Current & Recent Research

AAIR Charity awards applications (2016) – Funded projects

Stephan Holgate PhD Studentship: The role of ADAM33 in pre- and perinatal airway remodeling and the early life development of asthma.

Awarded to: Hans Michael Haitchi and Christopher Woelk, awarded to Joanne Kelly

Amount: £58,100 (additional University of Southampton, Faculty of Medicine funding £48,100) (October 2014 – October 2018)

Lay summary: In October 2015 Joanne spent 3 weeks (supported by AAIR travel grant) in the pulmonary biology and bioinformatics group in Cincinnati Children’s Hospital in the USA. Here she learned how to analyse large data sets from “next generation gene sequencing” (NGS) from our lung samples from our ADAM33 asthma model compared with “normal” lung samples.  Back in Southampton she further studied the list of genes that were different in the ADAM33 asthma model in our existing lung samples.

Furthermore, Joanne successfully established an epithelial cell culture model by growing the cells that line the major airways from our ADAM33 asthma model. She studied the function and leakiness of these cells in the presence of the ADAM33 protein and will also study the list of genes she discovered by NGS in our ADAM33 asthma model in these cells.

From the NGS data Jo has discovered a potential interaction between ADAM33 induced airway remodelling and airway inflammation, which she is studying in fibroblasts, structural airway cells that do or do not express ADAM33 protein.

During this PhD fellowship Joanne has also made contributions to and is a co-author in a recent publication in the Journal of Clinical Investigation (JCI) Insight about how ADAM33 initiates airway remodelling to promote asthma in early life.

Publications: 

E.R. Davies, J.F.C. Kelly, P.H. Howarth, D.I Wilson, S.T. Holgate, D.E. Davies, J.A. Whitsett, H.M. Haitchi. Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight. 2016 Jul 21;1(11). pii: e87632.

https://insight.jci.org/articles/view/87632

The press release from the University of Southampton related to our research publication had been widely covered by most major national newspapers as well as national radio and many other international media.

http://www.southampton.ac.uk/news/2016/07/adam-33-gene.page

PhD Studentship: Information provision preferences of food allergic and intolerant consumers when eating

Awarded to: Jane Lucas

Amount: £11,800 (March 2014 – March 2017)

Lay summary: During the initial stages of the PhD studentship, an exploratory study was conducted to capture online discussions surrounding the implementation of new EU-labelling law. These regulations require consumers to have access to information about allergen ingredients when buying foods.  Discussions via Twitter revolved around several key themes: mobilisation around the legislation the impact of legislation, continuing frustration when eating out, and the preparedness of businesses.  This study was presented as a poster at the University of Bath’s Faculty Research Showcase.

A further study focussed on discussions around a news article in which chefs had voiced concerns about the introduction of the new legislation.  Sources of data soon after the original news article included subsequent news articles, online comments on the original article, Twitter posts and discussions. Frames identified from a qualitative analysis emphasised medical concerns, responsibility, fairness of access, the political nature of the debate, and financial implications. This project was presented at the Psychology Conference, and Changing Lives, Changing Worlds Conference (both at the University of Bath).  It was also presented in poster form at the Faculty Research Showcase, where it won the gold award, and at the International Conference of Social Media and Society at Goldsmiths University.  The accompanying research paper is currently under review following journal submission.

The studentship continues to investigate how and why food allergic/intolerant individuals use social media (e.g., for support reasons, or gaining information), and investigate how credibility is inferred for the sources of information encountered.

Funding from AAIR has allowed research collaboration and communication through attendance at advisory meetings/workshops (e.g. with the FSA and associated researchers), meetings with allergy charities (e.g., Allergy UK, Anaphylaxis Campaign, and Coeliac UK), conference presentations, and associated training.

Publications: 

Hamshaw, R. J. T. (2015, June). Perceptions of new food allergen legislation on Twitter.  Poster presented at the Humanities & Social Sciences Faculty Research Showcase, University of Bath, England.  Abstract available from http://www.bath.ac.uk/hss/pdf/postgraduate-research-showcase/richard-hamshaw.pdf

Hamshaw, R. J. T. (2016, May) A frame analysis utilising media and social media sources: The 100 chefs incident. Poster presented at the Humanities & Social Sciences Faculty Research Showcase, University of Bath, England.  Available from http://www.bath.ac.uk/hss/news/documents/richard-hamshaw.pdf
This research poster was awarded 1st Prize in the Post-Confirmation category

Hamshaw, R. J. T. (2016, June) A frame analysis utilising media and social media sources: The 100 chefs incident. Research presented at the 3rd Annual Postgraduate Psychology Conference, University of Bath, England.

Hamshaw, R. J. T. (2016, July) A frame analysis utilising media and social media sources: The 100 chefs incident. Research presented at the 3rd Annual Faculty of Humanities & Social Sciences Postgraduate Conference, University of Bath, England.

Hamshaw, R. J. T. & Barnet, J. (2016, July) A frame analysis utilising media and social media sources: The 100 chefs incident.  Poster presented at the International Conference of Social Media & Society, Goldsmiths University, England. Information available from https://socialmediaandsociety.org/past-conferences/2016-2/2016-schedule/

Hamshaw, R. J. T., Barnett, J., & Lucas, J. S. (2016).  Framing Events and Taking Positions in an Online Food Allergen Debate: The 100 Chefs Incident.  Manuscript submitted for publication.

Research award: Development and validation of age specific health related quality of life measures for patients with primary ciliary dyskinesia

Awarded to: Laura Behan and J. Lucas

Amount:  £9,000

Lay summary: Support from the AAIR Charity, co-funded by FP7 BESTCILIA, has led to age-specific quality of life measures for patients with primary ciliary dyskinesia (QOL-PCD).  This work has provided the first disease-specific outcome measures to monitor PCD patients clinically, document the progression of their illness and assess the effectiveness of therapeutic interventions in clinical trials. Researchers from University of Southampton led the development and validation of QOL-PCD, involving patients from across Europe and North America. Our findings have shown QOL-PCD to be robust, reliable, responsive and valid.

In rare disease such as PCD, international collaborations are vital. It is important that QoL measures used in clinical trials are translated and tested comprehensively in each language. AAIR funding has enabled the QOL-PCD measures to be comprehensively translated in a number of languages for widespread use in international clinical trials across Europe, North America and the Middle East. The English, Danish, Dutch and German languages versions of the measures are already being used as outcome measures for a randomised clinical trial of azithromycin.

Finally, AAIR funding has enabled the PhD student working on this study to analyse the data, prepare a number of manuscripts, and submit her final thesis. It has also allowed for findings of the study to be presented to an international forum at the European Respiratory Society Congress, American Thoracic Society and at the COST Action BEAT-PCD Training School in Paris http://www.beatpcd.org/

Publications:

  • Behan, Laura. Leigh, Margaret W. Dell, Sharon D. Dunn Galvin, Audrey. Quittner,  Alexandra L.  Lucas, Jane S. Validation of a health-related quality of life instrument for primary ciliary dyskinesia: QOL-PCD (Submitted to Thorax).
  • Dell SD, Leigh MW, Lucas JS, Ferkol TW, Knowles MR, Alpern A, et al. Primary Ciliary Dyskinesia: First Health-related Quality of Life Measures for Pediatric Patients. Annals of the American Thoracic Society. 2016. (in press)

Presentations

  • Laura Behan: Health related quality of life measures for PCD. Cost Action BEAT PCD Inaugural Conference 2016
  • Jane Lucas: American Thoracic Society, San Francisco May 2016. Scientific symposium: The link between ciliary assembly defects, neonatal respiratory distress and bronchiectasis in adulthood: a primer on primary ciliary dyskinesia
  • Jane Lucas: European Respiratory Society Congress, London September 2016. Scientific Symposium: Diagnosing primary ciliary dyskinesia (PCD) in a molecular age

Posters

  • Laura Behan, Alexandra L. Quittner, Anika Lofruthe, Anu Kalayamthanam, Aristoula Toliop Audrey DunnGalvin, Bridget Contreras, Christine Edelbusch, Claudia E. Kuehni, Claudius Werner, Elizabeth Maurer, Eric G. Haarman, Helene Elgaard Kobbernagel, Irma Bon, Konstantinos Giannakou, Lea Heisch, Maria Philipsen, Niels Rutjes, Panagiotis Kouis, Tamara Paff, Jane S Lucas. Translation of QOL-PCD:  a cross-cultural patient-reported outcome measure for patients with primary ciliary dyskinesia. European Respiratory Society Congress 2016.
  • Claire O’Neill, Guillaume Thouvenin, Laura Behan, Delphine Habouria, Harriet Corvol, Annick Clément, Jane S Lucas, Aline Tamalet. French translation and linguistic validation of the QOL-PCD, a quality of life questionnaire for patients with Primary Ciliary Dyskinesia. European Respiratory Society Congress 2016.
  • Behan, Laura. Dunn Galvin, Audrey. Alpern, A. Morris, AM. Carroll, MP. Knowles, MR. Leigh, MW. Quittner, AL. Lucas, JS. Development, Translation and Validation of Health-Related Quality of Life Measures for Primary Ciliary Dyskinesia. Cost Action BEAT-PCD Training School 2016.
  • Behan LDunn Galvin AAlpern AMorris AMCarroll MPKnowles MRLeigh MWQuittner ALLucas JS. Development and validation of QOL-PCD – collaboration, participation and recruitment. Cost Action BEAT-PCD Training School 2016.

Travel Grant: Travel Fellowship for training in RNA-Seq Analysis of Lungs from Transgenic Mice Expressing Human ADAM33 pro and metalloprotease domains – A model for Asthmatic Airway Remodelling

Awarded to: Joanne Kelly and H. M. Haitchi

Amount: £1,653 

Lay summary: In October 2015 the AAIR Charity funded a travel grant so that I could visit our collaborators at Cincinnati Children’s Hospital in Ohio in the USA. The purpose of this trip was to learn, first-hand, how to process and interoperate complex data sets generated by state-of-the-art technology called next generation gene sequencing.

Using this technology the bioinformatics team at the Children’s Hospital were able to analyse lung samples from our ADAM33 asthma susceptibility model and compare them with “normal” lung samples. This method generates extensive lists of genes, identifying those that are different between the two types of lung sample. This method can provide data for the expression of all 30,000+ possible genes present in the lung and therefore it requires considerable expertise to analyse them.

After 3 weeks shadowing the expert team in Cincinnati I am now able to analyse the data generated from our lung samples here in Southampton, which should shed light on the processes by which ADAM33 initiates asthma at the origin of the disease. This time in Cincinnati was an invaluable experience, which will also help me to analyse results from our future research using this novel technology, as well as aiding others in data analysis of this sort.

Research equipment: Meso QuickplexSQ120

Awarded to: Laure Lau, P. Howarth, H. Arshad, A. Walls and H. M. Haitchi

Amount: 10,000

Lay Summary: The multi user MSD Quickplex SQ120 was purchased through AAIR Charity after receiving matching funding from the Head of CES and the Faculty of Medicine Research Management Committee. This has been up and running since March 2016.   Several projects in CES have already been benefited from this equipment. By taking advantage of the high sensitivity of MSD ELISA plate assays:

  • Dr Emily Swindle’s PhD student was able to detect IFN-beta release from human mast cells infected with cold virus.
  • Professor Christodouldas’ group has used the MSD ELISA plates to measure the IL-18 and IL-1beta release in human primary corneal fibroblasts in different conditions of Pseudomonas aeruginosa infection.
  • Dr Richard Felwick has been studying human colonic explant cultures for his PhD project. The MSD assay has provided him a high sensitivity platform in which to measure pro-inflammatory cytokine release from these samples. The multiplex format and small sample volumes needed were critical for these precious samples.
  • Dr Deiphine Boche‘s group were able to explore the inflammatory responses in precious post-mortem brain tissue from patients who had suffered from dementia and Alzheimer’s disease. She has measured pro-inflammatory cytokines.

Drs Walls and Lau have been seeking to establish an association between pro-inflammatory cytokines and mast cell proteases in the serum of patients with anaphylaxis in order to identify those susceptible to severe reaction.

Research equipment: Centrifuge Heraeus Megafuge 40R

Awarded to: R-M. Mackay, A. Walls, A. Postle, J. Madsen, H. Clark, P. Howarth

Amount: £3,400

Lay summary: Since purchasing our centrifuge, it has contributed to several lines of work. For example PhD and postdoctoral work investigating lung disease, infection and immunity. As well as industrial collaborations with Chiesi and GlaxoSmithKline. In addition, lipidomics, biochemists, immunologists and cellular biologists within the laboratory use the equipment, the results from these experiments, if successful will provide the basis of several research publications for several different fields of enquiry.

Poster Presentations:

Yaroslav Shkanov, Rose-Marie A Mackay, Rhys George, Laurie CK Lau, Rana

Abadalkareem, John Pedersen, Andrew F Walls. Dipeptidyl peptidase I (DPPI) cleaves surfactant protein D (SP-D): A mechanism for immune compromise in the lung.  The Europeon respiratory society, London 2016.

Yaroslav Shkanov, Rose-Marie Mackay and Andrew Walls. Characterisation of the interaction between mast cell proteases and surfactant proteinBritish Society for Allergy & Clinical Immunology (BSACI), London 2016.

Research Award: Investigating whether a species-dependent rhinovirus response in infected cells might be linked to respiratory disease outcome

Awarded to: Christopher McCormick and D. E. Davies

Amount: £9,968

Lay Summary: Rhinoviruses cause the common cold. While rhinovirus infection is a minor inconvenience for most people, in individuals with asthma infection can be life threatening. Rhinovirus produces two types of enzymes called proteases. It is known that the activity of one of the two proteases varies between different strains of rhinovirus, and it is also known that some strains are more pathogenic (ie. cause more illness) than others. We suspect that variation in pathogenicity may be linked to variation in protease activity. If correct, understanding how variation in protease activity alters an infected cell response could give us important insight into what is happening in the lungs of individuals with rhinovirus-induced severe asthma exacerbation.

Using AAIR funding we have developed two novel systems to look at the role of the viral proteases in airway disease. We have already found that there are big differences in the extent to which the proteases stop cells being able to produce their own proteins, and allow the virus to produce its own proteins. This has important consequences for the ability of the infected cell to fight off the invading virus and signal to the immune system for help. On-going work is trying to gain a better understanding of the molecular events underlying these observations.

AAIR funding covered the entire cost of lab reagents used and helped pay for someone to be in the lab doing the work. Data generated has allowed us to put in applications for studentship funding from Asthma UK, Wessex Trust and Kerkut Trust. A paper detailing our findings will soon be submitted for publication. We intend to submit a full grant application to continue this work next year.

Research Award: Do fibrous mineral dust particles elicit a pro-fibrotic response in a conditioned medium model of the distal airways?

Awarded to: R. Latouche, D. Smart and M. Loxham

Amount: £7,528

Lay Summary: Airborne dusts in the Afghan desert have been seen to cause lung disease in soldiers returning from the area, but we know little about their make-up and effect.  I previously found that this dust contains significant amounts of a mineral called palygorskite, which is of a fibrous shape similar to asbestos.  Palygorskite is not, however, found only is desert dust, but is used in a range of cosmetics and animal products, meaning that there is the potential for widespread exposure among the general population.  As such, we need to better understand its potential effects on the airways after inhalation.  The AAIR award allowed me to examine the effects of this dust in a model of the airways, constructed using cells from the airway surface, called epithelial cells, and cells called macrophages which patrol the surface of the airways and “eat” particles which we inhale.  The aim was to better understand how the presence of dust alters the way in which these two cell types communicate with each other – a process which is important in maintaining healthy airways.  I found that the two cell types do not react in the same way, with the macrophages being more susceptible than the epithelial cells to the toxic effects of the dust, but also potentially protected by the presence of the epithelial cells.  I also found that these effects were greater using pure palygorskite compared to the whole dust samples, suggesting that the palygorskite is a particular toxic component of desert dust.  Finally, I saw that desert dust caused increases in the levels of various molecules released by the two cell types, but that these responses were different when the cells were exposed together, compared to when only one cell type was studied.  As a result, we now better understand how desert dust might cause lung disease, and also have developed knowledge and experience of interactions between different lung cells when exposed to such dust.

Publications:

The research which has been performed as a result of this award will be written up into two papers – one focusing on the mineralogy and chemistry of the desert dust samples used, and another examining the effects of cellular exposure to the minerals.  Both will include reference to the AAIR charity award in the Acknowledgements/Funders section.  In addition, it will form a key part of my doctoral thesis, which will be submitted to the Faculty in December 2016.

Research Award: Evaluation of alternatively spliced Th2–related genes in alveolar macrophages and bronchial epithelial cells by Frac-seq, to investigate their influence on the modulation of proteomic output and relationship to disease severity in asthma.

Awarded to: R. T. Martinez-Nunez

Amount: £10,000

Lay Summary: Asthma has a strong genetic component, but we do not fully understand its molecular mechanisms. This hinders development of more efficient drugs targeting specific molecules in the lungs of people with asthma. Genes (mRNA) contain information to produce proteins, the main functional units in the cell. Traditional scientific approaches investigate levels of genes translating them into levels of protein production. We now know this is not accurate, as genes exist in different forms (isoforms), of which only a fraction generate proteins affected by regulators called microRNAs.

I developed Frac-seq, a technique measuring isoforms bound to the cellular machinery converting mRNA into proteins (ribosomes). Those mRNAs in ribosomes are missed with conventional scientific techniques. I analysed the role of microRNAs, key regulators of protein production, applying this method and comparing airway cells from volunteers with severe asthma against healthy volunteers. This revealed new asthma-specific microRNAs influencing nearly half of the changes we detected in asthma-related isoforms. These findings would be missed without applying Frac-seq. These microRNAs are potential novel candidates for drug development. Thanks to the AAIR Charity grant I have been able to fund part of this research hoping to publish my findings soon. The AAIR Charity funds also allowed me to investigate alveolar macrophages, key guardians of our lung immune response, uncontrolled in asthma. I am investigating novel isoforms related to inflammation not responding to current treatment options.  

Publications:

  • Martinez-Nunez R. T. , Wallace A., Coyne D., Bailey J., Jansson L., Ennajdaoui H., Rush M., Deinhardt K., Sanchez-Elsner T., Sanford J.R§. Rapamycin modulates nonsense mediated decay. doi: http://dx.doi.org/10.1101/028332. Manuscript accepter in Nucleic Acids Research. I conceived, conducted and analysed experiments, as well as writing of the manuscript. I am also the corresponding author. This paper benefited from overleft reagents purchased thanks to this grant, allowing me to explore RNA decay by mTOR signalling, of potential application in asthma in future projects.
  • Martinez-Nunez R. T., Rupani H., Niranjan M., Howarth P.H., Sanchez-Elsner T. MicroRNAs underlie genome wide transcriptome and translatome dysregulation in severe asthma airway epithelium. Manuscript in submission (November 2016). I conceived, conducted and analysed experiments, as well as writing of the manuscript. I am also the corresponding author. This is the main paper arising from the AAIR Charity grant.

Invited Talks:  

  • Studying post-transcriptional gene regulation with Frac-seq: rapamycin modulates nonsense mediated decay and microRNAs predominantly regulate genome-wide translation in asthma. Invited Talk in London RNA Club, November 2016.
  • Coordination of alternative splicing, translation and mRNA stability – all you ever wanted to know about polyribosomal mRNA sequencing – in human primary cells. DC/Macrophage Forum University of Southampton, September 2016.
  • Bronchial epithelium in severe asthma shows a mismatch between transcription and translation, as revealed by RibomiR-seq. Invited Talk in University College London, hosted by Prof Rachel Chambers. May 2016.

Conference Oral Presentations:

  • RibomiR-seq reveals that global microRNA binding fine-tunes the transcriptome but profoundly alters the translatome in severe asthma. SouthWest RNA Club, May 2016.
  • Global microRNA binding fine-tunes the transcriptome but profoundly alters the translatome: the application of RibomiR-seq to the understanding of epithelial cell activation in severe asthma. 31st Symposium Collegium Internationale Allergologicum, Charleston, South Carolina, April 2016.
  • RibomiR-seq reveals microRNAs fine-tune the transcriptome but profoundly alter translation in severe asthma. 14th Lung Science Conference, European Respiratory Society. Estoril, March 2016.
  • CES Club, Faculty of Medicine, University of Southampton. “microRNAs and translation two sides of the same coin”. March 2015.
  • Bioinformatics Journal Club, University of Southampton. “Frac-seq in asthma: RNA-seq of polyribosomes gives a new picture of disease”. January 2015.

Conference Poster Presentations:

  • T. Martinez-Nunez, H. Rupani, T. Sanchez-Elsner, P.H.Howarth. Polyribosome profiling and RNA-sequencing of human primary bronchial epithelial cells reveals novel and unique signatures of severe asthma. Lung Science Conference, European Respiratory Society. Estoril, March 2015. Poster Presentation and Travel Award.

PhD Studentship: The contribution of mast cells to rhinovirus infections in asthma

Awarded to: E. Swindle and D.E. Davies

Amount: £27,000 (October 2013 – September 2016)

Lay Summary: Asthma is a disease of the airways (the tubes that carry air into the lungs) which narrow from time-to-time (exacerbation) by triggers in the air making it difficult to breathe. Mast cells are a rare type of white blood cell that contribute to the symptoms of asthma triggered by allergens (e.g. pollen and dust). However, the common cold virus is a major trigger of asthma exacerbations and we do not know exactly how this occurs. We also do not know if or how mast cells respond to the common cold virus but we do know that these cells form part of an early warning system following infection with bugs (e.g. bacteria and viruses). Therefore this PhD studentship has been investigating how mast cells respond to infection with the common cold virus to help us understand their potential contribution to viral-induced asthma exacerbations. Charlene Akoto, who is in the final year of her PhD studentship, has shown that mast cells become infected with the common cold virus and are protected from infection following exposure to antiviral chemicals. She has presented her work at 2 international conferences (European Mast Cell and Basophil Research Network (EMBRN; Oct 2015) and European Academy of Allergy and Clinical Immunology (EAACI; June 2016)) and the Faculty of Medicine Research Conference (June 2016). At the EAACI Congress she received a travel scholarship to attend the meeting and also won ‘best oral abstract in session’.  Charlene continues to make excellent progress in her PhD studies which are to be completed in Sept 2017.

Publications:

  1. Oral presentation entitled ‘Mast cells support the replication of major and minor group rhinoviruses’ at the 7th European Mast Cell and Basophil Research Network (EMBRN) International Mast Cell and Basophil Meeting, Marseille, France (Oct 2015)
  2. Oral presentation entitled ‘Human mast cells support rhinovirus replication but are protected from infection by IFN-β’ at the European Academy of Allergy and Clinical Immunology (EAACI) Congress, Vienna, Austria (June 2016)
  3. Oral presentation entitled ‘Rhinovirus infection of human mast cells results in viral shedding which is inhibited by interferon’ at the Faculty of Medicine Research Conference, University of Southampton, Southampton, UK (June 2016).

Charlene has also prepared a manuscript of her current work entitled ‘Mast cells are permissive for rhinovirus replication: implications for asthma exacerbations’ which is currently under review in Clinical and Experimental Allergy (submitted Sept 2016). She also has received a Primerdesign silver studentship which gives her a discount on PCR reagents for gene expression analysis.

Research Title: The Role of CDHR3 in epithelial barrier function in asthma

Awarded to: Professor Donna Davies

Co-applicants: Dr Amrit Mudher  and Dr Jane Collins

Amount: £9934

Lay summary:

Asthma is a chronic disease characterised by exaggerated responses to harmless stimuli such as dust, air pollutants and pet dander. One factor that contributes to these abnormal responses in asthma is the ‘leakiness’ the cell sheet (epithelium) that lines the airways to form a protective barrier that should prevent penetration of components of the inhaled air like pollutants, allergens and pathogens.  Asthma also runs in families suggesting an underlying genetic susceptibility. While considerable progress has been made in identifying genes associated with inheritance of asthma, we know relatively little about how these genes work inside a cell and/or how the small changes in their genetic code modify their function to cause asthma.  We have used fruit flies (Drosophila) to study the function of an asthma gene called ‘CDHR3’.  In our pilot work, we found that the asthma variant of CDHR3 makes the airways of the flies ‘leaky’ whereas normal CDHR3 is without effect.   With support from the AAIR Charity, we investigated whether having the ‘asthma variant’ of CDHR3 causes epithelial cell cultures to be ‘leaky’ (as measured by their electrical properties), but we could not find a relationship.  However, by further investigating the function of CDHR3 in flies, we have found that it plays a specific role in ‘choreographing’ the movement of cells in processes linked to tissue repair.  We are now exploring this in our culture models.  If successful, our work will link a genetic association with a key defect in asthma and may pave the way for novel disease-modifying strategies.

Publications, presentations, IP, media interest or external grants arising from this award: 

DED was invited to give talks about the work at the British Thoracic Society (2017) and the European Research Society (2017).  In both cases, the AAIR Charity was acknowledged for funding.

MSc Allergy AAIR Bursaries Report

The MSc Allergy programme at the University of Southampton is designed to help healthcare professionals to gain a greater understanding of allergic diseases and to be able to translate this knowledge into their everyday practice. Offered by a World Allergy Organisation Centre of

Excellence, our programme draws on the clinical, research and education strengths at Southampton, and will help our students develop better treatment for their patients. Our programme brings them up to date with current best practice, allowing them to improve their management of patients with allergies. It will also give you them the skills to share their allergy knowledge with colleagues and patients.

Our MSc Allergy Bursaries Fund provides support to students to develop their skills so that they can improve the care of patients living with allergies. We are proud to award 3 AAIR Bursaries to students in September 2017. These were worth £1500 to each student and provided using combined funding of £3000 from the MSc Allergy Bursary Fund together with £1500 donation from AAIR. The recipients were:

Rebecca Briggs, Specialist Dietitian in Gastroenterology and Food Allergy, Derriford Hospital, Plymouth

Aneta Ivanova, a Paediatric Allergy Nurse Consultant at Sandwell and West Birmingham Hospitals NHSFT

Hazel Millar, Allergy and Immunology Clinical Nurse Specialist, West of Scotland Anaphylaxis Service, NHS Greater Glasgow and Clyde

Many thanks to all at AAIR for the support you have given to our students. It is very much appreciated by both them, and the staff on the programme.

Yours sincerely

Judith Holloway

PhD, PFHEA, NTF

Associate Professor in Allergy

Programme Leader, MSc Allergy

Director of PGT Programmes

Research Title: ADAM33 inhibitor and crystal structure project

Awarded to: Dr Hans Michael Haitchi

Amount: £23,100

Lay summary:

AAIR Grant Award 2013/2016 “ADAM33 inhibitor and crystal structure project” – “Discovery of novel ADAM333 inhibitors as potential new treatment for asthma”, awarded to Associate Professor Dr Hans Michael Haitchi in support of postdoctoral research fellow Rajendra Gosain from the department of chemistry.

Asthma is a very common disease in the UK, which runs in families suggesting an underlying genetic contribution.  The aim of our work is to understand how an asthma gene, known as ‘ADAM33’, contributes to the development of asthma. We have shown that the ‘faulty’ ADAM33 protein is not only increased in asthmatic lungs but plays an important role in driving the structural changes (remodelling) that occur in the airways of asthmatic patients. The aim of this project was to discover new chemical agents that can inhibit the ‘faulty’ ADAM33 protein and can be developed as a new asthma therapy.

Raj Gosain, a medicinal and structural chemist from the University of Southampton, was supported by this grant to discover new drugs that can block ADAM33. The ‘faulty’ ADAM33 protein is an enzyme with a unique protein structure that can cleave other proteins. We used a special computer program that allowed us to study new chemicals that would fit into this unique ADAM33 protein structure.  For this we searched large databases of known chemical structures and found two lead drugs that we made and optimised in our chemical laboratory.

We then tested these drugs as blocker for the ‘faulty’ ADAM33 protein in petri dishes in our laboratory. Both were very potent. We also sent the drugs to a company in the USA to test them on other proteins that are similar to ADAM33. We showed that these two drugs are highly specific for blocking ADAM33.

Based on these newly discovered drugs we applied for further funding from the Medical Research Council and Wellcome Trust as part of specific new drug development schemes. Our aim has been to further develop and test these drugs in our ADAM33 mouse models. We got very positive feedback for our applications, but both funders wanted to see more experimental data.

We have also been in discussion with international pharmaceutical industry for starting collaborations around our work of ADAM33 and we will use our exciting preliminary data for further grant applications.

Publications, presentations, IP, media interest or external grants arising from this award:

Abstracts and presentations: 

R Gosain, ER Davies, I Tews, G Chen, P Gale, ST Holgate, JA Whitsett, DE Davies, HM Haitchi. Development of novel ADAM33 inhibitors as airway anti-remodelling treatment in asthma. UoS/UHS Translational Clinical Research Conference, Southampton, 13 Nov 2013.

External grants applied for:

  • Medical Research Council (MRC) Developmental Pathway Funding Scheme Grant: Novel and selective small molecules inhibitors of ADAM33 for prevention or treatment of airway remodelling in asthma. PI: HM Haitchi, Co-PI: DE Davies, I Tews, PA Gale, R Gosain, M Bradley, Industrial partner: Synairgen. Applied July 2013 with positive feedback and invitation to reapply. Revised application: Aug 2014, not successful.
  • Wellcome Trust Seeding Drug Discovery Award: Novel and selective small molecule inhibitors of ADAM33-metalloprotease for prevention or treatment of airway remodelling in asthma. PI: HM Haitchi, Co-PI: DE Davies, I Tews, PA Gale, R Gosain, M Bradley, Industrial partner: Synairgen. Preliminary application: Nov 2014, not successful.
  • MRC Confidence in Concept (CiC), University of Southampton: Development of ADAM33 inhibitors for treatment of airway remodelling in asthma. PI: HM Haitchi, Co-PI: DE Davies, I Tews. Applied June 2017, not successful.

Discussions with international pharmaceutical companies of further developments of our lead compounds as ADAM33 inhibitors.

Research Title: The role of pericytes in ADAM33 induced airway remodelling in asthma.

Awarded to: Dr Hans Michael Haitchi

Amount: £11,762

Lay Summary:

AAIR Anuj Panchmatia Award 2014/2015 “The role of pericytes in ADAM33 induced airway remodelling in asthma” – “Understanding the role of the asthma gene, ADAM33, in the airways in asthma”, awarded to Associate Professor Dr Hans Michael Haitchi in support of postdoctoral research fellow Elizabeth R Davies.

Asthma is a common lung disease in the UK and is commonly triggered by exposure to allergens, viruses and pollutants. Asthma tends to run in families, which suggests an underlying genetic contribution.  The aim of our work is to understand the how an asthma gene, known as ‘ADAM33’, contributes to the development of asthma.

We recently published our exciting new discovery that the asthma gene ADAM33 plays an important role in driving the structural changes (remodelling) that occur in the airways of asthmatic patients (University of Southampton press release). Of great interest and very novel is the fact that this takes place without inflammation of the airways, which is contrary to current beliefs that inflammation is the driver of the development of remodelling in asthma. “Pericytes” are cells found within the walls of blood vessels and have stem cell properties (ie. they can give rise to many other cell types). When stimulated pericytes can grow and become smooth muscle cells and fibroblasts, both cell types, which are known to contribute to remodelling of asthmatic airways.

To elucidate the role of pericytes in this remodelled airways we studied lungs from mice producing the ‘faulty’ ADAM33 protein and lung tissue from patients with asthma. We have shown that markers for pericytes are increased in the lungs from mice producing the ‘faulty’ ADAM33 protein. Furthermore, when we studied these markers in small pieces of human lung tissue from healthy subjects and asthmatic patients we could detect the pericytes, and they seem to be different in healthy and asthmatic samples.

The support for Lizzie Davies as part of this subproject of our ADAM33 work has resulted in a first author publication in The Journal of Clinical Investigation-Insight 2016 and she has presented her work at several local, national and international meetings.

Based on this work, we were successful in a grant application for a Medical Research

Foundation/Asthma UK grant for 3 years in 2016, which allows us to further study the role of the ‘faulty’ ADAM33 protein in early life development of asthma.

Publications, presentations, IP, media interest or external grants arising from this award:

 Manuscripts:

  • R. Davies, J.F.C. Kelly, P.H. Howarth, D.I Wilson, S.T. Holgate, D.E. Davies, J.A. Whitsett, H.M. Haitchi. Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight. 2016 Jul 21;1(11). pii: e87632.

https://insight.jci.org/articles/view/87632

The press release from the University of Southampton related to our research publication had been widely covered by most major national newspapers as well as national radio and many other international media.

https://www.southampton.ac.uk/news/2016/07/adam-33-gene.page

Abstracts and oral presentations:

  • Elizabeth R. Davies, Joanne F.C. Kelly, Peter H. Howarth, Stephen T. Holgate, Donna E. Davies, Jeffrey A. Whitsett, Hans Michael Haitchi. Soluble Enzymatically Active ADAM33 Initiates Airway

Remodelling And Promotes Allergic Asthma In Early Life. Annual Meeting of COST BM 1201: Early Origins of Chronic Lung Disease: “The end of the beginning”. Athens, Greece, 3-4th of November 2016.

  • Elizabeth R. Davies, Joanne F.C. Kelly, Peter H. Howarth, Stephen T. Holgate, Donna E. Davies, Jeffrey A. Whitsett, Hans Michael Haitchi. Enzymatically Active sADAM33 Is Increased In Asthma

And Causes Airway Remodelling Without Inflammation, 31st Symposium of the Collegium

International Allergologicum in Charleston, South Carolina, USA, April 05th, 2016

  • Elizabeth R. Davies, Joanne F.C. Kelly, Peter H. Howarth, Stephen T. Holgate, Donna E. Davies, Jeffrey A. Whitsett, Hans Michael Haitchi. sADAM33 Causes Airway (P)Remodeling In Early Life

And Enhances Eosinophilic Airway Inflammation And Bronchial Hyperresponsiveness, 31st

Symposium of the Collegium International Allergologicum in Charleston, South Carolina, USA, April 05th, 2016

  • ER Davies, JA Whitsett, DE Davies, HM Haitchi. Soluble ADAM33 causes airway remodelling to promote allergic airway inflammation. Thorax 2015;70(Suppl 3): S128, A73. British Thoracic Society (BTS) Winter meeting, London, December 2015.
  • ER Davies, ST Holgate, DE Davies, JA Whitsett, HM Haitchi. The asthma susceptibility gene ADAM33 promotes structural remodelling to augment airway inflammation and bronchial hyperresponsiveness. Oral presentation at Faculty of Medicine Conference, June 17th, 2015, Southampton, UK.
  • ER Davies, ST Holgate, DE Davies, JA Whitsett, HM Haitchi. Asthma-Like Airway Remodelling Induced by ADAM33 Is Reversible. Oral presentation Breaking Boundaries Conference, Faculty of Medicine, University of Southampton, September 24th, 2014, Southampton, UK.

External grants:

  • Medical Research Foundation (MRF)/Asthma UK Research Grant (MRFAUK-2015-322): The impact of pre- and perinatal ADAM33 induced airway remodeling on sensitivity to environmental challenges and the early life development of asthma. PI: HM Haitchi, 2016 – 2019: £ 291,756

Stephen Holgate PhD Studentship: The role of ADAM33 in pre- and perinatal airway remodeling andthe early life development of asthma.

Awarded to: Dr Hans Michael Haitchi

Co-applicant: Dr. Christopher Woelk

Amount: £58,100

Lay Summary:

AAIR Stephen Holgate Studentship Award 2014-2018 “The impact of the asthma susceptibility gene, ADAM33, on early life development of asthma”, awarded to Associate Professor Dr Hans Michael Haitchi; IPhD student: Joanne FC Kelly. 

As part of our work supported by the AAIR charity, trying to understand asthma, we are investigating the role of an asthma gene, known as ‘ADAM33’, in the development of the disease. To do this we study mice producing a ‘faulty’ ADAM33 protein and compare these to ‘normal’ mice to see how ‘faulty’ ADAM33 has changed the airway.

Asthma is often triggered by exposure to allergens – such as pollen or house dust mite. Our recent work (JCI-Insight 2016) suggests that ‘faulty’ADAM33 may increase the strength of the response to these allergens. Work generated with help from the pulmonary biology and bioinformatics group in Cincinnati Children’s Hospital in the USA, using new technology, known as next generation RNA sequencing, has allowed us to identify some of the changes occurring in the airway in response to ‘faulty’ ADAM33. Our work has focussed on confirming these results in many samples and has led to the identification of the involvement of a type of inflammatory cells that might explain why the lungs are more susceptible to allergy. Our plan is now to continue these investigations, led by the results of our previous work, to try and understand how these cells may contribute directly to allergy susceptibility. For this Joanne has used special research technique to sort different inflammatory cells from whole mouse lungs, with and without the faulty ADAM33 protein, to study how they have been affected by exposure to the protein.

Furthermore, Joanne has been analysing the RNA-sequencing data (collaboration with Cincinnati Children’s Hospital, USA) from an experiment in mice where ADAM33 has been turned off and we have tried to trigger an allergic response. We have found that mice that do not have ADAM33 are less sensitive to developing allergy, highlighting the importance of ADAM33 in asthma. Further analysis of this data should help to identify unknown ways in which ADAM33 is involved in this response.

Joanne presented our recent findings based on the RNA-sequencing data as abstract and oral presentation at the Southampton Medical and Health Research Conference in June 2017 and at the British Thoracic Society (BTS) winter meeting in London in December 2017.

Additionally Joanne has also contributed to another abstract form our group that was presented at the BTS winter meeting 2017.

In May 2017 Joanne successfully transferred to the candidature for the degree of Doctor of Philosophy and she completed her 3rd year of her AAIR PhD fellowship in October 2017.

Publications, presentations, IP, media interest or external grants arising from this award: , IP, media interest or external grants arising from this award

  • JFC Kelly, ER Davies, ST Holgate, X Xu, JA Whitsett, DE Davies, HM Haitchi.

Soluble ADAM333 promotes susceptibility for allergic airways disease via non-Type-2-immune responses. Southampton Medical and Health Research Conference, 14-15th of June 2017.

  • Kelly JFC, Davies ER, Holgate ST, Xu X, Whitsett JA, Davies DE, Haitchi HM.

S89 Soluble ADAM33 augments the pulmonary immune response promoting allergic airway sensitivity. Thorax 2017;72:A55. http://thorax.bmj.com/content/72/Suppl_3/A55.1.citationtools

  • Davies ER, Kelly JFC, Whitsett J, Holgate ST, Davies De, Haitchi HM.

S85 Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by IL-13. Thorax 2017;72:A53. http://thorax.bmj.com/content/72/Suppl_3/A53.1.citation-tools British Thoracic Society Winter Meeting, 6 to 8 December 2017, QEII Centre Broad Sanctuary Westminster London SW1P 3EE.

Programme and Abstracts: Thorax, December 2017 Volume 72 Supplement 2 https://www.brit-thoracic.org.uk/document-library/learning-hub/winter-meeting-2017/bts-wintermeeting-2017-programme-and-abstracts/

Research Title: Assessment of the asthma specific emotional profile in individuals with asthma and their partners

Applicant: Judit Varkonyi-Sepp

Co-applicant: Professor Peter Howarth

Amount: £8,321

 Lay summary: We were awarded the grant to gain a better understanding of the nature of anxiety and depression in people living with asthma and the interaction with their partner’s distress. This is important because it is increasingly recognised that the well-being of patients living with chronic disease such as asthma and their partner’s well-being mutually influence each other. Since the award, we have secured two additional sites, Portsmouth Queen Alexandra Hospital and the Isle of Wight to collaborate on the study. The study also received great interest from across England and more sites are keen to join if this will become possible however initially we would like to offer participation to patients in the Wessex region only. The Southampton and Portsmouth sites are open and actively recruiting. Set up of the Isle of Wight sites is in progress.

Our work in progress has been presented at a conference and published in a society journal as listed below.  We aim to collect nearly half of our study data by the summer 2018. We are then planning to meet the patient and public involvement group that helped us shape the research so far, to discuss the data and where to present our work.

Publications, presentations, IP, media interest or external grants arising from this award:

Varkonyi-Sepp, J., Cross, A., & Howarth, P. (2017, Sept.). Setting up and initiating Patient and Public

Involvement as a collaborative process benefits research in its early stages. Poster presented at the British Psychological Society Division of Health Psychology Annual Conference, Cardiff 7 September, 2017. The poster won the ‘Delegates’ Choice’ award.

Varkonyi-Sepp, J., Cross, A., & Howarth, P. (2017). Setting up and initiating patient public involvement (PPI) as a collaborative process benefits research in its early stages. Health Psychology Update, 26(2), pp. 10-17.

Equipment Grant: FilmArray: multiplex rapid PCR system

Awarded to: Dr Tristan Clark

Co-applicant: Dr Nathan Brendish

Amount: £10,000

Lay Summary: The award from the AAIR charity was used to purchase a FlimArray machine. This is a rapid molecular platform that tests for a range of respiratory viruses and helped us to conduct several clinical trials. These trials compared testing hospitalised patients with the FilmArray compared to standard laboratory-based diagnostics tests. We showed that testing patients with the FilmArray led to improvements in clinical outcomes including of a reduction in unnecessary antibiotics and a reduced length of stay. It also showed improvements in the detection and treatment of influenza. These results were published in the Lancet Respiratory Medicine in May 2017. The work has also been presented at multiple international conferences in Amsterdam, Vienna, Riga, San Diego, Chicago and London. Pilot data from this study was used to support a

successful application for a prestigious NIHR Post-Doctoral Fellowship for the applicant who has now started this.  

Publications, presentations, IP, media interest or external grants arising from this award:

Brendish NJ, Malachira AK, Armstrong L, Houghton R, Aitken S, Nyimbili E, Ewings S, Lillie PJ, Clark TW. Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial. Lancet Respir Med. 2017 May;5(5):401-411.

This work has also been presented as an oral presentation the following conferences:

  1. ID week, San Diego 2017.
  2. European Conference Microbiology and Infectious Disease, Vienna 2017
  3. European Scientific Working Group on Influenza Conference, Riga 2017.
  4. Academy of Physicians Annual Meeting, London 2017.
  5. International Society for Influenza and Other Respiratory Viruses, Chicago 2016.
  6. European Conference Microbiology and Infectious Disease, Amsterdam 2016.

The pilot work which lead to this publication and used this equipment contented to the award of an NIHR Post-Doctoral Fellowship for the application

Research Title: Investigating whether a species-dependent rhinovirus response in infected cells might be linked to respiratory disease outcome

Awarded to: Dr Christopher McCormick

Co-applicant: Professor Donna Davies

Amount: £9,968

Lay Summary: Rhinoviruses cause the common cold. While rhinovirus infection is a minor inconvenience for most people, in individuals with asthma catching a cold can be life threatening. Rhinovirus produce two types of enzymes called proteases. It is known that the activity of one of the two proteases varies between different strains of rhinovirus, and it is also known that some strains are more pathogenic (ie. cause more illness) than others. We suspect that variation in pathogenicity may be linked to variation in protease activity. If correct, understanding how variation in protease activity alters an infected cell response could give us important insight into what is happening in the lungs of individuals with rhinovirus-induced severe asthma exacerbation.

Work over the last year has focussed on developing a novel system to look at how the rhinovirus proteases shut down the ability of the infected cell to express new genes, essentially preventing the infected cell fighting back. Using this system, we find that proteases from one of the three rhinovirus species (species A) more rapidly shuts down new gene expression compared to the other two species (species B and C). We also find that this ability to quickly shut down new gene expression is exclusively due to one of the two rhinovirus proteases, with the other protease playing no role. Interestingly, species A has been reported in some clinical studies to be more pathogenic, lending credence to our hypothesis that variation in protease activity could play a role in respiratory disease.

AAIR funding has covered all lab reagents costs associated with this project and helped pay for someone to be in the lab for 6 months, which was essential to get the work up and running. The findings of this study are being written up for publication, after which time applications for further grant funding will be submitted to continue this work.

 

PhD Studentship: The contribution of mast cells to rhinovirus infections in asthma

Awarded to: Dr Emily Swindle

Amount: £27,000

Lay Summary: Asthma is a disease of the airways (the tubes that carry air into the lungs) which narrow from time-to-time (exacerbation) by triggers in the air making it difficult to breathe. Mast cells are a rare type of white blood cell that contribute to the symptoms of asthma triggered by allergens (e.g. pollen and dust). However, the common cold virus is a major trigger of asthma exacerbations and we do not know exactly how this occurs. We also do not know if or how mast cells respond to the common cold virus but we do know that these cells form part of an early warning system following infection with bugs (e.g. bacteria and viruses). Therefore this PhD studentship has been investigating how mast cells respond to infection with the common cold virus to help us understand their potential contribution to viral-induced asthma exacerbations. Charlene Akoto, has shown that mast cells become infected with the common cold virus and are protected from infection following exposure to antiviral chemicals. She has also shown that a chemical released from epithelial cells also protects mast cells from releasing the common cold virus. During her PhD she has presented her work at 3 international conferences (European Mast Cell and Basophil Research Network (EMBRN; Oct 2015, May 2017) and European Academy of Allergy and Clinical Immunology

(EAACI; June 2016)) and the Faculty of Medicine Research Conference (June 2016, 2017). At the EAACI Congress she received a travel scholarship to attend the meeting and also won ‘best oral abstract in session’. Charlene has had her worked published in a research journal (Clinical and Experimental Allergy) for which she won the Wessex Medical Research prize for best research publication by a postgraduate research student at the Faculty of Medicine Research Conference in 2017. Charlene recently had her PhD examination and has now successfully completed her PhD studies.

Publications, presentations, IP, media interest or external grants arising from this award:

  1. Oral presentation entitled ‘Mast cells support the replication of major and minor group rhinoviruses’ at the 7th European Mast Cell and Basophil Research Network (EMBRN) International Mast Cell and Basophil Meeting, Marseille, France (Oct 2015)
  2. Prize: First place, three minute thesis competition at the Integrated PhD Programme Annual Away Day, Southampton, UK (Feb 2015).
  3. Oral presentation entitled ‘Human mast cells support rhinovirus replication but are protected from infection by IFN-β’ at the European Academy of Allergy and Clinical Immunology (EAACI) Congress, Vienna, Austria (June 2016)
  4. Oral presentation entitled ‘Rhinovirus infection of human mast cells results in viral shedding which is inhibited by interferon’ at the Faculty of Medicine Research Conference, University of Southampton, Southampton, UK (June 2016).
  5. Poster presentation entitled ‘Interleukin-33 enhances RV16 infection of human mast cells’ at the 8th European Mast Cell and Basophil Research Network (EMBRN) International Mast Cell and Basophil Meeting, Prague, Czech Republic (May 2017)
  6. Poster presentation entitled ‘Interleukin-33 enhances RV16 infection of human mast cells. University of Southampton, Faculty of Medicine Research Conference, Southampton, UK (June 2017)
  7. Prize: Wessex Medical Research prize for best research publication by a postgraduate research student. University of Southampton, Faculty of Medicine Research Conference,

Southampton, UK (June 2017)

  1. Research Publication entitled ‘Mast cells are permissive for rhinovirus replication: potential implications for asthma exacerbations. Akoto C, Davies DE, Swindle EJ (2017). Clin Exp Allergy. doi: 10.1111/cea.12879.

 

 

Research Title: Investigating cellular cross talk in the airway epithelial mesenchymal trophic unit following viral infection

Awarded to: Dr Cornelia Blume

Co-applicant: Dr Emily J Swindle

Amount: £5,350

Lay Summary: Inside the lungs, epithelial cells form a barrier between the outside world and the inside of our bodies. Underneath the epithelial barrier are cells called fibroblasts, which produce proteins which help repair the lung tissue. These 2 cell types work together to help keep our lungs healthy. Viruses such as the common cold virus can infect our lungs and damage epithelial cells, making symptoms of respiratory diseases such as asthma worse. We have made a model of the lung in the laboratory and exposed this to a component of the common cold. We found that the epithelial cells release chemicals that signal to the underlying fibroblasts. These fibroblasts respond by increasing the production of proteins that help repair the tissue. Our results suggest that different cells work together in the lungs and may co-ordinate repair responses to the common cold. The support of AAIR in this project contributed to data generated by Miss Chiara Banas, a integrated PhD student on her first year rotation project which we are currently preparing a manuscript for publication. She presented this work at the integrated PhD away day and at the Faculty of Medicine Research Conference.

Publications, presentations, IP, media interest or external grants arising from this award:

  1. Oral Presentation: Effect of dsRNA on extracellular matrix deposition in an in vitro model of the airway mucosa. Chiara Banas, Cornelia Blume, Donna Davies, Emily Swindle. MRC-DTP integrated PhD Away Day, Grand Harbour Hotel, Southampton, Feb 2017
  2. Poster Presentation: The effect of dsRNA on extracellular matrix deposition in an in vitro model of the airway mucosa. Chiara Banas, Cornelia Blume, Donna Davies, Emily Swindle. Southampton Medical and Health Research Conference, Faculty of Medicine, University of Southampton, June 2017

 

Research Title: Development and validation of age specific health related quality of life measures for patients with primary ciliary dyskinesia

Awarded to: Dr Laura Behan

Co-applicant: Professor Jane Lucas

Amount: £9,000

Lay Summary: Support from the AAIR Charity, co-funded by FP7 BESTCILIA, has led to age-specific quality of life measures for patients with primary ciliary dyskinesia (QOL-PCD).  This work has provided the first disease-specific outcome measures to monitor PCD patients clinically, document the progression of their illness and assess the effectiveness of therapeutic interventions in clinical trials. Researchers from University of Southampton led the development and validation of QOL-PCD, involving patients from across Europe and North America. Our findings have shown QOL-PCD to be robust, reliable, responsive and valid.  

In rare disease such as PCD, international collaborations are vital. It is important that QoL measures used in clinical trials are translated and tested comprehensively in each language. AAIR funding has enabled the QOL-PCD measures to be comprehensively translated in a number of languages for widespread use in international clinical trials across Europe, North America and the Middle East. The English, Danish, Dutch and German languages versions of the measures are already being used as outcome measures for a randomised clinical trial of azithromycin.

Finally, AAIR funding has enabled the PhD student working on this study to analyse the data, prepare a number of manuscripts, and submit her final thesis. It has also allowed for findings of the study to be presented to an international forum at the European Respiratory Society Congress, American Thoracic Society and at the COST Action BEAT-PCD Training School in Paris http://www.beatpcd.org/

We are currently applying for external grants to support the development and validation of Parental Impact questionnaires, for carers of children with PCD under the age of 6 years.

Publications, presentations, IP, media interest or external grants arising from this award:

Support from AAIR was acknowledged in all of these disseminations:

Publications

  • 1: Behan L, Rubbo B, Lucas JS, Dunn Galvin A. The patient’s experience of primary ciliary dyskinesia: a systematic review. Qual Life Res. 2017 Mar 30.
  • 2: Behan L, Leigh MW, Dell SD, Dunn Galvin A, Quittner AL, Lucas JS. Validation of a healthrelated quality of life instrument for primary ciliary dyskinesia (QOL-PCD). Thorax. 2017 Feb 28. pii: thoraxjnl-2016-209356.
  • 3: Dell SD, Leigh MW, Lucas JS, Ferkol TW, Knowles MR, Alpern A, Behan L, Morris AM, Hogg C, DunnGalvin A, Quittner AL. Primary Ciliary Dyskinesia: First Health-related Quality-of-Life Measures for Pediatric Patients. Ann Am Thorac Soc. 2016 Oct;13(10):1726-1735.
  • 4: Behan L, Dimitrov BD, Kuehni CE, Hogg C, Carroll M, Evans HJ, Goutaki M, Harris A, Packham S, Walker WT, Lucas JS. PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia. Eur Respir J. 2016 Apr;47(4):1103-12.
  • 5: Lucas JS, Behan L, Dunn Galvin A, Alpern A, Morris AM, Carroll MP, Knowles MR, Leigh MW, Quittner AL. A quality-of-life measure for adults with primary ciliary
  • dyskinesia: QOL-PCD. Eur Respir J. 2015 Aug;46(2):375-83.
  • 6: Behan L, Dunn Galvin A, Rubbo B, Masefield S, Copeland F, Manion M, Rindlisbacher B, Redfern B, Lucas JS. Diagnosing primary ciliary dyskinesia: an international patient perspective. Eur Respir J. 2016 Oct;48(4):1096-1107.

Research Title: Assessment of Bronchial Hyper-reactivity in the Isle of Wight Birth Cohort at 26-years to Support Characterisation of Asthma Remission and Persistence from Childhood to Adulthood.

 

Awarded to: Dr Ramesh J Kurukulaaratchy

 

Amount: £10,000

 

Lay Summary: The Isle of Wight Cohort (containing 1456 subjects) was established in 1989 to study the natural history of asthma. It has been followed regularly in the 1st 26-years.This proposal supported a sub-study to assess bronchial hyper-responsiveness via bronchial challenge tests in a subset of these subjects. Data collection is still ongoing and to date around 100 participants have completed bronchial challenge testing. The resulting findings will help assess the later outcomes of asthma patterns in the 1st 18-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.

 

The data generated from this study will be analysed on completion of data collection with a view to supporting characterisation of the Isle of Wight Birth Cohort at 26-years of age.

 

Research Title: Initial Characterisation of Difficult Asthma in the WATCH Study – Baseline Assessment

Awarded to: Dr Ramesh J Kurukulaaratchy

Amount: £3,500 

Lay Summary: The WATCH Study has now enrolled 375 participants with the creation of a significant database repository of information about severe asthma in clinical practice. The AAIR charity award has directly supported patient recruitment and involvement into the WATCH study by ensuring that the study was universally accessible without inconveniencing patients.

One WATCH substudy of mindfulness training in asthma (MIDAS) has completed with a manuscript currently under submission. That was presented at ERS 2016 as a poster presentation alongside 2 other poster presentations at that meeting outlining a) the methodology of the WATCH study and b) the impact of the WATCH study on general recruitment to other asthma studies at Southampton.

An NIH grant has been obtained to study the epigenetics of severe asthma within the WATCH cohort. An award from Boehringer-Ingelheim has also been secured to study biomarkers for different subtypes of severe asthma.

Further conference abstracts and manuscripts are now in preparation from the WATCH study.

Publications, presentations, IP, media interest or external grants arising from this award:

ERS 2016 Conference Presentations:

  1. Ainsworth B, Bain E, Griffiths J, Kurukulaaratchy R, Thomas M. Exploring the relationship between psychological dysfunction and perceived symptoms in the Wessex AsThma CoHort of difficult asthma (WATCH) study.
  2. Thirlwall Y, Gonzales F, Barber C, Gove K, Tariq K, Morgan A, Dennison P, Kurukulaaratchy RJ. The Wessex AsThma CoHort (WATCH) difficult asthma study; integrating research into the clinic.
  3. Thirlwall Y, Gonzales F, Barber C, Gove K, Tariq K, Morgan A, Dennison P, Kurukulaaratchy RJ. The impact of the Wessex AsThma CoHort (WATCH) study on recruitment to research.

External Awards:

  1. NIH 2R01HL114093-06A1 – The Epigenetics of Severe Asthma.
  2. Boehringer-Ingelheim – Characterisation of Severe Asthma.

Research Award: Reducing Worry in Asthma Patients (REWRAP)

Awarded to: Dr Ben Ainsworth

Amount: £6,272

Lay summary: We increasingly understand that asthma doesn’t just affect peoples’ lungs, but also causes stress and anxiety that affects peoples’ lives – people with asthma are 6 times more likely to suffer from anxiety than people without asthma.

Recently, research has looked at how ‘psychological’ treatments can help – such as cognitivebehavioural therapy (CBT), mindfulness & breathing retraining. In general, these treatments can help – but they aren’t for everyone, and they don’t always work. This may be because they are often ‘offthe-shelf’ psychological treatments, and aren’t specifically designed to help people with asthma.

To find out what makes an effective treatment, we want to find out how treatments like mindfulness and breathing training impact the stress and anxiety that is such an important part of people’s asthma. In particular, do these treatments make people feel better or reduce the worries that people with asthma have about their breathing? Does reducing worry mean that people with asthma can enjoy a better quality of life? And if someone isn’t worried, can we provide a ‘protective’ effect to help people if/when stressful events occur?

Using a psychological study that has successfully been trialled in people without asthma, a multidisciplinary team made up of psychologists, respiratory physicians and physiotherapists will see how practicing mindfulness or breathing retraining can reduce worrying in people with asthma who are randomly allocated to one of these interventions (or a control). This will help us understand the relationship between anxiety and asthma, and how psychological treatments can help it.

 

Research Award: Assessing the correlation between immune statues and asthma: from birth to early childhood study

Awarded to: Dr Aref Kyyaly

Amount: £8,600

Lay Summary: In Southampton, we have developed a programme of research into “early origins of adult diseases” by studying factors present in early childhood including those present before birth. To this end, we recruited pregnant women with asthma and allergy in their family (n=300) as their children are likely to be at high risk of asthma and (for comparison) 40 children with low risk (no parental asthma or allergy). When their infants were born, we collected a small amount of blood from the umbilical cord. We then saw these children at 6, 18 and 30 months to assess their asthma and allergy status and again collected a small amount of blood sample. We are currently examining them at 6-7 years of age to assess them for asthma, lung function and allergy. We plan to use this precious resource of data and samples to identify molecules in the blood samples that were collected at birth, which can predict the development of allergy at 3 and asthma at 6-7 years. Identification of molecules (biomarkers) associated with asthma and allergy will increase our standing of how asthma develops and what we can do to prevent asthma. With AAIR charity funding, we wish to analyse a small subset of approximately 40 samples to ensure that this plan of work is feasible and if we can see any hints with this small group. If successful, we will apply for a larger grant to a major funding body.

 

Research award: Can we treat Idiopathic pulmonary fibrosis (IPF) patients by promoting autophagy (“self-eating”)?

Awarded to: Dr Yihau Wang, Lecturer Biological Sciences

Amount: £10,000

Lay summary: IPF is a life threatening condition of the lungs where tissue becomes thickened, stiff, and scarred due to an unknown cause, which limits the amount of oxygen that gets into the blood. With less oxygen in the blood, IPF patients can get breathlessness from everyday activities like walking. Latest research suggests about 6,000 people are diagnosed with IPF every year in the UK. At the moment, there is no cure available for the disease and a better understanding of how it develops is therefore urgently needed to help us find more effective, long-lasting treatments.

In this project, we will look at a body mechanism called ‘autophagy’ (from the Greek for ‘self-eating’) and its potential link to the development of IPF: a healthy cell performs an ongoing clean-up process to keep functioning normally, by digesting built-up internal structures. In patients suffering from IPF, previously healthy cells become damaged through scar tissue, and we believe that this could be due to the healthy cells losing their ability to ‘self-eat’. In our research, we will test this theory by developing a 3-dimensional cellular model of IPF to get a better understanding how the disease develops.

The results of the project will help us inform further research and new treatments for sufferers to reduce symptoms of this devastating disease and improve their quality of life.

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