NIHRDataInsights/HRCSData huggingface dataset:
Title: Mechanisms, impact and therapeutic targeting of bacterial colonisation in COPD
Funder: Medical Research Council

Abstract: Lower airway bacterial colonisation (LABC) affects approximately 50% of patients with COPD at all stages of disease and may be important in driving inflammation and impairing the resolution of inflammation. Our central hypothesis is that defective innate and/or adaptive immunity (impaired macrophage and neutrophil phagocytosis and killing of bacteria or humoral and cellular responses) results in failure to clear bacterial and apoptotic cells from the lower airways in smokers who develop COPD. We suggest that the resulting LABC (usually with Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis) drives a persistent inflammatory response, which is resistant to cues for resolution of inflammation. This collaborative application brings together major UK centres with expertise in COPD mechanisms, microbiology and immunology. We aim to explore the links between LABC, chronic inflammation and clinical outcomes, including exacerbation frequency and disease progression in COPD patients. We will determine the prevalence and impact of LABC in COPD patients at all stages of the disease and examine how this may reflect impaired innate immunity and resultant chronic inflammation and altered immune responses. We will elucidate the molecular mechanisms for reduced bacterial phagocytosis and killing reported in alveolar macrophages, monocyte-derived macrophages (MDM) and circulating neutrophils and for the impaired clearance of innate immune cells (efferocytosis) in order to identify novel therapeutic targets. Preliminary studies have identified abnormalities in microtubular stability and sphingosine-1-phosphate signalling in defective bacterial clearance by macrophages that are reversible in-vitro. Delays in macrophage apoptosis also reduce bacterial clearance and can be targeted therapeutically. We will investigate the effect of reducing LABC in COPD patients with antibiotic therapy (oral and inhaled) on inflammation and immune responses as proof-of-concept. Finally, we will perform PoC studies in COPD patients with drugs identified as correcting defective bacterial clearance in COPD cells, including microtubule stabilisers, sphingosine signalling inhibitors and apoptosis modulators. We will study carefully phenotyped COPD patients from existing well characterised cohorts and collaborate closely with other work packages of the consortium. We will interact closely with several industrial partners who have agreed to provide tool compounds, technological skills, data analyses and expertise in trial design. This proposal represents a series of focused and deliverable projects that, through collaborative scientific discovery, will act as a unique platform for therapeutic translation. We believe that exploring LABC and abnormal innate immunity will enhance understanding of disease mechanisms and identify new therapeutic approaches and provide novel biomarkers for the assessment of new treatments.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: A tissue engineered construct to monitor mucosal immunity in asthma
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Asthma is a common lung disease characterized by wheeze and shortness of breath. It affects 5.1 million people in the UK, with an annual health care cost of £2.5 billion and 20 million working days lost. It is widely accepted in academia and industry that the ability of animal models to generate novel treatments in asthma has been disappointing. This may be because animal models fail to mimic key genetic and environmental interactions that cause the human disease. However, current alternatives using isolated human cells or tissues are relatively simplistic, and lack the dynamic influx of blood cells from the circulation that normally occurs in tissues in vivo. Thus, our multidisciplinary project will incorporate cells taken from the blood and airways of asthmatic volunteers into a microfluidic platform to enable delivery of blood cells to a tissue engineered construct comprising an endothelial (blood) and epithelial (airway surface) barrier. Our constructs will be integrated with multiparametric monitoring systems to assess the influx of blood cells into the tissue in response to viruses and air pollutants that trigger asthma attacks. This system has the potential to reduce the need for animals in target discovery and in screening new treatments for asthma


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Habitual Gait Speed: A Novel Marker of Exercise Intolerance and Prognosis in COPD
Funder: Medical Research Council

Abstract: Chronic Obstructive Pulmonary Disease (COPD) is responsible for over 25,000 deaths in the UK annually and is predicted by 2020 to be the third leading cause of death and the fifth leading cause of disability worldwide. The Forced Expiratory Volume in 1 second (FEV1) is the only physiological marker acceptable to new drug regulatory authorities. However FEV1 has several limitations. COPD is a heterogeneous disease, and FEV1 is relevant to only some of the patho-physiological processes and does not address systemic manifestations such as skeletal muscle dysfunction or the influence of co-morbidities. The minimal clinically important difference for FEV1 has not been universally established, and although FEV1 correlates with mortality, this correlation is weak. In advanced disease, FEV1 has little predictive value. In healthy older people, habitual gait speed (over 4 metres) predicts loss of independence, falls, nursing home admissions, dementia and death. Reasons for a slowing of habitual gait speed include lung function decline, skeletal muscle dysfunction secondary to sarcopaenia and de-conditioning, worsening dyspnoea, the presence of co-morbidities, poor balance, mood disorder and cognitive decline ? all factors observed in COPD. The proposed research study aims to evaluate the validity of gait speed as a marker of exercise intolerance and prognosis in COPD. Stable COPD patients will perform the 4-metre gait speed on two separate occasions a week apart to calculate inter-observer and inter-occasion reproducibility. Gait speed in COPD patients will be compared with healthy, age-matched, never smoking controls. The association between gait speed and existing measures of exercise capacity (both walking fields test and treadmill / cycle ergometry tests) will be assessed. The ability of gait speed to predict early hospital readmission in hospitalized patients at discharge following acute exacerbation of COPD will be prospectively evaluated. Furthermore, the ability of gait speed to predict mortality will be prospectively assessed in a cohort of 300 stable COPD patients followed up for a minimum of two years. Additional validated markers are required in COPD to provide a more comprehensive and clinically meaningful assessment of patients, particularly of the extra-pulmonary manifestations of the disease. The proposed research should be of interest to clinicians involved in the care of COPD patients, and also to the pharmaceutical industry as a validated marker of functional capacity and prognosis could guide the development and assessment of new therapies for COPD, particularly those where the primary focus is not on the lung.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Extra-cellular matrix inducible collagenase activity in asthma: a potential drug target against airway remodelling.
Funder: Medical Research Council

Abstract: Despite current therapies, patients with asthma develop progressive structural airway changes termed airway remodelling leading to airflow obstruction, bronchial hyper responsiveness, and worsening asthma symptoms Airway smooth muscle (ASM) hyperplasia and increased extracellular matrix deposition are key features of remodelling, with collagen I and tenascin-C particularly over expressed. We and others have shown that matrix factors enhance ASM proliferation, survival and strongly induce the expression of matrix metalloproteinase-1 (MMP-1), a collagenase causing increased airway contraction in model systems Here we will test the hypothesis that collagen I and tenascin-C increase MMP-1 activity worsening airway responsiveness and asthma symptoms Studies will be conducted in patients and primary ASM obtained from three groups: normal volunteers, those with asthma and mild BHR (methacholine PC20 5-8mg/ml) and those with asthma and moderate to strong BHR with a methacholine (PC20 less than 1mg). Patients will be evaluated for asthma control and airway function and will undergo bronchoscopy, bronchial washings and airway biopsy. ASM cells will be cultured from patients and used in the following studies. We will investigate the receptors and signalling pathways linking collagen I and tenascin-C to increased MMP-1 transcription, the proteases are responsible for MMP-1 activation and if this is different in asthma derived cells. To determine if enhanced MMP-1 activity increases airway contraction we will use a lung slice model. Lung slices from normal animals and those over-expressing MMP-1 will be treated with chronic allergen exposure to develop airway remodelling and the response to contractile agonists determined. Finally we will examine the effect of collagenase activity on airway contraction in human asthma: firstly by studying the expression and co-localisation of MMP-1, collagen I and tenascin C in the airways of patients with asthma by immunohistochemistry and in situ zymography. We will then examine if MMP-1 protein and collagenase activity in bronchial washings and biopsies are associated with airway reactivity as determined by bronchial reactivity and methocholine and peak flow variability using multiple logistic regression in different asthma phenotypes. The experiments will determine the role of these matrix factors in remodelling, particularly with regard to airway contraction and highlight targets for therapeutic intervention.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Defining the importance of IL-25 in rhinovirus-induced asthma exacerbations
Funder: Medical Research Council

Abstract: We hypothesise that rhinovirus infection induces IL-25, which in atopic asthmatics, amplifies Th2 responses in the airways causing asthma exacerbations. To test this hypothesis we will employ two state of the art in vivo models. First a human model of experimental rhinovirus infection in atopic asthma and healthy subjects. This will enable us to assess RV-induced IL-25 expression during asthma exacerbations and also to compare production in asthma and healthy subjects. Furthermore we will be able correlate IL-25 production with Th2 responses, mucus production, clinical illness severity and virus load. IL-25 protein will be measured in airway lining fluid by MSD and in bronchial biopsies by immunohistochemistry. IL-25 gene expression analysis of bronchial epithelial cells taken during bronchoscopy will also be undertaken. This study will be the first to assess the role of IL-25 in asthma exacerbations and be an important addition to the few published human studies. We also plan to use mouse models of RV infection and asthma exacerbation in which we can manipulate IL-25 activity and monitor Th2 immune responses and asthma-relevant markers of airways disease. Initially we will study rhinovirus infection (minor and major group) and IL-25 expression (gene and protein) in the lung using mouse infection models previously developed by us. Next we will use a model of rhinovirus induced exacerbation of allergic airways inflammation also previously developed by us. This will enable us to investigate the effect of RV infection and allergen challenge on IL-25 expression. Using a neutralising mAb we will determine the role of IL-25 in mediating AHR, Th2 immunity and airways disease in the exacerbation of allergic airways disease model. Administering the IL-25 neutralising mAb to an IL-13- reporter mouse will enable evaluation of the role of IL-25 on IL-13 expression. If IL-25 expression is induced and related to disease outcomes in the human model, AND causally related to Th2 mediated disease outcomes in the mouse in vivo model this cytokine will be a good target to direct development of novel treatments for RV-induced asthma exacerbations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Developmental Clinical Studies - development of vitamin D therapy to prevent acute lung injury.
Funder: Medical Research Council

Abstract: ALI is a major cause of respiratory failure in critically ill patients. Most patients affected are of working age and survivors experience a significant reduction in health-related quality of life, with 46% unable to return to work within 12 months. Currently, apart from protective ventilation strategies, no therapy has been conclusively proven to reduce mortality or improve functional outcome in survivors. Clearly this represents a major unmet health need. ALI is the final common pathway of response to a variety of direct pulmonary insults such as bacterial /viral pneumonia and gastric aspiration, or indirect insults such as abdominal sepsis or battlefield trauma. However, only a relatively small proportion of patients develop ALI, with research suggesting that genetic, demographic (age), social (smoking, alcohol abuse) and other factors play a role in determining who develops ALI. Patients undergoing transthoracic oesophagectomy are at significant risk of developing post operative lung injury (~28%), with the development of lung injury associated with a doubling of in hospital stay and significant mortality.Hospital episode statistics show that ~1500 to 2000 oesophagectomies are performed in England annually. There are no current readily available tests that can clearly identify those who are at high risk of ALI following oesophagectomy, and no therapeutic interventions proven to prevent its occurrence. Epidemiological studies have suggested a role for vitamin D deficiency in the risk of developing both viral and bacterial infection. Vitamin D has profound effects on human immunity acting as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the ?oxidative burst? potential of macrophages, therefore enhancing bacterial killing. In preliminary studies we have found that vitamin D deficiency/ insufficiency is ubiquitous in both patients with ALI and oesophagectomy cases who are at risk of ALI. Severe deficiency is associated with elevated systemic inflammatory response and an increased risk of developing lung injury in the oesophagectomy group. This proposal aims in a series of clinical studies to determine the proof of concept and optimal dosing strategy for administering cholecalciferol liquid preoperatively to prevent lung injury in oesophagectomy using established markers of bioactivity /efficacy in the setting of ALI. The proposed treatment is simple and if effective could be easily incorporated into widespread clinical practice. The results from this trial will provide the basis for future clinical studies investigating this and other preventative strategies in broader subject groups known to be at risk of ARDS such as pneumonia and sepsis.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: RESPIRATORY
Title: MRC-GSK Alliance: Mechanisms of interplay between allergy and viruses in asthma
Funder: Medical Research Council

Abstract: We apply to form an Alliance between GSK and the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma to discover and develop new approaches for prevention/treatment of asthma and asthma exacerbations. We will integrate research in areas of major strength for the Centre with the strengths in asthma drug discovery at GSK. The overall aim is to investigate mechanisms of interplay between allergy and virus infection in development of asthma and in acute asthma exacerbations. We will use human rhinovirus (RV) infection in asthmatic and healthy subjects to investigate roles of pre-existing/induced IgE, Th2 responses and RV infections in augmenting allergic responses in humans in vivo, alongside mouse models studies of breakdown of immune tolerance by virus infection and of virus exacerbation of allergic airway inflammation, to discover novel mechanisms where not technically possible in humans, and to investigate causal relationships with outcomes in vivo. Candidate mechanisms/drugs in GSK pipelines will then be tested in the mouse models above. We will investigate: 1. epigenetic modifications induced by RV infection in bronchial epithelial cells (BECs) ex vivo and mRNA/miRNA expression profiles of BECs and bronchoalveolar lavage macrophages, dendritic cells (DCs) and CD4+ T cells at baseline and during RV infection in vivo to identify molecules/pathways implicated in promoting Th2 responses. 2. whether RV infection in vivo increases production and affinity of IgEs against previous allergens and generates new allergen specificities (epitope spreading) by somatic hypermutation, receptor revision, class switching and affinity maturation leading to expansion of allergen-specific high affinity IgE-expressing B and plasma cells. We will determine whether RV induction/modification of these molecules/processes are related to pre-existing IgE levels/specificities or Th2 responses and virus load, clinical severity of asthma exacerbation (airway inflammation, symptoms, lung function and airway hyperresponsiveness) in vivo. We will purify lung DCs from the virus-induced breakdown of tolerance model to identify mRNA/miRNAs in DCs implicated in tolerance breakdown and determine whether these are replicated in lung DCs in the human model in vivo. Finally we will determine whether antagonism/agonism of molecules implicated in virus induced augmentation of Th2/IgE responses/tolerance breakdown in vivo, results in increased/decreased breakdown of immune tolerance or severity of RV induced exacerbation of allergic airway inflammation in mice in vivo. Accomplishment of these aims will identify targets for development of novel therapies for asthma and asthma exacerbations and will provide early proof of concept testing of some of these targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Refining models of fibrotic lung disease
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: IPF is a chronic, progressive, fibrotic lung disease of unknown aetiology with a median survival of less than 3 years and no proven, effective therapy. Furthermore, there has been a progressive increase in the incidence of IPF since the early 1980s. A major bottleneck in IPF research is the absence of a pre-clinical model that accurately predicts the response to treatment in IPF. Current models have been effective in understanding various mechanisms involved in IPF pathogenesis, but the data have been poorly translatable into the clinical domain. The aim of these studies is to develop translation pre-clinical models of IPF whilst refining, reducing and eventually replacing the use of existing animal models of disease. We will achieve this by 1) refining our current rodent lung slice model so that it can model lung fibrosis, 2) optimise imaging modalities that are clinically translatable and non-terminal thus reducing the numbers of animals required and 3) develop a human lung slice model of fibrosis such that the rodent model may eventually be replaced completely. Specifically we will harvest lung tissue slices and injure them ex-vivo, as well as injuring the lungs of rodents in vivo prior to harvesting slices to perform ex-vivo experiments. Having developed the lung slice model of fibrosis ex vivo we will cross validate the data with conventional models of fibrosis, and optimise functional MRI technology to permit non-terminal imaging and lung-function measurements. These studies will also generate more translatable outcome measures than conventional histological and biochemical measures of pulmonary fibrosis. Finally, in collaboration with the Manchester Lung Transplant Centre we will develop a human lung slice model of fibrosis analogous to the rodent slice model. These studies will facilitate improved translation of pre-clinical studies as well as reducing the number of animals required in these studies.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: RESPIRATORY
Title: Over three years: Does the prescribing of asthma controller medication according to beta2 receptor gene status improve quality of life in children with asthma?
Funder: Action Medical Research

Abstract: Background _x000D_Asthma affects one million children in the United Kingdom. Despite current asthma treatments, quality of life remains poor with many young people missing sports, school and work. Doctors currently follow the British Thoracic Society guidelines for treating asthma which recommend a stepwise approach. These researchers have found that a 'controller' medicine, salmeterol, commonly prescribed at Step 3, does not work effectively in some people. Salmeterol belongs to a class of drugs known as beta 2 agonists and when the team looked at the beta 2 receptor gene, they were able to identify two distinct gene variants: one was more common in patients responding well to salmeterol; the other variant was more common in patients who did not respond well to salmeterol. They went on to demonstrate in a preliminary study that children who had the second variant experienced significantly improved clinical symptoms and quality of life when prescribed an alternative treatment, montelukast, instead of salmeterol. These initial findings now need to be confirmed in a larger clinical trial._x000D_ The research project _x000D_This research aims to find out whether choosing an asthma medicine on the basis of genetic make up (genotype) leads to a better quality of life for young people with asthma compared to conventional NHS treatment where all patients are prescribed medicines according to a standard protocol. The team will recruit 240 participants aged 12 to 21 years who require add-on controller therapy. The genotypes of participants will be established and they will then be randomly assigned to one of two groups. In Group 1, prescribers will be advised to choose add on asthma treatment based on genotype. In Group 2, the prescriber will not know the genotype and will follow the standard prescribing protocol for asthma. The main outcome will be asthma-related quality of life after one year's treatment. If this study shows benefit from this genetic test, it will be important to find out if it is feasible to use this test as part of daily NHS care. From a broader perspective, if prescribing decisions directed by genotype are shown to help patients more than standard therapy, this will raise the possibility of genetically determined 'personalised' therapy for asthma becoming part of routine asthma treatment.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: RESPIRATORY