NIHRDataInsights/HRCSData huggingface dataset:
Title: Optimising hospital discharge of children requiring long term ventilation
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: The purpose of this project is to further develop our core research team and collaborators and recruit engagement of sites for the NIHR study. The objectives are to 1. Develop a strong collaboration (clinical and research partnerships) with the Long Term Ventilation Working Group (LTV). 2. Establish a core research team from four UK devolved nations and Ireland that will be responsible for designing the study. 3. Obtain up to date numbers of long term ventilated children in UK and Ireland to inform selection and recruitment. 4. Develop a UK and Ireland national inventory of institutions and service providers (including private providers) managing children requiring LTV. 5. Identify recruitment sites and establish local PI’s. 6. Establish PPI relationships and engagement in the study.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: RESPIRATORY
Title: Burden of Obstructive Lung Disease (BOLD) Global coordinating centre.
Funder: Wellcome Trust

Abstract: Chronic Obstructive Pulmonary Disease (COPD) is an irreversible obstruction of the airways. It is a poorly recognised but common disease that is a significant cause of death and illness worldwide, but our understanding of its causes and distribution are very incomplete. Samples each consisting of 600 people or more (aged >39 years) will be randomly selected from populations of at least 150,000 in mainly middle and low income countries worldwide. We will measure how much air people can blow o ut of their lungs, and how fast, before and after using an inhaler that opens up the airways. Further information on demographics, symptoms, illnesses, disability and quality of life will be collected. Information on smoking, occupation, exposure to burning wood or other organic matter and other potential risk factors for COPD will be supplemented with local economic information. Analyses will estimate what percentage of each population has COPD and how severe their disease is. How COPD aff ects people's lives will be assessed and the likely financial and economic costs estimated. We will assess the strength of each risk factor and how much effect it is having in each population. This will provide essential information for prevention and treatment programmes for COPD.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: RESPIRATORY
Title: Epithelial/immune interactions underlying development and resolution of allergic airway inflammation and remodelling influence of genes and environment.
Funder: Wellcome Trust

Abstract: The central hypothesis behind this project is that the lung is held in balance by a complex series of interactions between the immune system which maintains the body s defence against infection and the lung epithelium which is the cellular barrier that protects the lung from the external environment. In asthmatic individuals the influence of genetic background and external environmental pressures works to disturb this balance so that innocuous environmental proteins such as house dust mite are c apable of inducing harmful inflammatory reactions within the lung. We hypothesise that the changes to lung structural cells, termed airway remodelling develop in parallel to these inflammatory reactions and both contribute to the decreased lung function that is characteristic of asthma. We will use mouse models of asthma to delineate the cellular and molecular pathways that result in this damage and establish how they are affected by age, infection or pollution. We will determine how some of t he genes thought to make individuals more susceptible to asthma affect these pathways. Moreover, we will investigate one candidate molecule called transforming growth factor beta in detail to determine whether it functions as a pro- or anti-inflammatory molecule within the lung epithelium of allergic mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Life course inequalities in asthma: estimating its burden and understanding its aetiology.
Funder: Wellcome Trust

Abstract: The purpose of this research is to describe the magnitude of inequalities in asthma throughout the life course and to identify the mechanisms that underlie them, thus providing means of reducing the burden of disease due to this condition and advancing the knowledge on its underlying causal risk factors. The term asthma groups a variety of symptoms together; separating these into more homogenous groups will help differentiate which exposures are most relevant in causing this condition. Only stud ies with very detailed information can do this. In this project some of the most informative birth and adult cohorts internationally will be used. Understanding the magnitude of asthma inequalities is key to measuring the extent of the inequitable burden of this condition on subgroups of the population. Understanding the mechanisms that generate these inequalities is key to reduce this burden in the population.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: RESPIRATORY
Title: Risk factors for asthma in Cuba: a cohort study.
Funder: Wellcome Trust

Abstract: Despite the fact that asthma is a common disease with a prevalence of 5-10% in children, the cause of asthma and associated allergic disease is unknown. It is evident that asthma is a disease that is associated with economic development or a 'western lifestyle', although the environmental factors that are responsible remain unidentified. Cuba is an unique society that has been governed by a communist governent for 50 years, remaining relatively economically isolated to the present day. Howeve r, the social services provided including healthcare and sanitation are good and life expectancy is comparable to that seen in the USA. The population living in Cuba have thus been exposed to a unique combination of environmental exposures which combined with the good primary care networks permit an ideal opportunity to investigate the risk factors for asthma and associated allergic disease. We propose to collaborate with the Institute of Epidemiology in Habana to establish a cohort of approx imately 2000 children recruited at the age of 12 months. These will be followed up for six years with the aim of identifying the main risk factors for asthma and allergic disease in this population.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: RESPIRATORY
Title: Role of IgE in the Pathogenesis of Non-Atopic Asthma.
Funder: Wellcome Trust

Abstract: An antibody called immunoglobulin E (IgE) plays a key role in asthma. In sensitive individuals, IgE captures specific allergens (e.g. grass-pollen allergens), which activates mast cells in the lung leading to the symptoms of asthma. Allergen sensitivities are identified by skin prick tests with common allergens. However, 30% of asthma patients, termed non-atopic , fail to respond to common allergens. We suggest that they have IgE antibodies for allergens that are confined to the lung, or that certain IgE molecules stimulate mast cells in the absence of allergen. Non-atopic asthma patients have the most severe disease and are the most difficult and costly to treat. We plan to analyse the underlying IgE mechanisms Our novel procedures may be adapted for clinical use to provide more incisive diagnosis and allow personalised therapies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: RESPIRATORY
Title: The functional importance of dysregulated alveolar steroid metabolism in acute and resolving lung injury.
Funder: Wellcome Trust

Abstract: Acute lung injury (ALI) is a devastating disease that has no specific treatment. It has a mortality rate of 40% and kills more people in the UK per year than either breast cancer or AIDS. This project aims to establish if an imbalance in the local levels of cortisol is present within the lung in patients with ALI. This may be important as we have tried to treat ALI with steroids in the past but this has proved unsuccessful. We hope that this research will identify a potential reason for the fail ure of steroid therapy in ALI, and to potentially identify novel targets for new treatments..


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Oxidative stress-induced inflammatory gene expression and ageing in COPD: role of sirtuin-1 and histone methylation
Funder: Wellcome Trust

Abstract: COPD, which includes emphysema and small airway obstruction, is one of the commonest diseases in the UK with a high mortality and is a common cause of disability with increasing healthcare spending. COPD involves chronic inflammation of the lungs that persists even when patients stop smoking and for which there are no effective anti-inflammatory treatments. COPD is slowly progressive and usually occurs in elderly patients. There is accelerated ageing of the lungs in COPD and we have shown that a n important molecule that counteracts the effects of ageing (sirtuin-1) is reduced in the lungs, probably as a result of increased oxidative stress. We wish to examine how oxidative stress reduces sirtuin-1 and what the consequences of this reduction are on lung inflammation. This is linked to our previous research looking at a related molecule called HDAC2, which is also reduced by oxidative stress. There is impaired production of antioxidants in COPD in response to increased oxidative stress a nd this may be mediated through suppressive effects of sirtuin-1 on a molecule (Nrf2) that controls antioxidant production and an enzyme Suv39H1 that increases inflammation, thus even further increasing oxidative stress and its inflammatory consequences. This may lead to novel treatment approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: The role of fibroblast hyaluronan in the modulation of innate immunity in the lung.
Funder: Wellcome Trust

Abstract: The hypothesis to be tested in this PhD is that fibroblasts (through the release of hyaluronan (HA) fragments) play an important role in dictating the immune status of the lung in the steady state, the severity of acute lung in flammation and that their influence is long lived. To test this hypothesis we aim to: 1) Examine the distribution of fibroblasts and myofibroblasts in the lung at steady state and during/following following inflammation in wild type mice and those lacking specific genes (CD200, OX40L, CD44); including their expression of high molecular mass HA and the release of truncated fragments into the airway lumen/lung interstitium. Note: human sputum specimens will be available to analyse HA fragments collected as part of the MOSAIC consortium from patients hospitalised due to Avian H 1 N 1 influenza infection; 2) Examine the ability of influenza infection to cause susceptibility to bacterial super infections in CD44 (the receptor for HA) depleted mice. 3) Define myofibroblast recruitment and immune pathophysiology to influenza virus and secondary bacterial super-infection in mice conditionally lacking HA synthase 2 (that controls HA expression)


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: RESPIRATORY
Title: The importance of airway epithelial integrity in fibrotic lung disease; direct and indirect effects of IL-33 on airway epithelium, fibroblasts and macrophages in response to airway damage.
Funder: Wellcome Trust

Abstract: Many chronic lung diseases are characterised by significant fibrosis including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and asthma but the cellular mechanisms, in particular early potentially reversible processes underpinning fibrosis, remain poorly understood and potent anti-fibrotic treatments are an unmet clinical need. It is thought that lung fibrosis encompasses a common response of dysregulated wound repair in response to persistent, repetitive injury to the airway epithelium. The IL-1 family of cytokines, in particular IL-33, have recently been highlighted as potential key players in this process. IL-33 expression is predominantly in ?lining? cells; epithelium, endothelium and fibroblasts and is elevated in several fibrotic conditions. To date, there is a paucity of data fully elucidating the role of novel IL-1 family cytokines to establish if they are a viable anti-fibrotic target in chronic respiratory conditions. This projects aims to establish an in vitro model to characterise the expression and release of IL-1 1 cytokine family, particularly IL-33, as alarmins in response to airway cellular damage, mimicking damage observed in disease states. The relevance of this in vivo will be established utilising the post lung transplant condition of obliterative bronchiolitis (OB). OB provides a window into other chronic fibrotic lung conditions but the increased rapidity of airway remodelling (loss of FEV1 >700ml/yr) which occurs in this condition provides an opportunity to evaluate the role of IL-1 family members in fibrosis from initiation to advanced disease enabling evaluation of IL-33, and other IL-1 family members, as a potential translational targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Receptor tyrosine kinase regulation of mast cell-airway smooth muscle beta2-adrenoceptor function in asthma.
Funder: Wellcome Trust

Abstract: Asthma affects 10% of the population and is an important cause of illness at all ages. Narrowing of the bronchial tubes (airways) is caused by spasm of their muscle, and produces breathlessness and wheezing. Reliever drugs called beta-agonists form an important part of asthma treatment by reversing/preventing muscle spasm in the airways. However, in some patients, beta-agonists do not work very well, and may make asthma worse. We believe (hypothesise) that the interaction of the airway muscle wi th another type of cell called the mast cell, releases chemicals which prevent beta-agonists from working properly. We will test this hypothesis by investigating the following: 1. The ability of mast cell and airway muscle-derived chemicals to inhibit beta-agonist function in these cells 2. The ability of mast cells and muscle when grown together to inhibit beta-agonist function in these cells 3. Whether expression of proteins that inhibit beta-agonist responses is increased in bronchial biopsies from subjects with asthma compared to healthy controls, and their correlation with clinical measurements such as the response to reliever therapy. This work has the potential to provide new treatments which target harmful proteins, and in turn improve beta agonist function and safety in asthma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Overcoming ethnic differences: A 3D approach to body physique for predicting lung function in children (suggested acronym: The SLIC [Size and Lung function In Children] Study).
Funder: Wellcome Trust

Abstract: Sophisticated statistical modelling and state-of-the-art technologies will be used to identify parameters of body physique that can better explain between-subject variability in Lung Function (LF) in young children across ethnic groups and socio-environmental exposures. This will allow development of more reliable prediction equations for children irrespective of ethnicity, thereby enhancing management of lung disease and reducing ethnic differentials in health provision. Spirometric LF and bo dy physique (shape, size and composition) will be measured in a multi-ethnic sample of ~1,600 London primary schoolchildren (5-10y). The extent to which clinically applicable measures of physique (standard anthropometry and bioelectrical impedance) can be used to substitute for high-accuracy methods (3D scans and isotopes respectively) will be investigated. Repeated measurements after 12m in healthy children (~80-90% of total population recruited) will facilitate interpretation of serial changes in children with respiratory disease. After adjusting for sex, age and standing height, the extent to which ethnic differences in LF can be minimised by including relevant measures of body physique will be determined. The potential influence of socio-economic, familial and environmental determinants (derived from parental questionnaires, health records, air pollution records and activity monitors) on LF, body physique and the relationship between the two will be investigated.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: RESPIRATORY
Title: Investigation into the role of VEGF (Vascular Endothelial Growth Factor) in the development of pulmonary fibrosis.
Funder: Wellcome Trust

Abstract: VEGF is a substance that is produced in large amounts in the air sacs of healthy lung and is thought to be important for maintaining the normal barrier that exists between the air sacs and lung blood vessels. Breakdown of this barrier plays a role in the development of pulmonary fibrosis (IPF), a devastating 'scarring' lung disease with a poor prognosis of 3-5 years. These facts have led me to suggest that VEGF may be important in IPF development. Fibroblasts are cells in the lung that are norm ally involved in scarring (or fibrosis) and I propose that different forms of VEGF may alter the activity of fibroblasts to allow IPF to develop. Evidence from a preliminary experiments show that VEGF and VEGF receptors are produced by fibroblasts and VEGF stimulates fibroblast growth. I propose to investigate the following: 1) identify/quantify the levels of VEGF and receptors produced by fibroblasts from healthy subjects and IPF patients and what factors can change them. 2)the effect of VEGF on normal and fibrotic fibroblasts growth and potential for inhibition 4)whether genetically modified mice, producing an inhibitory VEGF form, are resistant to a laboratory induced form of lung fibrosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: In-vivo testing of a novel rapid response intravascular fibre optic oxygen tension sensor to detect Cyclical Atelectasis and direct ventilator therapy inAcute Respiratory Distress Syndrome.
Funder: Wellcome Trust

Abstract: In the sick lung' which afflicts many critically ill patients on the Intensive Care Unit, air sacs (alveoli) can begin to collapse in expiration and snap open again in inspiration. This cycle repeats itself with every breath and is known as cyclical atelectasis. Mechanical ventilation of the lungs exacerbates this process and can cause further mechanical lung damage, and this can induce an inflammatory reaction which affects and damages other body organs. The mortality from ARDS is 30-50%. It is well established that prevention of cyclical atelectasis, by manipulation of the way in which ventilation is delivered, is beneficial to patients. The problem is that clinicians have no reliable and direct means of knowing when the process is occurring or if it is responding to therapy. We believe that the presence of oxygen oscillations' (breath by breath variations in the pressure of oxygen) in arterial blood can be used to detect the occurrence of cyclical atelactasis in the lung. Clinicians could use such a signal to adjust the ventilator settings guided by the amplitude of the oscillations thus minimising the atelactasis and mitigating the cascade of deleterious effects. Our proposed rapid-response oxygen sensor will measure these oxygen oscillations in real time.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Differential tumour necrosis factor receptor (TNFR) activation in acute lung injury (ALI).
Funder: Wellcome Trust

Abstract: Acute lung injury, which commonly follows severe pneumonia, is associated with critical illness and kills approximately 40% of sufferers. Despite 40 years of investigation, there are currently no treatments for this common lethal condition. The work of our collaborators suggests that targeting a specific mediator (tumour necrosis factor: TNF) of lung injury may help to halt the progression of lung damage. We have a unique opportunity to study the effects of a new drug that we believe blocks the most damaging effects of TNF (gifted to us from the manufacturer) in a new model we have developed that allows us to study and injure human lungs that we can keep alive outside the body after death. The results of our work will characterise the role of a key mediator of acute lung injury and help to establish a new model for studying this condition. Ultimately we hope to develop new drugs to treat patients with this lethal condition.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Wellcome Trust Clinical PhD Programme at Imperial College London: 'The critical role of lung-marginated monocytes in transplant-associated acute lung injury'.
Funder: Wellcome Trust

Abstract: Lung transplantation is often the only option remaining for lung disease sufferers. There is a shortage of donor organs available and the procedure itself is high-risk and complicated by the lungs functioning poorly, or failing, soon after transplantation. It has long been thought that this is due to injury to the lungs from being temporarily without a blood supply, known as ischaemia (e.g. during transportation),in combination with the reintroduction of blood in the recipient, known as reperfusion. More recent evidence suggests that lungs may be inflamed whilst in the donor (donor lung inflammation (DLI)), predisposing them to more severe injury from ischaemia reperfusion. This may occur if lung donor patients are exposed to infection, artificial ventilation or stomach contents entering the lung whilst unconscious. We hypothesise that DLI predisposes lungs to a more severe injury after ischaemia-reperfusion and thus are likely to function poorly or even fail post-transplantation. We have setup an experimental model using a mouse lung to replicate this process and allow us to identify the exact mechanisms, determine the predisposing factors and look at potential therapeutic avenues for attenuating such an injury, and ensuring recipients have the best chance of success with their new lungs.


Research activity codes: 6.4 SURGERY
Health categories: RESPIRATORY
Title: Manipulation of wnt/beta-catenin signalling to improve airway regeneration in tissue engineered constructs.
Funder: Wellcome Trust

Abstract: Patients with irreversible damage to the throat and windpipe region have limited treatment options, and whilst reconstruction is possible patients are often left with the misery of being unable to talk or swallow. Tissue- engineering organs is an attractive solution and increasingly viable, demonstrated by our groups recent success in transplanting the worlds first stem-cell grown windpipe. Despite the life saving clinical success, a number of hurdles exist before this technology can be translat ed to every day clinical practice. Namely there is a pressing need to improve regeneration of cells lining these constructs to stop scarring and infection and help with cough, speech and swallowing. This project aims to improve regeneration by promoting the growth of a complete and functioning graft lining using stem cells. In my proposal I will identify the key cells necessary for regeneration and the intracellular triggers that make this happen. My results will help to provide strategies to im prove regeneration in the airways and define methods to improve the construction of tissue engineered organs.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: RESPIRATORY