincinnati Children’s Hospital Medical Center (CCHMC), USA), which shows that the presence of sADAM33 causes remodelled airways (more vessels and smooth muscle) independently of airway inflammation. This model also appears to be more sensitive to allergen exposure, resulting in more inflammation and increasingly ‘twitchy’ airways after exposure.
This is exciting and we wish to understand how sADAM33 induces this remodelling and how this enhances allergen induced airway inflammation. This would help us to explain the underlying mechanisms and find new treatment options for asthma.
The objectives of this travel fellowship are: 1. To be trained in Cincinnati to use state-of –the art technology to analyse novel mechanisms that are involved in lung biology, which has been enabled by a generous invitation by Jeff Whitsett. 2. To analyse such data that have been generated in Cincinnati from lungs where sADAM33 induced airway remodelling has been shown. (222 words)
Title: Establishing how human rhinovirus variation influences clinical outcome in patients with asthma and other respiratory diseases
Awarded to: Christopher McCormick and D. E. Davies
Lay Summary: Rhinoviruses are a cause of the common cold. They are usually relatively harmless, but in people with asthma infection often results in worsening of symptoms that can be so severe that they cause hospitalisation or death. Some types of cold virus are associated with more severe respiratory complications compared to others. One possible reason for this could be due to differences in the activity of two enzymes produced by the virus, as these enzymes are responsible for blocking an infected cell’s ability to fight off infection. Our hypothesis is that these differences in enzyme activity will drive different signals released by the virus-infected cell to cause inflammation. Our plan is to develop a simple model system that allows us to examine how the enzymes act within cells while avoiding introduction of unwanted variables which would otherwise complicate interpretation of results. Outcomes from this project are several-fold. Firstly, our results will aid understanding of why different rhinoviruses might trigger different disease pathologies. Secondly, the work will help identify inflammatory chemical mediators that are differentially released by cells infected with pathogenic versus non-pathogenic strains of virus. Such molecules offer potential as drug targets and as biomarkers for early diagnosis of severe rhinovirus-induced respiratory complications. Availability of such biomarkers would allow expensive drugs for the treatment of rhinovirus-infections to go to those individuals who would benefit most.
Title: To investigate of freezing and defrosting change the possibility of having an allergic reaction to prawns
Awarded to: Hasan Arshad, A. Walls, J. Lucas, J. Holloway and C. Venter
Lay Summary: Food allergies caused by shellfish and fish are often seen in teenagers and adults. Despite many studies looking at possible treatment of food allergies, the only way of managing food allergies at present is to avoid the food(s) involved. This can be time consuming and affect people’s quality of life. Those suffering from food allergies that can potentially cause severe reactions such as prawns are particularly anxious.
One possible method of treating and perhaps even resolving food allergies is to give small amounts of that food to the person over a period of time, gradually increasing the amount given. This is referred to as Oral Immunotherapy (OIT) and has shown success in studies dealing with milk, egg and peanut allergy. So-far no one has studied OIT in adults with shellfish allergy.
We are developing a prawn paste that we can give to prawn allergic individuals over a period of time in order to reduce or resolve their allergy. We are planning a large trial to test the effectiveness of this method in the treatment of prawn allergy. It is crucial that the main prawn protein (tropomyosin) and other relevant proteins are still present in the prawn preparation after freezing and defrosting.
In this pilot project, we will prepare the prawn paste, freeze and defrost it and then test if 1) the prawn allergens are still present and 2) in sufficient quantities that will cause an “allergic” reaction in a test tube (in a laboratory).