NIHRDataInsights/HRCSData huggingface dataset:
Title: Phenotypic characterisation of non-smoking COPD
Funder: Medical Research Council

Abstract: COPD affects over 300 million people worldwide and is a leading cause of death in the western as well as developing countries. Most of the basic and clinical research is in tobacco smoke-induced COPD. Non-smoking COPD is emerging as an important phenotype of COPD but is very poorly understood. The overall aim of this proposed study is to better characterise the non-smoking phenotype of COPD and to investigate how it differs from smoking COPD. Our main objectives are to: (1) Study and compare the clinical, physiological, radiological and inflammatory profiles in induced sputum and bronchoalveolar lavage, systemic inflammation and co-morbidities of non-smoking COPD with smoking-induced COPD in India and UK. We will also study disease progression of non-smoking COPD in India over 3 years; (2) Study bacterial colonization of lower airways in non-smoking COPD and exposed controls using culture and 16s rRNA metagenomic profiling, and whether this is linked to impaired bacterial phagocytosis by macrophages and neutrophils; (3) Study histone deacetylase and phosphoinositide-3-kinase activity in the sputum and alveolar macrophages of non-smoking COPD to better understand the molecular mechanisms of lung inflammation; (4) Study DNA methylation patterns of non-smoking COPD to understand epigenetic dysregulation; (5) Quantify and compare the black carbon content in the cytoplasm of alveolar macrophages from biomass smoke-induced COPD and smoking COPD subjects; (6) Study the impact of replacing biomass fuel with liquefied petroleum gas on indoor air pollution, alveolar black carbon content and its effects on lung health using physiological and sputum cellular and inflammatory mediator profiles. The study will be conducted using well established and validated methods and will provide new knowledge in this field of respiratory medicine that will not only benefit clinicians, respiratory researchers, public health workers, pharmaceutical industry, but also the policy makers.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Developmental Clinical Studies - ACE inhibitors to augment the effects of pulmonary rehabilitation in COPD
Funder: Medical Research Council

Abstract: Need addressed: COPD is a major worldwide public health problem characterised by breathlessness, reduced physical activity and significant skeletal muscle impairment. Pulmonary rehabilitation (PR) can improve the skeletal muscle impairment that occurs in COPD, but there is a need to develop therapies to enhance and sustain this effect. Proposed solution: We propose to test the hypothesis that angiotensin converting enzyme inhibitors (ACE-I) will augment the improvements in exercise capacity seen following PR, enrolling 80 patients in a double-blind, placebo-controlled, parallel group study powered to demonstrate an increase in peak workload on cycle ergometry. Rationale: PR is an effective therapy in COPD but the response may be suboptimal in some individuals because of oxidative and nitrosative stress. Biopsy evidence shows that pathways associated with muscle growth and fibre shift are attenuated in some patients. Angiotensin II is known to influence IGF-1, myostatin, the ubiquitin-proteasome proteolytic pathway, inflammatory pathways involving NFkB and angiogenesis. Hypertensive patients taking ACE-I are stronger than those on other therapies, ACE-gene polymorphism has been shown to influence the response to training and influence quadriceps strength in COPD. One trial has shown that ACE-I can improve exercise capacity in COPD. We will also take quadriceps muscle biopsies and will seek funding separately to analyse these so that the mechanisms underlying improvement can be best understood. Development plan: ACE-I are already widely used for the treatment of hypertension and heart failure, have a good safety profile and are off patent. They could therefore be rapidly adopted if the treatment indication proposed here was found to be supported. Therefore if the results of the proposed trial were positive the next step would be to seek funding for a larger multicentre study powered according to patient relevant and health economic outcomes.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: The chitinase family: Does sibling rivalry shape lung homeostasis, inflammation, and response to helminth-induced damage?
Funder: Medical Research Council

Abstract: Glycoside hydrolase family 18 (GH18) members, acidic mammalian chitinase (AMCase) and chitinase-like proteins (CLPs), are dramatically increased in Th2-driven lung pathologies, but their functions remain largely unknown. We have strong evidence for cross-regulation between GH18 members and thus aim to delineate the specific functions of AMCase/CLPs in the context of the entire family. Whilst AMCase is highly conserved across species, CLPs differ due to the rapid evolutionary divergence of the CLP family in mammals. By investigating the dynamics of AMCase-CLP family interactions, we can shed light on both the evolutionary and proximal purpose of GH18 proteins, with relevance to human disease. For this study we have a range of unique tools, including a potent AMCase inhibitor, a neutralizing monoclonal antibody against 2 CLPs and mice genetically deficient in each of the family members. Our 1st aim is to assess and compare the impact of each of the Th2-induced family members on the naïve lung by gene transfection. A microarray analysis will provide an unbiased view of the genes altered by exposure to different GH18 family members. Co-transfection, blocking reagents, and gene KO mice will highlight inter-family dynamics. In vitro studies, that assess the effects of AMCase and CLPs on cell lines, will elucidate common patterns in function between human and mouse family members, an important step toward translation. Our 2nd and 3rd aims are to apply our blocking tools and KO mice to two distinct models of lung pathology in which the family 18 members are known to be major players. Using the OVA allergy model, with a focus on eosinophils and neutrophils, as we have evidence these are differentially regulated by AMCase and CLPs, we will assess the downstream impact of AMCase/CLP manipulation on airway inflammation. Using a nematode migration model we will investigate AMCase/CLPs alters the level of physical damage to the lung that leads to long-term structural changes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: The development and clinical applications of 111-Indium-labelled eosinophil scanning
Funder: Medical Research Council

Abstract: Eosinophils are pathogenic in asthma, but the precise intra-pulmonary compartment relevant to eosinophilic damage is unclear, and reliable methods to quantitate and track eosinophilic inflammation and the effects of treatment thereon are lacking. We have previously developed methods involving the injection of autologous radiolabelled neutrophils to quantify the trafficking of human neutrophils in vivo in health and disease. We wish to apply these techniques to eosinophils, with the aim of delineating for the first time eosinophil kinetics, distribution and fate in human health and disease. We have already established 'gold standard' recovery and intravascular residence times for eosinophils using minimally manipulated 111In-labelled and re-injected buffy coat cells. These values will be compared to those obtained for 111In-labelled purified eosinophils to ensure that the latter behave in a physiological manner on re-injection. Using purified autologous re-injected 111In-labelled eosinophils we will determine the physiological distribution and fate of these cells by blood sampling and gamma-camera imaging. Eosinophil migration into the airways will be analysed in greater depth using double-headed gamma camera SPECT. Applying low administered activities of 111In-labelled eosinophils and whole body counting plus sequential blood and sputum analysis will allow us to quantify eosinophil loss from the airways. All of these parameters will be studied in healthy volunteers and compared with values obtained for asthmatic subjects; eosinophil recruitement in response to segmental allergen challenge will also be assessed. In 'proof of priniciple' studies, we will determine the ability of corticosteroids to modulate the recruitment of eosinophils to the lung. Ultimately, this methodology should allow clinical imaging and quantification of eosinophilic inflammation in vivo, and permit the non-invasive assessment of new and existing eosinophil-targeted therpeutic interventions.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.
Funder: Medical Research Council

Abstract: cAMP is a pivotal second messenger able to exert a panoply of cell type specific effects. A multigene family of phosphodiesterases (PDEs) provide the sole means for degrading cAMP and are thus poised to play a key regulatory role in cells. Highly specialised regulatory properties, coupled with cell specific patterns of expression, provide each cell type with a sophisticated and unique means of regulating intracellular cAMP. This diversity offers potential for developing highly specific therapeutic agents. There is great interest in developing PDE4 family selective inhibitors for treatment of Chronic Obstructive Pulmonary Disease (COPD). However, the deployment of PDE4 inhibitors as therapeutics has been limited by side effects, such as nausea. It is now appreciated that PDE4 activity is attributable to a large family of isoforms This has prompted the notion that selective inhibition of particular PDE4 isoforms may maximise therapeutic benefit whilst minimising side effects. Different cell types have unique complements of PDE4 isoforms and recent technological advances place us now at a stage where we can determine how individual PDE4 isoforms sculpt cAMP gradients in cells to underpin compartmentalised cAMP signalling and control specific cellular processes. Inherent in this is the concept pioneered by our laboratory that the intracellular targeting of individual types of PDE4 isoforms to specific signalling complexes is fundamental to their functioning. Thus, not only may altered expression, targeting and regulation of individual isoforms contribute to various pathological conditions but disrupting the intracellular targeting of specific PDE4 isoforms in cells may provide a novel means of generating therapeutics aimed at disease-related PDE4 isoforms while minimising side-effects. As a route to identifying novel therapeutic targets we propose to define the functional role, modes of intracellular targeting and and regulation of PDE4 isoforms associated with COPD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Developmental Clinical Studies - A clinical trial of metformin in COPD exacerbations
Funder: Medical Research Council

Abstract: OBJECTIVE. To determine whether a rapid dose escalation regimen of metformin can lower blood glucose reliably and safely in individuals during acute exacerbations of COPD. STUDY DESIGN A randomised, double-blind, placebo-controlled trial of metformin in patients hospitalised for COPD exacerbations. Other inclusion criteria: age 50-85yrs, study entry within 72 hours of admission. Exclusion criteria: pre-existing diabetes; increased risk of lactic acidosis or hypoglycaemia. INTERVENTION Participants will be randomised 2:1 to receive metformin or placebo for 28-35 days. Metformin dose will escalated rapidly to 1g twice-daily (or placebo equivalent) on day 4. Study treatment will be in addition to standard care. ENDPOINTS. Metformin will be considered effective for COPD exacerbations if (compared to placebo) it reduces mean hospitalisation blood glucose by 1.5mmol/L (primary endpoint). A reduction in 28 day fructosamine will confirm reduction in blood glucose over the whole study period. Metformin will be considered safe if there are no cases of lactic acidosis (increase in serum lactate with metabolic acidosis not attributable to other cause) or other protocol-defined severe adverse events. It will be considered tolerable if at least 75% of patients take at least 50% of their tablets and less than 30% patients taking metformin drop out of the study. APPLICATION/EXPLOITATION. If metformin meets these criteria for reliable and safe blood glucose lowering during COPD exacerbations, this will provide clear justification for progression to a large multicentre randomised controlled trial, powered to detect an effect of metformin on clinical endpoints. Confidence for progression to this follow on study will be increased if there are trends in improvement in patient reported outcomes or increases in time to next exacerbation. Conversely, failure to meet these criteria will clearly indicate that there is no justification for progressing to such a trial.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Developmental Clinical Studies-validation of the utility of a novel smartprobe detecting neutrophil activation/elastase activity in acute lung injury
Funder: Medical Research Council

Abstract: a) Healthcare need addressed: To allow clinicians in intensive care units (ICU) to rapidly and accurately determine the aetiology of deteriorating respiratory function or clinical status suggested, for example, by new infiltrates on the chest x-ray (CXR). b) The technology/solution: We will employ a combined approach utilising recent advances in bronchoscopic confocal imaging for bedside-based, in situ real-time imaging together with the local, microdosed, instillation of next-generation 'smart' molecular probes targeting neutrophil activation (NAP). This will allow patient delineation for specific drug targeting and stratify/inform clinicians immediately for prognosis: specifically the presence and activity of neutrophils. c)Methodology: The study will be conducted in two phases. The first involves administering NAP to healthy volunteers with experimental lung inflammation. The second phase moves to a 100-patient clinical study in ICU. NAP will be delivered directly into inflamed lungs and 'heat maps' of pulmonary neutrophil dependent lung injury will be generated by pCLE. d) Impact on healthcare: Accurate, dynamic cellular/molecular diagnosis would lead to stratification of patient care and tailored prescribing patterns, including the use/non-use of expensive and potentially toxic anti-bacterials and ultimately reduced ventilator dependency and reduced mortality and morbidity in critically ill patients. This approach is applicable to disease detection/stratification/therapeutic intervention in other organs accessible by fibreoscopy.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Development of a novel anti-inflammatory nanoparticle for the treatment of Acute Lung Injury
Funder: Medical Research Council

Abstract: Acute Lung Injury (ALI) is a serious condition associated with significant morbidity, mortality and healthcare resource utilisation, for which no effective pharmacologic treatment is available. ALI is caused by the uncontrolled activation of immune cells, resulting in an unregulated cycle of inflammation that leads to damage to the alveolar epithelial-endothelial barrier, leading to acute respiratory failure and the need for mechanical ventilation. This is therefore an area of clear unmet clinical need for effective anti-inflammatory therapies. We have developed a novel nanoparticle which has potent anti-inflammatory effects. Here we will investigate its application in ALI by examining effects in two clinically relevant murine models of ALI (intratracheal LPS and cecal ligation and puncture), ex vivo patient and volunteer alveolar macrophages and a human ex vivo lung perfusion model. This project will provide data on physiological outcomes and toxicity upon administration with our nanoparticle to determine if further development into preclinical trials is warranted.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Molecular Optical Imaging of Key Targets in the Fibrogenic Pathway in Man
Funder: Medical Research Council

Abstract: Fibrotic diseases of the lung and other organs constitute a heavy burden of morbidity and untimely deaths. Idiopathic Pulmonary Fibrosis (IPF) is diagnosed late (on CT scans/lung biopsy) and has an appalling mortality. It is currently impossible to identify patients with Adult Respiratory Distress Syndrome (ARDS) and other inflammatory lung diseases that are developing secondary fibrosis. Moreover there are no effective therapies for fibrosis despite it being a highly active cellular process which should be accessible to intervention. Part of the problem has been the time required to establish drug effectiveness in vivo and the poor utility of existing biomarkers. The innovative translational pathway detailed herein will create novel active markers of fibrogenesis in situ to rapidly establish early diagnosis and efficacy of much needed new therapies in scarring diseases of the lung and other organs. Supported by a previous MRC 'devolved' DPFS award our team has already synthesised a highly-specific human neutrophil smartprobe which has been validated exhaustively in vitro and in vivo using pCLE and is now in GMP synthesis for human application. From this strong foundation we are confident of achieving the aims of the current application. KEY GOALS: 1) To allow clinicians to rapidly and accurately determine the presence of active fibroproliferation. 2) To apply cutting-edge bronchoscopic confocal imaging technology (pCLE) partnered with local instillation of highly specific and sensitive 'smart' molecular probes at microdose concentrations (<100 mcg). 3) To generate a novel portfolio of GMP-grade materials for first-in-man validation studies that are commercially valuable. 4) To develop potentially gold-standard methodologies for rapidly assessing the efficacy of new antifibrotic drugs in clinical trials and for patient stratification. This strategy will accelerate the pharmaceutical development and clinical application of antifibrotics.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: MicroRNAs and their epigenetic regulation as key factors in airway macrophage dysfunction in asthma.
Funder: Medical Research Council

Abstract: 1) We will determine the expression of a group of microRNAs (miR27a, miR-128, miR-135b, miR-141, miR-148a, miR-150, miR-152, miR-155, miR-340, miR-345, miR-374a, miR-375) and potential targets in peripheral blood monocytes and airway macrophages from asthmatic patients recovered by bronchoalveolar lavage (BAL) and compared to healthy donors. This will also be undertaken on BAL macrophages obtained from asthmatics before and after repeated experimental allergen challenge and on BAL macrophages exposed ex vivo to viral challenge. This will be done by RT-qPCR and Western Blot (the latter only for the genes involved in the defective pathways). 2) We will determine the functional role of the group of candidate microRNAs (as above) and miR-155 in regulating the pathways and cellular functions mentioned in the previous point. We will determine the effect of microRNAs on these pathways by employing synthetic oligonucleotides to manipulate microRNA expression, and the outcome will be measured by determining TNF-alpha and IFN secretion by ELISA. Pathogen binding ability to Haemophilus Influenzae and streptococcal sp, each labelled with propidium iodide, will be assessed by flow cytometry. 3) To determine whether this group of candidate microRNAs and their target genes are controlled by epigenetic marks in peripheral blood monocytes and asthmatic macrophages from patients in relationship to different levels of clinical severity (mild, severe asthmatics) or in relationship to the impact of environmental stimuli (in vivo experimental allergen challenge and in vitro exposure to rhinovirus). Comparison will be made to findings from healthy volunteer macrophages. The epigenetic studies will be done by Chromatin Immunoprecipitation determining the methylation of histones at the promoter of the relevant genes. We will actively exploit and protect any IP at the University of Southampton through the Research and Innovation Services office.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: MICA: STELAR (Study Team for Early Life Asthma Research) consortium - Asthma e-lab and identification of novel endotypes of childhood asthma
Funder: Medical Research Council

Abstract: Asthma epidemiology is reaching the limit of what can be achieved through conventional hypothesis-driven research. We hypothesise that asthma is not a single disease, but a condition comprising multiple distinct disease entities (asthma endotypes), each with characteristic pathophysiology and risk factors, and that unbiased novel endotypes of asthma can be identified using complex, rich and expanding datasets from existing UK birth cohort studies by applying a combination of biostatistical and machine learning methods. We propose to form a major Alliance between MRC-funded network of all UK-based birth cohorts designed to study asthma (STELAR consortium), expertise in epidemiologically oriented health informatics research (NW Institute for Bio-Health Informatics) and experts in statistical machine learning (Microsoft Research Cambridge). We will capitalise on the unique collection of well characterised birth cohorts with harmonised clinical outcomes (ALSPAC, SEATON, MAAS, Ashford, Isle of Wight). We will create a secure web-based research environment (Asthma e-Lab) to support consistent recording, description and sharing of data and emerging findings across all partners, thus enabling collaborative epidemiology in near-real-time. The activities of data managers and researchers from the 5 STELAR sites will be made visible to one another, supporting team coordination and peer support and creating a scientific social network to enrich the ongoing modelling and interpretation. We will create and maintain across the consortium annotated dependency graphs of the problem space around the organising principles underlying asthma, and use a machine learning approach interactively over the combined datasets via Asthma e-Lab to discover the unbiased endotypes of asthma. Our findings may underpin new trials of asthma prevention and treatment, personalised for specific endotypes and may help identify novel targets for the discovery of endotypes-specific stratified treatments.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: RESPIRATORY