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Research Projects: Understanding the underlying biology of asthma

These research projects aim to understand the underlying biological causes of asthma.

Asthma is a complex condition. Understanding the underlying biological causes of asthma is essential for us to find out more about it and learn what we can do to treat it.

These are all of our currently funded projects in this area.

Projects

MRC-Asthma UK Centre in Allergic Mechanisms of Asthma

The MRC-Asthma UK Centre in Allergic Mechanisms of Asthma is one of our flagship research centres, supporting cutting-edge, world-leading research. Asthma UK has supported the Centre since 2011. The Centre is a collaboration between King's College London and Imperial College London.

Understanding more about how our immune system reacts to allergens

  • Researcher: Dr Anna Furmanski started her Fellowship while a Senior Research Associate in the Immunobiology Unit at the University College London (UCL), Institute of Child Health. She has now moved to a post as a Senior Lecturer in Immunology at the University of Bedfordshire.
  • Start date: April 2013
  • How long will the project run for? 39 months
  • Project type: Research Fellowship
  • Cost: £224,655

Project title: The role of Hedgehog signalling in potentiating Th2 immune pathology in asthma

In allergic asthma substances called allergens – such as animal fur, pollen or house-dust mite droppings – irritate the airways, causing them to tighten and become inflamed. This leads to wheezing, coughing and mucus production, and can sometimes provoke life-threatening asthma attacks. In asthma, immune cell reactions to allergens are inappropriate and unwanted because, to us, allergens should be harmless substances. It's not really understood why some people are particularly prone to making allergic-type immune responses. The study of the immune system in asthma and allergy is therefore important to understanding why these relatively innocuous substances trigger asthma.

There is a type of protein called Hedgehog (Hh) proteins and when in the lungs they cause inflammation, especially the type of inflammation that is related to allergic reactions. There are more Hh proteins in the lungs of people with asthma. Dr Furmanski will test the idea that by controlling the amount of Hh proteins in the lungs, the allergic response in people with asthma can be reduced.

This work will increase our understanding of asthma and will take us further towards treatments for the condition.

As a result of the support received by Asthma UK, Dr Furmanski has been awarded the position of senior lecturer at the University of Bedfordshire. In this role, she will also lead a research team conducting this research; this is just one of the ways that support from Asthma UK is increasing the number of researchers working in asthma research.

Understanding how certain genes influence asthma

  • Researcher: Dr Ian Sayers is an Associate Professor and Reader in Respiratory Molecular Genetics at the University of Nottingham
  • Start date: October 2013
  • How long will the project run for? 36 months
  • Project type: Project grant
  • Cost: £178,594

Project title: Functional Genomics of the IL33/ST2 axis: a therapeutic target for asthma

New technological techniques have allowed a much more detailed investigation of genes relating to asthma. All genes have various 'types' within the general population, and research has recently found certain types of several genes that increase the chance of someone developing asthma. In this research, Dr Ian Sayers and his team of collaborators will further investigate two related genes, called IL33 and ST2, which they believe may play a major role in lung function and inflammation.

The scientists will examine what about the specific types of these genes increase the chance of asthma developing. They will investigate how these change the function of the cells lining the airway and how this might lead to asthma. Understanding the changes that occur in people with asthma on a cellular level is a vital first step to developing targeted new treatments.

Investigating fungi in the lungs and which are causing allergies

  • Researchers: Professor Andy Wardlaw is supervising the PhD student, Eva-Maria Rick at the University of Leicester.
  • Start date: October 2014
  • How long will the project run for? 48 months
  • Project type: PhD studentship
  • Cost: £97,394

Project title: Exploring the lung fungal microbiome and prevalence of fungal sensitisation in refractory asthma

Asthma attacks can be triggered by airborne allergens such as pollens and fungal spores.

Around a quarter of a million of people have asthma that is so severe they are unable to get good control of their asthma, despite using high levels of asthma medicines. Many people in this group have difficulty breathing almost all of the time, and suffer from frequent, serious, life-threatening asthma attacks needing hospital admissions.

People with severe asthma are more likely to be allergic to fungi and there is mounting evidence to suggest that fungi may be a potential cause of lung damage in severe asthma. About 70% of people with severe asthma are allergic to fungi compared to 20 - 30% of people with mild to moderate asthma and 5% of the general population. Whilst there is growing understanding of the role of allergens such as pollens in asthma, we are still unclear as to the role fungi have in worsening asthma.

As scientists begin to analyse the different types of fungi, an increasing number of fungi are emerging that cannot be grown using standard methods or cannot be accurately identified from how they look. Using existing techniques like taking a sample from the lungs and growing or 'culturing' fungi in the lab may therefore miss many fungi that are important in asthma.

DNA methods are increasingly being used to supplement traditional approaches to identifying bacteria and fungi. This approach has revealed a vast number of organisms (mainly bacteria) that can inhabit the human body that were previously unknown. Not much work of this kind has been done with fungi.

This studentship will investigate the hypothesis that there are fungal species that may be having a bad effect on asthma that are being missed because we cannot detect them. This study aims to use a cutting edge DNA-based approach to detect and identify fungi from the lungs of people with severe asthma and investigate whether these fungi are capable of inducing allergies. This is an essential first step in finding out how important different fungi are in asthma.

In the short term, this research should generate new knowledge and in particular, if Eva-Maria is able to identify one or more novel allergenic fungi from the airways of people with severe asthma, it would open the door to lots of other avenues which would have a direct bearing on the lives of people with asthma.

If there are no commercially available tests for the allergenic fungi identified, this would provide support for development of such a test, enabling a better understanding and clinical management of fungal allergy.

Investigating small genetic changes that can lead to big effects in the lungs

  • Researchers: Professor Alan Knox is supervising PhD student Klaudia Kaczmarek at the University of Nottingham.
  • Start date: October 2014
  • How long will the project run for? 48 months
  • Project type: PhD studentship
  • Cost: £96,800

Project title: Exploring Histone Arginine Methylation as a therapeutic target in asthma: regulation of CXCL-8 secretion

There are two underlying causes of asthma: inflammation in the lungs, and tightening of the airway muscles. These two things contribute to each other.

The muscles surrounding the airways are made up of cells called airway smooth muscle cells. These cells are able to tighten the airways but also make chemicals that add to the inflammation in the lungs. One of these chemicals is called interleukin 8. This project will focus on uncovering why more interleukin 8 is made by cells in the airways of people with asthma.

All of our cells contain all of our DNA – this is a lot of information, and each cell will only need to use a tiny amount of it to do its job well. The body has a very clever system to 'wrap up' the DNA that isn't needed so that it fits into a small space, and for highlighting the genes that should be used by a cell. This means that a cell in the muscles in our airway only 'sees' information that will help it to be an airway muscle cell and irrelevant information about its job, for example information about the colour of our eyes, is locked out of the way.

However, sometimes there are genes within a cell that are needed sometimes and not others – these will be 'visible' to a cell, and a separate clever signalling process is used to show which genes should be 'on' and which should be 'off' at any time, and so whether proteins like interleukin 8 should be made or not.

Sometimes, this signalling process goes awry and gives the cells the wrong signal – this can result in cells that misbehave. This ‘misbehaviour’ can be caused by a person's contact with environmental factors. For example, irritants from smoking and diesel fumes and allergens like pollen and animal dander, all of which can trigger asthma symptoms.

The researchers will investigate how this signalling process is causing different levels of interleukin 8 to be produced, and will also test a variety of different drugs to see if they can change the signalling.

Looking for a reason why the common cold causes asthma attacks

  • Researchers: Dr Lisa Parker will be supervising PhD student Jake Mills at the University of Sheffield.
  • Start date: October 2014
  • How long will the project run for? 48 months
  • Project type: PhD studentship
  • Cost: £96,800

Project title: Exploring how tenascin-C may worsen acute asthma attacks in response to the common cold virus

Respiratory infections are responsible for the majority of all acute asthma attacks, with the common cold virus (also known as human rhinovirus or HRV) being the main cause. There are so many rhinoviruses that it's currently not possible to develop a vaccine that protects against all of them. We need to find ways to stop them causing such severe problems for people with asthma. However, what happens within the airway during a viral-induced asthma attack is still not fully understood. This study will investigate how a molecule called tenascin-C, which plays a role in the amount of inflammation that occurs in the lungs, might be involved in these acute asthma attacks.

Tenascin-C is a protein generated when the body is under stress or damaged, for example during disease and has been found in greater amounts in people with asthma, especially following the inhalation of an allergen.

The researchers in Sheffield now have new data showing that human rhinovirus infection also increases tenascin-C levels in airway cells, and that tenascin-C can increase the harmful response seen during a viral infection.

This study will generate new knowledge of the underlying changes within the airways of people with asthma that leaves them more susceptible to a virus-induced asthma attack.  This will help us to understand why some people are more likely to suffer from a severe and sudden asthma attack in response to a cold and importantly, produce information that could help design much needed new medicines.

This study is the first to explore the influence of tenascin-C on viral-induced asthma attacks.

Understanding how immunotherapy alters the immune response to allergen in the airways

  • Research: Professor Hannah Gould, MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London
  • Start date: October 2014
  • How long will the project run for? 12 months
  • Project type: Innovation grant
  • Cost: £49,881

Innovation Grant title: Single-cell analysis of the local nasal B cell response to allergen immunotherapy

Most people with asthma, especially children, are allergic. Allergens, like pollen or house-dust mite droppings are a common cause of asthma attacks and children with allergic eczema, allergic rhinitis (hayfever) or food allergies are more likely to develop asthma. Treating people with allergens that they are susceptible to via immunotherapy has been shown to have long-term benefits as this effect is maintained after treatment is stopped. However, although allergen immunotherapy is effective in some people with mild or moderate asthma, it can be dangerous in people who have a tendency towards severe allergic reactions. 

Professor Hannah Gould and her team at King's College London will be focusing on unravelling the biological mechanisms of immunotherapy.

Allergic reactions are triggered by a class of antibody called IgE that is produced by a specialised cell of the immune system called a B lymphocyte (or B cell). IgE antibodies 'recognise' allergens so that, when a person with IgE is exposed to the particular allergen, the IgE activates the immune system and causes inflammation.

We know that people treated with allergen immunotherapy produce different types or 'classes' of antibodies as a result of treatment. These antibodies (of the IgA and IgG class) can also recognise allergens but competitively inhibit allergic reactions and so are termed protective or blocking antibodies. Very little is known about the differences in the B cells that produce either pro-allergic IgE antibodies or anti-allergic blocking antibodies. Professor Gould's laboratories have shown that in people with asthma and hayfever, pro-allergic IgE responses can develop exclusively within a person's lung or nose.

Antibodies identified to have protective effects against asthma can also be manufactured by scientists to treat patients with allergy. Therefore Professor Gould and her team intend to analyse nasal B cells in patients receiving allergen immunotherapy.

Growing a 'breathing' copy of a lung slice to better examine asthma

  • Researcher: Dr Amanda Tatler is a researcher at the University of Nottingham
  • Start date: October 2015
  • How long will the project run for? 36 months
  • Project type: Project grant (funded in collaboration with the Medical Research Foundation (MRF))
  • Cost: £299,633 (Asthma UK's contribution is £166,706 – this was funded in collaboration with the MRF)

Project title: Development of a novel ex vivo 'Breathing' lung slice model to investigate the dynamic relationship between tidal ventilation, deep inspiration and the development of airway remodelling.

Poorly controlled asthma can lead to airway remodelling, where airways change and become narrowed permanently. This makes breathing even harder and compounds the symptoms experienced by people with asthma.

It is thought that airway remodelling is triggered by the release of a certain chemical by airway muscle cells.

During normal breathing deep breaths are occasionally taken unconsciously – it's thought that these deep breaths stretch the airway muscles and reduce the risk of their constriction. This process is thought to be less effective in people with asthma though, which may lead to the increased risk of airway remodelling.

Researchers are able to keep slices of lung tissue from mice alive and healthy in the lab and measure their function and response to changes in their environment. However, this artificial environment for the cells can't mimic breathing. These researchers are interested specifically in the reactions of these lung slices to the stretching that occurs during breathing.

To overcome this, the researchers will utilise technological advances and combine the slices of lung tissue along with a type of material that can be stretched. They will attach the lung tissue to this flexible material, allowing the researchers to use the stretching to mimic 'breathing'. This will create an artificial 'breathing lung slice'.

This novel invention will allow researchers to measure chemical signals and changes within the lung slices to better understand their responses and potential ways to prevent airway remodelling. The researchers will make this technology available to other researchers around the world in the future, advancing research into asthma with this innovative technique.

Airway remodelling is irreversible damage to the lungs that permanently reduces the ability to breathe and is more common in people who already struggle with severe asthma. Being able to prevent this damage would dramatically improve the lives of people with asthma.

Investigating the role of an asthma risk gene in airway remodelling

  • Researcher: Dr Hans Michael Haitchi is a researcher at the University of Southampton
  • Start date: January 2016
  • How long will the project run for? 36 months
  • Project type: Project grant (funded in collaboration with the Medical Research Foundation (MRF))
  • Cost: £291,756 (Asthma UK's contribution is £84,724 – this was funded in collaboration with the MRF)

Project title: The impact of pre- and perinatal ADAM33-induced airway remodelling on sensitivity to environmental challenges and the early life development of asthma.

Various genes have been identified that make it more likely for individuals to develop asthma, but it is still not clear exactly how these genes play a role in the development of the condition or why.

Small changes in a particular gene, called ADAM33, are associated with development of asthma and airway 'twitchiness', which is a common feature of the disease.  ADAM33 is thought to play a role in the lungs of young children, possibly even before a baby is born.

What's not understood, however, is how and why the altered ADAM33 gene causes susceptibility for development of asthma. Better understanding of how ADAM33 works may provide ways to save babies from being born with a predisposition for asthma.

The ADAM33 gene makes an enzyme called ADAM33, which is attached to cells in the airway muscles. In asthma, it has been found that the ADAM33 enzyme becomes detached from these cells and higher levels of the detached enzyme are associated with poorer lung function. The researchers think that when the ADAM33 enzyme detaches it causes problems by affecting cells that shouldn't come into contact with it. This results in subtle changes in the airway wall (termed airway remodelling) involving over-growth of cells that cause the airways to narrow, among other asthma-associated changes.

The researchers want to see if, even before birth, airway remodelling can occur as a result of the rogue ADAM33 enzyme acting on developing lung cells that it wouldn't normally come into contact with.  Then they want to see how the remodelling affects reactions to irritants such as allergens later in life. They think that babies born with airway remodelling will be more sensitive to allergens, such as house dust mites, leading to the symptoms of asthma.  This increase in sensitivity would help explain why the lungs of people with asthma are affected by allergens whereas non-asthmatic people are not affected even though we all breathe the same air. They will investigate this using mice with the different form of the ADAM33 gene and also investigating cells from the nose of newborn babies.

This research will allow researchers to understand more about the rogue ADAM33 enzyme and how it affects responses to environmental triggers to produce asthma-related symptoms.  It will also show us whether the animal models that are used in the lab show similar results to those seen in humans. This is important because we want to make sure that if we are using animals, they really help our understanding of the disease in people so that their use results in more knowledge and progress towards better treatment.

It is hoped that this work will lead to development of drugs that block the effects of the rogue ADAM33 enzyme. These may eventually be treatments that prevent people with this faulty gene from developing asthma in the first place. 

Investigating a potential reason why asthma is more severe in some people

  • Researcher: Dr Tara Sutherland is a researcher at the University of Edinburgh
  • Start date: January 2016
  • How long will the project run for? 36 months
  • Project type: Project grant (funded in collaboration with the Medical Research Foundation (MRF))
  • Cost: £289,232 (Asthma UK's contribution is £86,770 – this was funded in collaboration with the MRF)

Project title: Chitinase-like proteins: the missing link in allergen-induced neutrophilic inflammation.

Inflammation is a core underlying cause of asthma. People with asthma have inflammation in their lungs, which can be made worse by triggers such as allergens or pollution. For most people with asthma, preventer inhalers can be used to reduce the inflammation in the lungs.

People with severe, poorly controlled asthma often have a different type of inflammation compared to people with milder forms of the disease – but what processes lead to this is unclear. Current treatments do not work very well in people with severe asthma, possibly as a result of this different kind of inflammation; understanding the behaviour of cells involved in this type of inflammation could help to identify targets for treatments for people with severe asthma.

There are types of proteins called CLPs (chitinase-like proteins) that are made by cells found in the lungs of people with asthma, and are produced at higher levels in people with more severe asthma. CLPs cause inflammation and greater amounts of them in people with more severe asthma may explain the greater inflammation present in their lungs.

CLPs have also been shown to be a cause of the different type of inflammation seen in people with severe asthma, by sending signals that tell these immune cells to move into the lungs.

We know that 'asthma' is not just one condition, but that there are many different types of asthma with many different things happening inside the lungs. This research will take us a step closer to understanding what is happening in the lungs of people with severe asthma, and move us closer to developing a treatment to stop the inflammation that causes their disease.

Current treatments don't work very well for people with severe asthma, so a better understanding of the differences occurring in their lungs and moving towards better treatments is essential.

Looking for small genetic differences as a cause of asthma

  • Researcher: Dr Rachel Clifford is a researcher at the University of Nottingham
  • Start date: March 2016
  • How long will the project run for? 36 months
  • Project type: Project grant (funded in collaboration with the Medical Research Foundation (MRF))
  • Cost: £299,645 (Asthma UK's contribution is £89,894 – this was funded in collaboration with the MRF)

Project title: Airway smooth muscle (ASM) DNA methylation: A novel target for asthma therapy

All of our cells contain all of our DNA – this is a lot of information, and each cell will only need to use a tiny amount of it to do its job well. The body has a very clever system to 'wrap up' the DNA that isn't needed so that it fits into a small space, and for highlighting the genes that should be used by a cell. This means that a cell in the muscles in our airway only 'sees' information that will help it to be an airway muscle cell and irrelevant information about its job, for example information about the colour of our eyes, is locked out of the way.

However, sometimes there are genes within a cell that are needed sometimes and not others – these will be 'visible' to a cell, and a separate clever signalling process is used to show which genes should be 'on' and which should be 'off' at any time.

Sometimes, this signalling process goes awry and gives the cells the wrong signal – this can result in cells that misbehave. In the case of asthma, it's thought that airway muscle cells in people with asthma have this confusion, which results in them becoming more 'twitchy' and contracting too often, causing asthma symptoms.

We think that things that act as triggers for some people’s asthma symptoms – such as allergies, or smoking - play a role in this faulty signalling, which may be why they cause asthma symptoms.

Dr Clifford has previously worked on techniques to better understand this signalling system and how to use that information to understand problems in cells.

Researchers have identified several genes that are particularly interesting in airway muscle cells – Dr Clifford will now examine these to see if the signalling for which genes should be 'on' or 'off' is different in people with asthma than those without the condition.

There is the potential to create drugs that target this signalling process, and may be able to correct it if it's different in the airway muscle cells of people with asthma. Knowing what these differences are, and what genes the signals are different for, is a crucial first step towards this.

Although a treatment utilising this knowledge may be some years away, taking the first step is incredibly important – at Asthma UK we involve people affected by asthma in selecting the research that we fund, and they see the potential in this area of research and this researcher.

Improving ways to tackle the cold virus and stop this causing asthma attacks

  • Researcher: Dr Aurelie Mousnier is a researcher at Imperial College London
  • Start date: May 2016
  • How long will the project run for? 36 months
  • Project type: Project grant (funded in collaboration with the Medical Research Foundation (MRF))
  • Cost: £300,000 (Asthma UK's contribution is £90,000 – this was funded in collaboration with the MRF)

Project title: Analysis of rhinoviruses replication complexes to identify host cell targets for the development of antiviral drugs for the treatment of asthma exacerbations.

Many people with asthma find that viral infections, including the common cold, are a trigger for their asthma symptoms – estimates suggest that 85% of childhood and 60% of adult asthma attacks are triggered by viral infections. People with asthma also report that they often have much more severe symptoms when they catch a cold than people without asthma.

The common cold viruses are known as rhinoviruses.

Rhinoviruses, like all viruses, rely on infecting our own cells and 'hijacking' them to replicate themselves and survive. Our cells can usually detect when they've been invaded by a virus and turn on an antiviral defence mechanism.

Recent studies have shown that people with asthma have an antiviral defence mechanism that is not as effective – this may explain why people with asthma experience symptoms of a cold for longer, causing worse asthma symptoms.

Previous attempts to make drugs to tackle the cold virus have focused on tackling the virus itself. The researchers in this project propose to instead find a way to target the cells that the viruses are attacking with a treatment.

When viruses 'hijack' our cells, they use our cells' machinery to make proteins and replicate themselves. It may be possible to create a treatment that stops them from being able to do that by blocking the machinery, but without killing the cell. Additionally, if such a drug was inhaled directly into the lungs it has the potential to reach exactly where it's needed without having widespread effects on cells throughout the body.

This project represents an excellent opportunity to take the first step on an exciting journey towards improving symptoms and stopping asthma attacks in a large proportion of the 1 in 11 people in the UK who have asthma. If this is successful and lays the groundwork for the development of new treatments, this avenue of research may bear fruit in 5-10 years.

 

Looking at genes and the environment to work out what causes wheezing in preschool children and find treatments to prevent development of asthma

  • Supervisor: Dr Sejal Saglani
  • Type of grant: PhD studentship
  • Institution: Imperial College London
  • Grant amount: £100,000
  • Grant duration: 48 months
  • Start date: October 2016

Project title: Gene-environment interactions mediating preschool wheeze: the role of 17q21, farmyard microbes and innate cytokines

About one-third of children under the age of 5 experience wheezing and breathlessness, but not all of them go on to develop asthma by school age. Children with asthma have a reduced lung function by age 6 that is irreversible.

Recent research has shown that some children who wheeze when they have a cold or other viral infection before the age of three, who don’t go on to develop asthma and are thought to have outgrown it, are actually at an increased risk of developing lung conditions like COPD as adults.

There are no medicines to prevent the progression from wheeze to asthma, or ways to predict who will prevent lung damage later in life.

Previous studies have shown strong associations between a particular area of DNA, including two particular genes -  called ORMDL3 and GSDMB - and people who wheeze in early life and go on to develop asthma.

Additionally, we know that growing up on a farm protects children from developing asthma as the types of bugs that they breathe in seem to be protective.  Even those with the genetic susceptibility of the genes above halve their chance of developing asthma following viral wheezing early in life if living on a farm.

We therefore have evidence for the first time of an interaction between a patient’s genes and the environment that they are exposed to in determining the development of asthma. However, the biggest problem with all of the studies that have looked at genes and farming environments is that they only suggest a link, they do not prove causation, and they do not explain how the interactions are working to prevent asthma.

This research will further investigate the relationship between these two particular genes and the microbes present on farms that may prevent the development of asthma. Understanding how the two interact will also tell us more about the genes and why they have the effect that they do.

We currently have no way of identifying which viral wheezers will develop asthma and this project has the potential to change this.  We hope this project will pave the way to help researchers to develop a way to test which children with wheeze and breathlessness are likely to go on to develop asthma and other lung conditions. This project has a huge potential impact - it is the first step to identifying genetically susceptible children and giving them appropriate medicines that will protect them from developing asthma and lung damage and possibly move us towards treatments to mimic the effects of a farm environment and stop this from happening.

 

Can the activity of inflammatory cells in the airways of children with severe asthma be used to monitor their asthma and guide treatment?

  • Researcher: Professor Sejal Saglani
  • Institution: Imperial College London
  • Grant amount: £49,995
  • Grant duration: 18 months
  • Start date: October 2016

Project title: Granulocyte activation and functional interactions with the bronchial epithelium and asthma control in children

Currently, there are only a few tests for adults with severe or difficult asthma that doctors can use to measure response to different medications, doses and asthma control (which encompasses lung function, symptoms, and asthma attacks) and this relies on measuring the number of two particular types of immune cells in the blood or phlegm – these cells are called eosinophils and neutrophils.

However, simply measuring the numbers of these cells does not work in the same way as children, leaving us with no tests to better understand their asthma or measure how it is responding to treatments or changing.

The researchers describe this poor situation as being 'Like treating diabetes without measuring blood sugar.'

It has been shown that, in children, measuring how active these cells are may be a better way to measure their asthma severity and control. Early research has also found that there may be a different pattern in the locations of the immune cells in the lungs of children, and that may impact on their asthma control.

Furthermore, understanding how the two types of cell interact with each other may provide further information about a child’s asthma, such as how well it is responding to treatments and the treatments that are helping, and help doctors to treat them in the best way that they can.

The researchers aim to see if a combination of activity of the two cells can be measured in some easy way, for example with a blood test, that can then be used as a guide to improve the treatment of children with severe asthma.

The types of things that the researchers will be measuring and linking to asthma control can be measured in standard laboratories – this means that, if they discover a good combination of things to measure that can act as a good indicator of asthma control, labs and clinics wouldn’t struggle to run these tests and these could easily be incorporated into standard care.

It is hoped that if the researchers see promising patterns in the activity of the immune cells and other measures that relate to asthma control, that with further research we could see a test that can be used to guide the treatment of children with severe and difficult asthma in five to 10 years.

Investigating signals that tell our cells when to destroy proteins - and the role they play in asthma

  • Researcher: Dr Carlos Maluquer de Motes
  • Institution: University of Surrey
  • Grant amount: £48,074
  • Grant duration: 18 months
  • Start date: January 2017

Project title: A systems biology approach to reveal how the ubiquitin system contributes to asthmatic inflammation

In people with asthma, the immune system is overactive in the lungs and airways, causing inflammation in response to triggers that would not normally be recognised as ‘dangerous’. Current drugs to treat this inflammation, while effective in most people with asthma, can result in side effects and tackle the inflammation in a general way.

In order to develop drugs that work better for people with asthma, and work for all people with asthma, we need to better understand the specific processes going on in the airway inflammation so that we can develop specific ways to stop these from occurring.

There is a particular system in the body that is responsible for which and when proteins in each cell are destroyed after they have done their job. This is essential for the healthy functioning of cells and their reaction to their environment.

Whenever this switch-off mechanism fails to work properly an inflammatory response is seen, similar to the overactive inflammation observed in asthma.However, it’s thought that this process is what underlies the overactive inflammation in asthma.

This system uses a variety of different 'markers' to identify the proteins that are to be destroyed, in a pattern and process that we don’t fully understand. Identifying the specific markers and patterns involved in the airways could provide the key to shutting off the harmful inflammation that occurs during asthma, and with reduced side effects than current drugs.
Dr Maluquer de Motes' research team have already identified some of these specific markers.

The research team will continue to identify the specific markers that are involved in airway inflammation.

They will also investigate which markers are involved in causing inflammation in people without asthma, and which are specific to reaction to known causes of asthma attacks such as infection by a virus (like a cold), so identifying the markers that are unique to asthma.

Current asthma treatments do not work for everyone, may have side effects (especially when people need to take high doses of oral steroids for long periods), and are very general in their targeting of inflammation.

By better understanding the specific proteins and chemical signals in airway cells that can lead to inflammation, the researchers can put us on the path to developing much more specific drug treatments for people with asthma, with fewer side effects and that will hopefully benefit many more people with the condition.

Uncovering a different way that allergic asthma can be triggered

  • Researcher: Professor Brian Sutton
  • Institution: King’s College London
  • Grant amount: £49,754
  • Grant duration: 12 months
  • Start date: October 2016

Project title: High-resolution Cryo-EM studies to uncover a novel mechanism in allergic asthma

For many people with asthma, airborne allergens such as pollen are a trigger for their asthma symptoms. There are treatments that can help people to overcome these allergic reactions in some cases – called allergen immunotherapy - however, in order to successfully develop this technique we need to understand more about the allergens, including what they look like and how they cause allergic reactions so that we can develop treatments to combat them.

Allergen immunotherapy is currently used as a treatment for some people with strong allergic reactions. This is a process where someone’s immune system is ‘desensitised’ to an allergen through being exposed to small amounts of it at first, increasing the amount given over time.

This ‘reprogrammes’ the immune system into tolerating the allergen and no longer recognising it as a threat, and so no longer triggers an immune response.

However, in order to develop a drug that can be given to people for this treatment, researchers must first understand how the allergen causes an allergic reaction. They need to do this through understanding what shape the allergen is and how it interacts with our immune cells: allergens react with particular parts of our immune system, called IgE antibodies, in a way that is like a lock and key – only specific shaped 'keys' will work in specific IgE 'locks', and researchers need to find out what that shape is for each individual allergen so that they can block the locks and stop the allergen from triggering an allergic reaction.

Investigating the shape of the allergen on a molecular level, and how it interacts with our immune cells, is essential for researchers to be able to copy that in a drug that can safely be given to people during allergen immunotherapy.

There are techniques that researchers use in the lab that can enable them to see the shape of an allergen and understand how it causes the reaction that it does. These techniques include using incredibly powerful microscopes so that the researchers can see the detailed structure of a protein or molecule, down to the individual atoms.

This is an essential first step in designing methods to stop the reactions from happening.

In this project, the researchers will investigate the shape of a particular grass pollen, which is a common allergen and can cause particularly strong allergic reactions in the lungs of people with asthma. Usually, many pieces of a particular allergen - e.g. lots of a particular type of pollen particle - would need to be inhaled before triggering an allergic reaction. But this particular grass pollen seems to be able to trigger an allergic reaction by single allergen molecules, making any reactions faster and stronger.

Professor Sutton’s research team are experts in exploring and understanding the shape of protein molecules like this, and understanding how they interact with each other, such as allergens with antibodies. Their work was behind the discovery of the shape of IgE, the antibody produced by the immune system that causes allergic reactions – this discovery has since led to the development of many new drugs to treat asthma.

A better understanding of the shape and interactions of a common strong allergen could lead to a future treatment for many people with asthma whose symptoms are triggered by it. If researchers can use this information to develop effective allergen immunotherapy for this type of grass pollen, people with asthma could be treated to stop this allergic reaction from happening and triggering their asthma symptoms.

Stopping a major trigger of asthma symptoms could greatly increase the quality of life for many people with asthma, stop asthma attacks, and take us a step closer to curing asthma.

Investigating how female hormones could affect asthma and its symptoms

  • Researcher: Professor Aziz Sheikh
  • Institution: University of Edinburgh
  • Start date: October 2016
  • Total cost: £50,000

Project title: Exogenous sex steroid hormones and asthma in females of reproductive age: a population-based prospective cohort study using the Optimum Patient Care Research Database

The UK ranks among countries in the world with the highest prevalence of asthma. The burden on families and society is substantial and is now a point of concern to policymakers. Identifying potential factors that can be modified through clinical interventions will be important for the prevention and management of asthma and allergy in the UK.

Asthma is more common in boys than in girls, but following puberty the risk is greater in females than in males. This suggests that the female sex hormones may play a role in the risk of asthma in females. To date, many studies into this have been poorly designed to clearly address this question and results have been contradictory.

Professor Sheikh recently analysed the Scottish Health Survey data and found that females of reproductive age who were using hormonal contraceptives had substantial reductions in asthma exacerbations and the number of care appointments they had with their GP. This suggests that it may be the fluctuations in hormone levels that lead to asthma symptoms, rather than the presence of the hormones themselves. Further examining this and the role that hormonal contraceptives could play in reducing asthma symptoms and severity will lead to a better understanding of this poorly researched area and could suggest potential treatment options.

Professor Sheikh now plans to undertake a more carefully designed epidemiological study using GP primary care data in the UK.

He will investigate whether external sex steroid hormones (such as those in hormonal contraceptives) have the potential for the management of asthma in females. If his findings from the analysis of the Scottish Health Survey are confirmed in this new study, Professor Sheikh’s ultimate goal is to then progress efforts towards testing whether external sex steroid hormones have any clinical benefits for the management of asthma in females.