NIHRDataInsights/HRCSData huggingface dataset:
Title: Adenovirus-CAR interaction: a model to probe cell adhesion dynamics in normal and asthmatic airway epithelium.
Funder: Medical Research Council

Abstract: The study sets out to identify how Coxsackie and Adenovirus Receptor (CAR) functions in bronchial epithelial cells in order to create tight junctions and then focus on how this plays a role in patients with asthma. In order to address this question, bronchial epithelial cell lines have been developed that either over or under express CAR. These will then be challenged by biologically relevant cytokines (including IL 5 & 13) to determine the importance of CAR in their response. This will be undertaken by several methods, including western blotting and a variety of imaging techniques. Importantly a more physiologically relevant model will be incorporated into the project to provide additional insights. An organotypic model will be used as this will grow the epithelial cells in a three dimensional structure to mimic to some degree the natural environment found in airways. The study will also create phosphorylation specific antibodies and test with further imaging and biochemistry techniques for the integrins and structural proteins activated and controlled by CAR localised to junctions. Finally primary cell culture and histological staining of normal and asthmatic patients bronchial samples will determine whether our greater understanding of changes in CAR function are playing a key role in the biology of asthma. These advances will have a broad range of benefits for other scientists as a greater understanding of the importance of CAR in tight junctions will advance all work in the complicated biology of epithelial cell interaction. Given that defects in this epithelial interaction, in particular tight junction formation, have been shown to be relevant to many disease processes such as asthma and cancer biology there are also opportunities for identifying new targets for medical treatments.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFECTION
Title: Defining the effects of transplant immunosuppressants on innate immunity to fungi
Funder: Medical Research Council

Abstract: Aim: To define the effects of the calcineurin inhibitor FK506 on innate immunity to aspergillosis Objectives: 1. Define the effects of FK506 on innate immunity to A. fumigatus in vivo. Methodology: Outcome from pulmonary aspergillosis will be characterised in wild-type C57BL/6, Rag2 -/-, Dectin-1 -/- and Myd88 -/- mice immunosuppressed with FK506/control. This will enable the effects of FK506 on the innate host response to aspergillosis to be determined and whether these effects are mediated via TLRs or Dectin-1 fungal pattern recognition receptors. 2: Characterise the effects of FK506 on A. fumigatus phagocytosis Methodology: Alveolar macrophages and neutrophils will be isolated from C57BL/6, Dectin-1 -/- and Myd88 -/- mice, treated with FK506/control, and challenged with A. fumigatus conidia. Phagocytosis efficiency and killing will be determined by flourescence microscopy and culture. Killing defects will be further characterised by time-lapse microscopy, ROS and NO assays. 3: Identify the pathways required for calcineurin-dependent phagocytosis of A. fumigatus Alveolar macrophages/neutrophils will be isolated from C57BL/6 mice and challenged with A. fumigatus after treatment with FK506/control. Calcineurin-dependent signalling pathways will be identified by transcript profiling. The role of identified pathways in fungal killing will be defined by siRNA. Aim 4: Validate key observations in lung transplant patients with aspergillosis Key observations identified in components 1 to 3 will be validated in alveolar macrophages and neutrophils from lung transplant patients with pulmonary aspergillosis and controls. Scientific and medical opportunities: These studies will advance our understanding of how the main transplant immunosuppressive FK506 impairs innate fungal immunity. These findings will have broader implications for the role of the calcineurin pathway in innate immunity to other infectious diseases and transplant rejection.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY;INFECTION
Title: The roles of Pellino-1 in the control of airway viral infection.
Funder: Medical Research Council

Abstract: Exacerbations of asthma and COPD are triggered by viral infections. We have shown that an E3 ubiquitin ligase, Pellino-1, regulates inflammatory responses to rhinoviruses. Our hypothesis is that Pellino-1 is expressed in the human airway, regulated in disease and during viral infection, and its knockdown will reduce responses to airway viral infection with rhinovirus without impairing control of viral replication. Objective 1: To examine Pellino-1 expression in tissues from patients with varying levels of severity of COPD, and patients with asthma. Data will be paralleled by a study of human viral infection, determining Pellino-1 expression in the nasal respiratory epithelium during an active viral infection. Objective 2: To explore the roles of Pellino-1 in vivo. We have generated collaborations providing access to a Pellino-1 knockout mouse, and will establish models of rhinoviral infection. These models will allow us to determine how Pellino-1 regulates inflammation in a dynamic model of viral infection, complementing the static and dynamic expression studies in objective 1. Objective 3: Explorations of how Pellino-1 regulates signalling in human cells. We will identify the binding partners of the Pellino-1 protein through a mass spec approach, and explore in detail how Pellino-1 regulates key aspects of responses to viruses, focusing on control of epithelial apoptosis and inflammatory signalling. Critical assays will be repeated in primary cells from patients with asthma and COPD, in order to determine whether disease modifies roles for Pellino-1. These studies will allow us to further our understanding of the roles of Pellino-1 in the control of viral infections. Through a combined in vitro and in vivo approach, in which the human studies of tissue, virally-infected cells, and virally-infected patients parallel studies in the mouse, we will explore the biology of Pellino-1 and the pathways it regulates, in order to enable its therapeutic targeting.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFECTION
Title: Defects in alveolar macrophage innate immune function and increased susceptibility to pulmonary infections in HIV-infected adults
Funder: Wellcome Trust

Abstract: HIV-infected adults have increased susceptibility to lung infections caused many pathogens. This is a consequence of the effects of HIV on lung immunity. HIV targets mainly two types of immune cells: T-lymphocytes and macrophages (phagocytes). In the lung HIV targets alveolar macrophages (AM) as the host phagocyte of choice. AM are the predominant phagocytes in the lungs and the first line of defence against infections acquired through the respiratory route. They function as primary scavengers of particulate material that penetrate deep into the lung. The high incidence of pulmonary infections in HIV-infected individuals suggests strongly that HIV impairs the ability of AM to clear infections. To assess the effect of HIV on inherent AM immune function, we propose to conduct a comprehensive analysis that exploits new and rigorously quantitative methods for assessing phagocyte function. This will be achieved by 1) conducting a broad screen to detect how HIV infection modulates inherent AM immune function, 2) determining if pulmonary infections exacerbate HIV-induced impairment of AM function, and 3) determing the mechanisms behind any defects in AM function.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFECTION
Title: The effect of inhaled corticosteroids on viral and bacterial infection in chronic obstructive pulmonary disease.
Funder: Wellcome Trust

Abstract: Chronic obstructive pulmonary disease(COPD) is a common, disabling disease, which is characterised by acute flare-ups(exacerbations). Inhaled steroids are frequently used to treat patients with COPD as they have been shown to reduce exacerbations, which are mainly caused by viral infections. However, there has been some criticism over the studies that have assessed steroid inhalers in COPD and some experts feel that they may not be of benefit in this condition. In addition, some studies have rep orted increase in complications such as pneumonia (mainly caused by bacterial infection) associated with their use. Our study will use an experimental mouse model, which shows many similarities to human patients with COPD, to assess the effects of inhaled steroids on viral and bacterial infection and to determine if they have any effects on the immune system's ability to fight infection. We will assess whether steroids have a beneficial or detrimental effect on respiratory infections. This research will be potentially very important as it will give unique insight into the effects of inhaled steroids and mechanisms involved and could help clinicians to decide on whether widespread use of these drugs in COPD should continue and whether the concerns over their use are justified.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY;INFECTION
Title: Procoagulant signalling in Streptococcus pneumoniae induced acute lung injury.
Funder: Wellcome Trust

Abstract: The bacterium Streptococcus pneumoniae is a common cause of chest infections and of acute lung injury (ALI). There are no effective therapies for those who develop ALI and 35-50% of patients die despite supportive care. Evidence suggests that there is a link between developing ALI and the proteins responsible for blood-clotting. More specifically, the link between ALI and blood clotting involves a cell surface receptor, termed proteinase-activated receptor-1 (PAR1). Activation of this receptor b y blood clotting promotes inflammation, a major cause of ALI. Preliminary data from the host centre suggest that blocking PAR1 reduces inflammation in the lungs and so should protect against ALI. I will perform experiments in a mouse model of disease to confirm that blocking PAR1 reduces lung inflammation following S. pneumoniae induced-ALI without causing more infection. This fellowship project will determine whether blocking PAR1 could be an effective treatment of ALI. Further studies with hum an lung cells will then allow me to discover the exact biological mechanisms involved.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFECTION
Title: Discovering the role of mucosal associated invariant T cells in respiratory immunity.
Funder: Wellcome Trust

Abstract: Patients with airways diseases such as asthma and chronic obstructive pulmonary disease (COPD) suffer from exacerbations which are usually triggered by infections. Respiratory infections cause 6% of global human disease, being the second leading cause of years of life lost whilst COPD and pneumonia are ranked as the 3rd and 4th leading causes of mortality worldwide. It is not well known how microbes trigger these exacerbations or the development of pneumonia. I have found that a new type of immu ne cell, called MAIT-cells, is deficient in the lungs of asthmatics which may explain their high risk of infection. My aim is to study these cells in-depth in the lungs of people with frequent chest infections to determine the consequences of this deficiency and how these cells respond during lung infection. I will combine this with other laboratory based models to study the role of these cells in protecting against the development of pneumonias which frequently follow after viral infections. If I achieve my goal we will better understand the immune responses which protect us from lung infections. Such knowledge may help to develop new treatments to prevent exacerbations of lung diseases and could lead to the development of improved vaccines.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFECTION
Title: Opportunity-Led Research Proposal: Microbial community composition in the airways of patients with chronic lung infection
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Research by The CF & Airways Microbiology Research Group at Queen’s University Belfast, jointly led by Prof.essors Elborn and Tunney, is focused on the improved detection and treatment of polymicrobial infection in patients with chronic respiratory diseases such as Cystic Fibrosis (CF), non-CF bronchiectasis and chronic obstructive pulmonary disease (COPD). This high impact, ground-breaking research is translational in nature with novel methodologies used in clinical studies to address important clinical questions directly impacting the health of patients. This is combined with investigations into the normal airways microbiome and how this is altered in CF and bronchiectasis. We have published extensively in this area in leading and high impact Journals (1-8). We are currently working on a US-Ireland R & D Partnership Project Grant, funded by the HSC R & D Office, to study the role of anaerobic bacterial infection in CF. This research programme is the largest single study ever undertaken to investigate the microbiology of CF airway infection, with over 170 CF patients and 50 healthy controls recruited in Northern Ireland and samples processed at multiple timepoints from each CF patient. The proposed application for ‘Opportunity-Led Research’ funding is to cover consumable costs associated with further and more detailed analysis of samples collected as part of this study. Funding is also requested to cover the costs associated with a further project which will complement and add considerable added scientific and clinical value to the work being undertaken in the US-Ireland study. This pioneering new project is in collaboration with the KU Leuven (Belgium), a World-leading Transplant Centre, and will determine microbial community composition in explanted lungs collected from patients with a range of chronic respiratory conditions.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFECTION;CONGENITAL DISORDERS
Title: Investigating how the presence of neutrophils in the lungs prior to infection with respiratory viruses can exacerbate disease severity in mice
Funder: Wellcome Trust

Abstract: Respiratory viruses such as RSV, influenza viruses and the recently emerged SARS-CoV-2, represent a major global burden to public health. While infection with such viruses will often only result in mild “cold-like” symptoms, many will result in severe disease and require hospitalisation. Why some people get seriously ill while others only develop mild symptoms is not yet understood. Recent studies in both humans and mice have suggested that the presence of white blood cells, known as neutrophils, in the lungs prior to infection with respiratory virus results in more severe disease. The aim of this project is to investigate how the presence of these neutrophils alter the immune response to respiratory virus and ultimately how this drives more severe disease. To achieve our aims, we will use mouse models to characterise how and which parts of the immune environment in the lung that is changed by the presence of neutrophils prior to infection with respiratory virus and how this influence the severity of disease. This work will help us to better understand why some individuals are more at risk of severe disease following respiratory viral infection and help the development of effective treatments and vaccines.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of Endoglin in the development of pulmonary complications of scleroderma
Funder: Arthritis Research UK

Abstract: In scleroderma, pulmonary disease represents one of the most prevalent and serious disease complications. Two main areas of lung disease have been identified. Damaged to the pulmonary vasculature, which presents as pulmonary arterial hypertension (SSc-PAH), and scarring of the interstitial lung tissue in pulmonary fibrosis (SSc-PF), often leading to secondary pulmonary hypertension. These manifestations are the main cause of morbidity and account for up to 60% of all scleroderma-related deaths. Evidence from clinical studies of these two pathologies strongly implicates the loss of normal cellular responses towards transforming growth factorβ(TGFß) as an important contributing factor in disease pathogenesis. Endoglin is a critical TGFß co-receptor which differentially regulates TGFß signalling determining key cell responses. In preliminary studies we have shown altered tissue expression, distribution and shedding of cell surface endoglin, along with elevated circulating levels of soluble endoglin in scleroderma. Here, the objectives are to fully assess endoglin expression and levels in scleroderma, correlate with disease activity, delineate the transcriptional regulatory mechanism(s) and examine the role of endoglin isoforms in vascular barrier function and tissue remodelling. Finally, genetic manipulation of endoglin in pre-clinical models of PAH and PF will highlight the impact of endoglin on disease pathogenesis in vivo.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: Single-cell analysis of the local nasal B cell response to allergen immunotherapy.
Funder: Asthma UK

Abstract: <p>Allergen immunotherapy (AIT) represents the most promising approach for the prevention and cure of allergic asthma. While the basic mechanisms of allergen immunotherapy are becoming clearer, there remain gaps in our understanding. The effects of allergen immunotherapy on local mucosal B cells are poorly defined, this is despite the clear importance of the allergic mucosa in the generation and persistence of allergen-specific IgE. This study will provide a fundamental understanding of the mechanisms underlying the effects of AIT on the allergen-specific B cell response in the target organ, revealing how to improve this treatment and perhaps prevent the disease. Nasal biopsies will be obtained from patients enrolled in a clinical trial of sublingual AIT before and after 12 months of treatment. Dissociated biopsies will be subjected to multi-colour flow cytometry to phenotype the nasal B cell population. Single B cells will then be FACS sorted, using index-tracking, into individual wells. Matched heavy- and light-chain sequences from single nasal B cells will be amplified by PCR and cloned into antibody expression vectors. Recombinant antibodies will be characterised for a specificity, affinity and function. The characteristics of the resulting antibodies will be related to B cell phenotype to investigate whether particular subsets of B cells are associated with characteristic antibody responses. This information will be used to develop biomarkers of successful immunotherapy and lead to better understanding of the local B cell response to treatment and changes in practice.</p>


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: Contribution of Innate lymphoid cells to steroid resistance in paediatric asthma
Funder: Asthma UK

Abstract: <p>Asthma remains a common childhood disease, and for a significant number of children is a serious problem resulting in numerous hospital visits and missed school. We have determined that children with severe therapy resistant asthma (STRA) exhibit abnormal lung function, eosinophilia, airway remodelling in the absence of detectable levels of Th2 cytokines. Moreover these patients remain symptomatic even when taking high dose steroids.&nbsp; This project will test the overall hypothesis that innate lymphoid cells (ILC) are present in the lungs of children with STRA and contribute to resistance to steroids. Innate lymphoid cells are thought to be involved in the development of acute allergic inflammation in mouse models of asthma and have been detected in lungs from adult asthmatic patients. We will characterise ILC populations in children with STRA, by determining their molecular phenotype and cytokine secretion pattern, using FACS as well as immunohistochemical staining and confocal microscopy. Our preliminary data indicates that we can find ILCs in bronchiolar lavage from children undergoing clinically indicated bronchoscopy however they are present in small numbers. In order to perform functional analysis and determine if innate lymphoid cells in the airways mediate steroid resistance we will isolate ILCs from tonsils collected as part of routine tonsillectomy from asthmatic and non-asthmatic children. &nbsp;We will determine how steroids influence the cytokine secretion patterns of in vitro cultured ILCs. We will also assess the number and phenotype of T cells and innate lymphoid cells in sputum samples collected from severe asthmatic children undergoing treatment with triamcinolone over a four month period. This will enable us to directly test the longitudinal effect of steroids on ILC phenotype. The results from this study will provide significant insight towards understanding of the role of ILCs in the development of childhood STRA, and the particular influence of steroids on their function.&nbsp; Ultimately this work will enable us to tailor therapy towards steroid resistant phenotypes in children.</p>


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM
Title: Novel approach to inhibit Amphiregulin activity in order to prevent inflammation-associated airway remodelling.
Funder: Asthma UK

Abstract: <p>Asthma affects millions of people worldwide and is associated with significant morbidity despite treatment with corticosteroids. Chronic asthma is tightly linked with enhanced tissue remodeling, for which the EGF-R has been shown to be of crucial importance. We reported recently that one of the EGF-R ligands, Amphiregulin, is a type-2 cytokine. In the lungs, Amphiregulin is expressed by mast cells, basophils and type-2 innate lymphoid cells (ILC2), and high levels of Amphiregulin are found in the sputum of asthma patients. Our recent data show that this EGF-like growth factor is a central mediator of myofibroblast differentiation and tissue remodeling during the chronic phase of asthma.</p> <p>In this proposal, we will develop strategies to pharmacologically interfere with the function of Amphiregulin in the lungs. We thereby will use inhibitors that specifically will prevent the processing of Amphiregulin into its functional form. These inhibitors will then be developed further and be tested for their therapeutic efficacy to prevent tissue remodeling in a chronic bronchial antigen-exposure model.</p> <p>We expect these studies to result in a new type of drug that can be applied to interfere with the process of tissue remodeling in asthma patients.</p>


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM