Variants of mast cell tryptase as markers and mediators of inflammation and tissue remodelling in asthma
Lead Research Organisation:
University of Southampton
Department Name: Inflammation Infection and Repair
Abstract
Asthma and other allergic diseases represent a major health problem in this country. These conditions are associated with the release into the lungs of substantial quantities of an enzyme called tryptase. This has become a new target for drug development.
There are multiple forms of tryptase, prominent among which are the alpha and beta forms. We propose to investigate the degree to which asthmatic patients may exhibit genetic differences in the tryptases they possess. The relatively little studied alpha tryptase will be purified and its properties compared with those of beta tryptase.
The pattern of release of tryptases from cells will be studied, and the extent to which they are released into blood or fluids lining the lung examined. We shall carefully investigate the ability of the different tryptases to alter the function of cells to promote inflammation and structural alterations in the lung. These studies should advance understanding of fundamental processes of allergic disease and on the new approaches to treatment directed against tryptases.
There are multiple forms of tryptase, prominent among which are the alpha and beta forms. We propose to investigate the degree to which asthmatic patients may exhibit genetic differences in the tryptases they possess. The relatively little studied alpha tryptase will be purified and its properties compared with those of beta tryptase.
The pattern of release of tryptases from cells will be studied, and the extent to which they are released into blood or fluids lining the lung examined. We shall carefully investigate the ability of the different tryptases to alter the function of cells to promote inflammation and structural alterations in the lung. These studies should advance understanding of fundamental processes of allergic disease and on the new approaches to treatment directed against tryptases.
Technical Summary
Tryptase, the major product of human mast cells, is emerging as a key mediator of inflammation and tissue remodelling in asthma and other allergic conditions. This tetrameric serine protease is often considered as a single enzyme, but multiple sequences have been derived, and a family of related proteases mapped to chromosome 16p13.3. We shall investigate the degree of genetic variation at this site in families with bronchial asthma, and examine the potential for linkage with features of disease. Alpha tryptase will be purified from a recombinant expression system and enzymatic properties investigated with synthetic and natural substrates. Comparison will be made with the more extensively studied beta tryptases, and the degree to which heterotypic tetramers may form will be examined. The cellular expression and release will be examined of alpha and beta of tryptase in vitro, and in vivo in body fluids from patients with allergic conditions. The ability of alpha tryptase to stimulate altered gene expression in epithelial cells and airway smooth muscle cells will be investigated using microarray procedures, and compared with the patterns with beta tryptase. The release of selected cytokines, matrix components or mediators, and the rate of cell proliferation in response to alpha and beta tryptases will be investigated, exploring potential proteolytic and non-proteolytic mechanisms. The abilities of alpha tryptase to provoke pro-inflammatory changes following transfer to a guinea pig model will be assessed and compared with those of beta tryptase. This integrative biology approach should yield crucial information on the mediator actions of human tryptases and their potential as targets for therapeutic intervention.
Organisations
- University of Southampton, United Kingdom (Lead Research Organisation)
- Anti-Doping Laboratory Qatar (Collaboration)
- Cairo University (Collaboration)
- Bayero University Kano (Collaboration)
- Tanta University (Collaboration)
- Uk Centre for Ecology & Hydrology, Wallingford (Collaboration)
- Spanish Network Centre for Mastocytosis (Collaboration)
- University of Paris XII: Paris-Val-de-Marne (Collaboration)
- Suez Canal University (Collaboration)
- University of Paris Diderot (Paris 7) (Collaboration)
- Borstel Research Centre (Collaboration)
- Changzhou University (Collaboration)
- National Research Institute for Child Health and Development (Collaboration)
Publications

Abdelmotelb A
(2010)
Alpha Tryptase: Potential Roles in Inflammation Distinct from those of ß-tryptase
in Journal of Allergy and Clinical Immunology

Abdelmotelb AM
(2014)
Alpha-tryptase gene variation is associated with levels of circulating IgE and lung function in asthma.
in Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

Abe K
(2006)
Up-regulation of protease-activated receptor-2 by bFGF in cultured human synovial fibroblasts.
in Life sciences

Agis H
(2006)
Identification of Basogranulin (BB1) as a Novel Immunohistochemical Marker of Basophils in Normal Bone Marrow and Patients With Myeloproliferative Disorders
in American Journal of Clinical Pathology

Agis H
(2006)
Identification of basogranulin (BB1) as a novel immunohistochemical marker of basophils in normal bone marrow and patients with myeloproliferative disorders.
in American journal of clinical pathology

Alzahrani M
(2020)
Novel method for assessing basophil activation by measuring altered expression of membrane-bound and intracellular basogranulin stores
in World Allergy Organization Journal

Bergqvist A
(2015)
Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control.
in Clinical science (London, England : 1979)

Biggs TC
(2019)
Immunological profiling of key inflammatory drivers of nasal polyp formation and growth in chronic rhinosinusitis.
in Rhinology


Bradding P
(2006)
The role of the mast cell in the pathophysiology of asthma.
in The Journal of allergy and clinical immunology
Description | Anaphylaxis provoked by anaesthetics |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guidance committee |
Impact | The guidelines will encourage the routine collection of blood samples for the measurement of mast cell tryptase. |
Description | Risk factors for anaphylaxis |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guidance committee |
Impact | Increases awareness of anaphylaxis as a clinically important condition |
Description | Asthma UK Project Grant |
Amount | £148,000 (GBP) |
Organisation | Asthma UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2006 |
End | 11/2009 |
Description | Educational grant |
Amount | £50,000 (GBP) |
Organisation | Novartis |
Sector | Private |
Country | Global |
Start | 09/2012 |
End | 09/2015 |
Description | European Union Cooperation in Science and Technology COST scheme |
Amount | € 10,000 (EUR) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 04/2012 |
End | 09/2012 |
Description | FSA, Studentship |
Amount | £60,000 (GBP) |
Organisation | Food Standards Agency (FSA) |
Sector | Public |
Country | United Kingdom |
Start | 11/2007 |
End | 11/2010 |
Description | Flexibility and Sustainability Funding (FSF) |
Amount | £86,259 (GBP) |
Organisation | National Institute for Health Research |
Department | Comprehensive Clinical Research Network (Coordinating Centre) – NIHR |
Sector | Public |
Country | United Kingdom |
Start | 09/2011 |
End | 09/2013 |
Description | Graduate studentship |
Amount | £70,000 (GBP) |
Organisation | Iraqi Government |
Sector | Public |
Country | Iraq |
Start | 09/2014 |
End | 09/2018 |
Description | Graduate studentship |
Amount | £70,000 (GBP) |
Organisation | Bayero University Kano |
Sector | Academic/University |
Country | Nigeria |
Start | 02/2015 |
End | 01/2019 |
Description | Higher Education Innovation Funding |
Amount | £15,000 (GBP) |
Organisation | Higher Education Funding Council for England |
Sector | Public |
Country | United Kingdom |
Start | 03/2014 |
End | 06/2014 |
Description | Impact Acceleration Account |
Amount | £18,000 (GBP) |
Organisation | Natural Environment Research Council |
Sector | Public |
Country | United Kingdom |
Start | 11/2013 |
End | 03/2014 |
Description | Institute for Life Sciences/Faculty Studentship |
Amount | £60,000 (GBP) |
Organisation | University of Southampton |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2014 |
End | 09/2017 |
Description | Lullaby Trust Project grant |
Amount | £10,000 (GBP) |
Organisation | The Lullaby Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2015 |
End | 08/2015 |
Description | NERC Environment and Human Health Programme NE/E009417/1 Plant virus infection as a determinant of pollen allergenicity |
Amount | £60,678 (GBP) |
Funding ID | NE/E009417/1 |
Organisation | Natural Environment Research Council |
Sector | Public |
Country | United Kingdom |
Start | 06/2008 |
End | 06/2010 |
Description | NERC Innovation Grant |
Amount | £81,000 (GBP) |
Organisation | Natural Environment Research Council |
Sector | Public |
Country | United Kingdom |
Start | 04/2009 |
End | 12/2010 |
Description | National Research Priority Funding |
Amount | $930,000 (USD) |
Organisation | Qatar Foundation |
Department | Qatar National Research Fund |
Sector | Charity/Non Profit |
Country | Qatar |
Start | 12/2013 |
End | 09/2017 |
Description | New and Emerging Applications of Technology Programme NEAT H039 Development of discriminating tests for allergic reactions to medicines and anaesthetics, based on the assay of unique products of mast cell and basophil activation |
Amount | £244,408 (GBP) |
Funding ID | H039 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 11/2006 |
End | 07/2010 |
Description | Part funded studentship |
Amount | £21,000 (GBP) |
Organisation | University of Southampton |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2012 |
End | 09/2015 |
Description | Petroleum Technology Development Fund Scholarship |
Amount | £75,000 (GBP) |
Organisation | PTDF Petroleum Technology Development Fund Nigeria |
Sector | Public |
Country | Nigeria |
Start | 01/2020 |
End | 12/2024 |
Description | Research grant |
Amount | £8,937 (GBP) |
Organisation | Asthma Allergy & Inflammation Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2016 |
End | 09/2018 |
Description | Santander Internationalisation Fund |
Amount | £1,000 (GBP) |
Organisation | Santander Universities |
Sector | Private |
Country | United Kingdom |
Start | 03/2012 |
End | 06/2012 |
Description | Scholarship |
Amount | £10,000 (GBP) |
Organisation | Government of Egypt |
Sector | Public |
Country | Egypt |
Start | 03/2016 |
End | 10/2016 |
Description | Wessex Medical Trust, States of Jersey Research Grant |
Amount | £45,000 (GBP) |
Organisation | States of Jersey |
Sector | Public |
Country | Jersey |
Start | 04/2008 |
End | 09/2010 |
Title | Assay for mast cell chymase |
Description | Diagnostic assay |
Type Of Material | Technology assay or reagent |
Year Produced | 2010 |
Provided To Others? | Yes |
Impact | Improved diagnosis |
Title | Improved assay for mast cell tryptases |
Description | New monoclonal antibodies have been prepared and incorporated into new prototype assays for tryptase |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | Production of new monoclonal antibodies against tryptases has led to development of better assays for these proteases. |
Description | Ahmed Abdelmotelb |
Organisation | Tanta University |
Department | Faculty of Medicine |
Country | Egypt |
Sector | Academic/University |
PI Contribution | Provided training for PhD student over four years, and subsequently supervised as a research fellow |
Collaborator Contribution | Provided PhD student for 4 years |
Impact | Successful completion of PhD course Publications pending |
Start Year | 2006 |
Description | Basophil markers |
Organisation | Cairo University |
Department | Department of Biochemistry |
Country | Egypt |
Sector | Academic/University |
PI Contribution | Supervision of PhD student |
Collaborator Contribution | PhD studentship awarded with consumables |
Impact | Research publications, training of PhD students |
Start Year | 2007 |
Description | Bayero University Kano |
Organisation | Bayero University Kano |
Country | Nigeria |
Sector | Academic/University |
PI Contribution | Training of two PhD students |
Collaborator Contribution | Two PhD studentships awarded |
Impact | Presentations at international meetings, publications pending, and PhD students trained |
Start Year | 2013 |
Description | Changzhou University, China |
Organisation | Changzhou University |
Country | China |
Sector | Academic/University |
PI Contribution | Presentations at Changzhou University, arrangements for student supervision, collaborative research, joint grant publications and grant applications. |
Collaborator Contribution | Travel funding to China, collaborative research, joint grant applications. |
Impact | One research paper published, and another in advanced preparation. A research grant awarded in China for the joint work, and another application will shortly be submitted. |
Start Year | 2015 |
Description | Chaza Mecheri |
Organisation | University of Paris XII: Paris-Val-de-Marne |
Country | France |
Sector | Academic/University |
PI Contribution | training in cell culture, studies with mast cell proteases |
Collaborator Contribution | training of student in research practice |
Impact | publication pending |
Start Year | 2012 |
Description | Helmut Haas |
Organisation | Borstel Research Centre |
Country | Germany |
Sector | Private |
PI Contribution | Graduate student from our lab conducted studies in the partner laboratories using reagents prepared by our group |
Collaborator Contribution | Provided training in new molecular biology procedures |
Impact | Studies conducted included in a PhD thesis Publication pending |
Start Year | 2009 |
Description | Helmut Haas |
Organisation | Borstel Research Centre |
Country | Germany |
Sector | Private |
PI Contribution | Graduate student from our lab conducted studies in the partner laboratories using reagents prepared by our group |
Collaborator Contribution | Provided training in new molecular biology procedures |
Impact | Studies conducted included in a PhD thesis Publication pending |
Start Year | 2009 |
Description | Hirohisa Saito |
Organisation | National Research Institute for Child Health and Development |
Country | Japan |
Sector | Academic/University |
PI Contribution | Supervised a PhD student for a period of one year supported by his institution in Japan |
Collaborator Contribution | Graduate student worked in our laboratory for one year |
Impact | Study presented at national meeting Publication pending |
Start Year | 2011 |
Description | Luis Escribano |
Organisation | Spanish Network Centre for Mastocytosis |
Country | Spain |
Sector | Charity/Non Profit |
PI Contribution | Development of improved methods for diagnosis and clinical modelling of mastocytosis. |
Collaborator Contribution | Provision of samples from well characterised cases of mastocytosis. |
Impact | publications |
Start Year | 2007 |
Description | Mogib Khedr |
Organisation | Suez Canal University |
Department | Faculty of Pharmacy |
Country | Egypt |
Sector | Academic/University |
PI Contribution | Provided training for a PhD student over 4 years |
Collaborator Contribution | Provided a PhD student for 4 years |
Impact | Successful completion of PhD course Several presentations at national and international meetings. One paper published and further publications pending |
Start Year | 2008 |
Description | Novel inhibitors of tryptase as anti-allergic agents |
Organisation | UK Centre for Ecology & Hydrology |
Country | United Kingdom |
Sector | Public |
PI Contribution | Access to data and intellectual input into collaborator's research. |
Collaborator Contribution | Provision of novel reagents |
Impact | Grant funding from NERC |
Start Year | 2009 |
Description | Plant virus-induced alterations in the allergenicity of pollen |
Organisation | UK Centre for Ecology & Hydrology |
Country | United Kingdom |
Sector | Public |
PI Contribution | Access to data and intellectual input into collaborator's research. |
Collaborator Contribution | Provision of research materials, and useful discussions |
Impact | Grant funding from two separate NERC-led initiatives. Research paper published |
Start Year | 2008 |
Description | Sayed Goda |
Organisation | Anti-Doping Laboratory Qatar |
Country | Qatar |
Sector | Public |
PI Contribution | Supervision of research fellow and three research assistants. Set up a split site graduate student programme. |
Collaborator Contribution | Provision of staff to work in our laboratory Provision of materials from their institution |
Impact | Grant award. Presentations at national and international meetings |
Start Year | 2013 |
Description | Uli Blank |
Organisation | Paris Diderot University |
Country | France |
Sector | Academic/University |
PI Contribution | training in techniques related to calcium flux and provision of laboratory facilities |
Collaborator Contribution | training in techniques of kidney cell culture |
Impact | New information on fundamental processes in kidney disease |
Start Year | 2012 |
Description | Support to mastocytosis patients' support group - York |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Participants in your research and patient groups |
Results and Impact | As a researcher in the mast cell field I was approached to give a talk at a meeting which led to the foundation of a support group for mastocytosis suffers in the UK (first national meeting was in York). There has been frequent contact since then and I have advised subsequently on aspects of the condition, on research in the field, etc. The group is growing in size and in influence, and is now exploring setting up a research charity. |
Year(s) Of Engagement Activity | 2007 |