NIHRDataInsights/HRCSData huggingface dataset:
Title: United Kingdom Refractory Asthma Stratification Programme (RASP-UK)
Funder: Medical Research Council

Abstract: This programme will test a novel stratification strategy in severe asthma to improve clinical management and accelerate development of new therapies. There are 4 components: 1. Stratification by adherence to regular corticosteroid (CS) treatment. Objective identification of adherence to inhaled CS to (a) precisely identify truly CS unresponsive asthma phenotypes where new drugs are needed and (b) avoid inappropriate use of new complex therapies in patients who could be effectively controlled on inhaled CS. 2. Biomarker-based titration of CS therapy. In the absence of CS responsive inflammation, clinical response to CS is minimal and inappropriate CS escalation causes significant morbidity. In a 1-year, multi-centre randomised clinical trial, comparing biomarker titrated CS therapy to standard care, we will examine if individualised titration of CS dose using validated biomarkers (exhaled nitric oxide, blood eosinophil count and serum periostin) improves asthma outcome. This will also address another key question, specifically what proportion of patients with severe asthma develop typical eosinophilic airways inflammation associated with Type 2 cytokines (T2) on progressive CS withdrawal. 3. Identification of new therapeutic targets. Prior genetic/mechanistic studies of asthma have not stratified on inflammatory phenotype; thus, understanding of the pathophysiological mechanisms in which T2 inflammation is absent is poor. We will undertake deep-phenotyping of the stratified cohorts to identify important structure/function relationships. 4. Clinical trials programme for new T2 and non-T2 therapies. Stratification by inflammatory phenotype is central to novel target-specific therapies and biomarker-driven therapeutic options now exist for severe asthma. We will use our established clinical infrastructure to engage with pharmaceutical companies to facilitate access to stratified severe asthma patient populations for Phase 2 proof of concept studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: What is the role of microvesicles in the development of acute lung injury?
Funder: Medical Research Council

Abstract: Aims and Objectives I aim to establish the significance of Microvesicles (MVs) in Acute Lung Injury (ALI), investigating three central objectives: 1. To explore if patterns of MV release can be used to distinguish between the phases of ALI. 2. To investigate the inflammatory mediators and biological cargo carried in MVs 3. To identify the role of MVs in the pathogenesis, potentially inspiring novel therapeutic targets. Methodology I will use clinically relevant mouse models of ALI, where the acute inflammatory, fibrotic and resolution phases are readily identifiable. MV kinetics/profiles (i.e. number and cell origin) will be identified in these phases by flow cytometry and will be compared. To characterise the information relayed through MV in ALI, MV pellets will be collected from different acute and chronic ALI models and intra-vesicular mediators (e.g. interleukins and cytokines) will be measured by ELISA/flow cytometry. RNA from MVs will be extracted and quantified through real-time RT-PCR. To characterise the functional significance of MVs in ALI, I will produce MVs from alveolar cells and incubate them with other alveolar cells both in-vitro and in-vivo. Cellular responses will be assessed to determine if MVs can activate intra-alveolar cells. Attenuation of these responses in models where MV production/uptake is inhibited (i.e. in knock-out mice or though pharmacological means) will also be assessed. Scientific and medical opportunities These results will provide crucial information for the scientific community on the pathophysiology of ALI, potentially identifying a novel, previously unexplored communication pathway between intra-alveolar cells. This may explain why therapies for ALI to date have proved ineffective and as such the results from this project may allow the development of new opportunities for therapeutic strategies for ALI.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Pathways to peak lung function: Genetic, environmental and lifestyle influences on maximally attained lung function in young adults.
Funder: Medical Research Council

Abstract: The research has two main objectives: 1. To measure lung function in a population of 5,000 young adults that have been followed from birth in a longitudinal cohort study 2. To model lung function developmental trajectories from mid-childhood to physiological peak and to investigate their association with specific early life exposures (birth size and gestation, early growth, obesity, physical activity, tobacco smoke exposure and wheezing phenotype). Participants in the ALSPAC study will be invited to a research clinic. Lung function will be measured using spirometry according to accepted standards for performance and quality control of these measurements (European Respiratory Society/American Thoracic Society). The measurements will be made by research clinic staff trained and supervised by the principal investigator. Subjects will be asked to perform at least three technically acceptable forced expirations (from a maximum of eight attempts) into a pneumotachograph and the resulting flow volume curves will be displayed on a computer screen for immediate inspection by the fieldworker. Spirometry will be repeated 15 minutes after inhaled bronchodilator (salbutamol 400 mcg). Data will be anonymously linked to other information collected during the course of the ALSPAC study. Lung function data will be analysed by modelling developmental trajectories using linear and non-linear models. Outcomes will be continuous and categorical (obstructive, restrictive). Associations between these and exposures will be analysed using linear and logistic regression equations respectively. We will use structured lifecourse epidemiological approaches to look for critical periods and cumulative effects of exposures. Structural equation models will be used to examine mediators on pathways between early life exposures and lung function. We will deal with missingness in the data using multiple imputation and , within SEM, Full Information Maximum Likelihood methods.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: RESPIRATORY
Title: RHiNO: Respiratory Health In Preterm Neonatal Outcomes
Funder: Medical Research Council

Abstract: Aim 1: Respiratory status of preterm-born children The primary aim is to identify 7-12 year-old preterm-born children born at <=34 weeks gestation who have airway obstruction of FEV1<=85% for further detailed study. From our questionnaire study, 1,053 (55%) of the 1,926 children born at <=34 weeks gestation had "wheeze-ever". We shall randomly invite these children to identify 200 who have marked airway obstruction (%FEV1 <=85%). We shall also invite asymptomatic control children without airway obstruction (FEV1>85%) born preterm (n=50) or at term (n=50). Aim 2: Assessment of mechanisms of airway obstruction: a. Atopic status by skin prick testing b. Exhaled breath condensate c. Exhaled nitric oxide d. Induced sputum e. Pulmonary diffusion capacity f. Whole body plethysmography g. Lung spirometry h. Maximal exercise by cycle ergometer Mechanistic data will be compared between the preterm group with airway obstruction and preterm- and term-control groups. Aim 3: Modification of the underlying mechanisms After mechanistic study, children not on corticosteroids will be randomised to blinded treatment with inhaled active drugs or placebo. Children on corticosteroids will be "washed-out" and randomised to active drug treatment. b-g above will be repeated after the 12-week treatment period to assess the clinical and mechanistic responses to drug treatment in children born preterm with airway obstruction. Aim 4: Study the pulmonary structure by hyperpolarised gas MRI in those with FEV1 <=85% (a) who do not respond to inhaled drug therapy compared to (b) responders; and (c) preterm and (d) term controls without airway obstruction. Children will undergo structure-functional imaging at 1.5T to assess structural changes in lung morphology and motion. Gd-DTPA contrast enhanced perfusion imaging will be used to assess perfusion heterogeneity and V/Q matching. The results will be compared between the groups to identify structural and functional differences.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Genetic and Functional Characterization of the IgE Repertoire and Compartmental Regulation of IgE Activity in the Pathogenesis of Asthma
Funder: Medical Research Council

Abstract: Our project aims to elucidate allergen-dependent and allergen-independent IgE pro-inflammatory mechanisms in atopic and non-atopic asthma. We will characterise the expressed Ig gene repertoire and functions of IgE antibodies in the nose, lung and peripheral blood from 10 non-atopic and atopic asthmatics and healthy controls, distinguished by skin prick tests. Peripheral blood (50 ml) and respiratory mucosal tissues (three nasal and 10 bronchial biopsies) will be obtained from all individuals. Ig repertoires will be captured by cell-direct emulsion RT-PCR and 5'-RACE PCR. The samples will be subjected to deep-sequenceing on the Pacbio RSII system, which delivers the required long-reads with sufficiently high accuracy. Several bioinformatics pipeline and mathematical models (e.g. Hill's diversity, BASELINe, PHYLIP) will be applied to investigate the "natural history" of IgE-expressing B cells. Paired Ig heavy- and light-chain sequences identified by sequencing and phylogeny analysis will be expressed as recombinant IgE proteins using our in-house rapid expression cloning system (40 IgEs in total). The proteins will be functionally characterized for antigen-specificity and affinity and pro-inflammatory activities using assays such as ELISA, ImmunoCAP ISAC, carbohydrate microarray, SPR, mast cell and basophil activation tests and facilitated antigen binding. We will measure de novo synthesis of total and allergen-specific IgE from cultured mucosal biopsies. In our recent study of Ig repertoires in allergic rhinitis, we found significant differences between groups of seven allergic patients and three healthy controls. Therefore, we expect to be able to detect significant differences in this project with 10 subjects/group. Appropriate statistical methodology (ANOVA, parametric, non-parametric) will be used, depending on the nature of data set, and post-hoc adjustments (e.g. Bonferroni correction) will be applied.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Discovery of genome-wide SNP associations for lung function
Funder: Medical Research Council

Abstract: Large GWAS, and analysis of lung function in the extremes of UK Biobank, have brought the total number of lung function associated loci to 52, of which a growing number show association with COPD risk. Larger sample sizes and more sophisticated approaches to variant measurement and imputation are needed to identify additional genetic loci, especially for low frequency and rare variants which might have individually larger effects than common variants. We will utilise sample sizes of up to 600,000 research participants with lung function data through consortium collaborations and UK Biobank, in conjunction with new array designs and larger imputation reference panels to achieve this. We had a lead role in the design of the Affymetrix UK Biobank array through our MRC-funded UK BiLEVE project. Key features of the array include: i) selection of tag variants to optimise imputation of low-frequency variants; ii) improved "exome chip" content based on larger sequencing resources than previous arrays; and iii) custom content designed to maximise coverage of candidate respiratory regions. We have established expertise and pipelines in the analysis of this array which has been shared with additional studies, including the China Kadoorie Biobank, enabling a trans-ethnic meta-analysis of lung function. These studies will not only contribute to fine mapping of signals but, crucially, will provide the substantial number of loci required to more completely undertake pathway analyses and enable scientists worldwide to evaluate the functional importance of these signals.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: MICA: Non-invasive quantitative ventilation imaging by MRI of fluorocarbon gases
Funder: Medical Research Council

Abstract: We are developing non-invasive and radiation-free methods for imaging lung ventilation properties, using new Magnetic Resonance Imaging (MRI) technologies. Our methods provide quantitative measures with potential for translation to clinical practice. Respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma have a major impact on health. Existing techniques to objectively measure lung ventilation properties have significant limitations. For example, spirometry gives no anatomical information and CT scans incur an ionising radiation dose. There is a pressing need for techniques allowing safe, objective, repeatable and quantifiable measurements of ventilation properties. A recently described technique employs a fluorocarbon gas (perfluoropropane) as an inert, inhalable tracer that can be imaged by MRI. Critically, this approach does not involve gas hyperpolarisation, so can be implemented on clinical MRI scanners with minimal additional hardware. Our study seeks to develop 19F-MRI of perfluoropropane by testing its ability to quantify ventilation defects, representing a step towards the ultimate goal of implementation in clinical practice. Specifically, we will determine the reproducibility of the methods in healthy volunteers, use the methods to quantify the degree of airway disease in asthma and COPD patient cohorts, and benchmark performance of 19F-MRI against established hyperpolarised MRI methods. Studies will be performed at two sites (Newcastle and Sheffield), laying the groundwork for future multisite clinical trials. Our study team brings together MR physicists and clinical academics with longstanding experience of respiratory conditions, MR technical approaches, and translational research. Our preliminary studies have confirmed feasibility and safety in healthy volunteers. 19F-MRI of inhaled perfluoropropane represents a nascent field that we are well positioned to develop and apply, and to exploit its clinical potential.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Impact assessment of diagnostic tools for multi-drug resistant and (MDR-TB) drug sensitive tuberculosis (TB) in the Philippines
Funder: Medical Research Council

Abstract: The objective of the research is to support the cost-effective roll-out of new tools and algorithms for the diagnosis of tuberculosis (TB) and multi-drug resistant TB (MDR-TB) in the Philippines. This will lead to improvements to TB/MDR-TB case detection and cure in the Philippines and promote the economic development and welfare of the country. The tools investigated will include the molecular test Xpert MTB/RIF and new point of care tests under development. The research programme will have 5 components: 1. Data collation- Data on the infrastructure, performance, and costing of the processes for TB and MDR-TB diagnosis and treatment will be collated. The sequence of events that patients follow in order to be diagnosed and start appropriate treatment will be mapped. 2. Model development- A computer model of the patient pathways using the innovative Virtual Implementation modelling approach will be developed. The approach produces a dynamic and visual representation of the pathways and will be used to project patient and health system outcomes. The model will be tested using data from Cavite province. 3. Cost effectiveness analysis- Outputs from the model will be used to estimate the incremental cost effectiveness of alternatives (Cost per Disability Adjusted Life Year (DALY) averted). 4. Strategy development - Working with policy makers from the National TB Programme (NTP) a strategy for the scale-up of new diagnostic tools and algorithms will be developed for Cavite province that takes account of the projected impacts and cost effectiveness of each option. 5. Capacity Building & Dissemination- An easy to use version of the model will be made available to the NTP and the De la Salle Health Sciences Institute (DLSHSI) using WITNESS software (www.lanner.com/en/). Training and support will be provided so researchers and the NTP can develop a strategy for new diagnostics in other provinces of the Philippines. Manuscripts will be submitted for publication.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Redox sensitive TRP ion channels in the interaction between human lung mast cells and oxidative stress
Funder: Medical Research Council

Abstract: Oxidative stress has been implicated in the pathogenesis of mast cell dependent lung diseases including asthma, acute lung injury and pulmonary fibrosis. An interaction between oxidative stress and mast cells is an important pathologic event. Although oxidative stress can result from prolonged excessive production of reactive oxygen species (ROS), ROS are also recognised to play roles in normal physiology. Therapies that directly but non-specifically target oxidative stress have failed in clinical trials, perhaps because of interference with physiological ROS signalling and regulatory mechanisms. We hypothesise that the redox-sensitive TRP channels TRPA1 and TRPM2 function as sensors of oxidant-antioxidant balance in human lung mast cells (HLMC), and participate in regulating intracellular ROS production and Ca2+ signalling. We predict that the regulation of responses to OS by TRP channels in HLMCs is determined by the stimulus duration and intensity, and is important in the pathophysiology of mast cell-driven lung diseases. I have preliminary evidence for the functional expression of these channels in HLMCs. My goals are to delineate the role of these channels in HLMC activation in conditions of OS, using patch-clamp electrophysiology, calcium imaging and mediator assays; and ROS production using fluorescent ROS indicators. I also aim to determine whether tissue expression of these channels in human bronchial biopsies is altered in asthma using immunohistochemistry.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Can combined cellular and 11beta-hydroxysteroid dehydrogenase-1 gene therapy attenuate inflammation in acute respiratory distress syndrome?
Funder: Medical Research Council

Abstract: 1) Is the phagocytic function (including efferocytosis) of Alveolar Macrophages (AMs) impaired in ARDS patients compared to normal volunteers? ARDS patients will be recruited & AMs isolated from broncho-alveolar lavage fluid. Flow cytometry will be used to determine uptake of fluorescently labelled apoptotic neutrophils, E. coli & S. aureus bioparticles by AMs. 2) Do HSD-1 overexpressing tMSCs enhance the function of human AMs from ARDS patients more effectively than transgene-inactive tMSCs? AMs from ARDS patients will be cultured with transgene-activated & transgene-inactivated tMSCs, in the presence of cortisone. After 24hrs, basal cytokine release will be assessed using ELISA. Phagocytosis and efferocytosis assays will also be performed as described above. 3) Will HSD-1 overexpressing tMSCs attenuate inflammation in murine models of lung injury more effectively than transgene-inactive tMSCs? I will use 2 different models of lung injury in HSD-1 knockout mice: intra-tracheal LPS to model direct lung injury, and caecal ligation & puncture to model indirect lung injury. We will utilise standard markers of lung injury to assess the impact of transgene-activated vs transgene-inactivated tMSCs. 4) Determine if HSD-1 over-expressing tMSCs can modify alveolar steroid metabolism in a human ex-vivo lung perfused (EVLP) model injured with LPS. I will work with Prof Matthay's group at UCSF who have experience using the EVLP model. All lung lobes will receive LPS & cortisone. For each lung, one lobe will receive transgene-activated tMSCs intra-bronchially and the other saline. After 4 hours, BAL would be performed, & mass spectrometry performed on the BALF to determine cortisol and cortisone concentrations. Opportunities: This translational work will help determine if local up-regulation of HSD-1 by tMSCs will attenuate inflammation in ARDS by restoring AM function. Exploitation: Data generated will be published in high citation peer reviewed journals


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: RESPIRATORY
Title: Alpha-1-antitrypsin (AT) deficiency and the serpinopathies: pathobiology and new therapeutic strategies
Funder: Medical Research Council

Abstract: We described the polymerisation of mutants that underlie antitrypsin deficiency and developed new paradigms for the liver and lung disease associated with this condition. We have also described the polymerisation of mutants of antichymotrypsin that have been associated with COPD and mutants of neuroserpin that cause a novel dementia that we called familial encephalopathy with neuroserpin inclusion bodies (FENIB). We grouped these diseases with others that result from polymerisation of mutants of the serpins as the serpinopathies. We have used biochemistry, biophysical analysis, crystallography, NMR, cell and induced pluripotent stem cells, monoclonal antibodies and Drosophila models of disease to dissect the structural basis of polymer formation and the cellular consequences. We are in late lead optimisation stage of developing small molecules that block polymerisation with GlaxoSmithKline. However it is critical that we understand the pathobiology of antitrypsin deficiency and serpinopathies in more detail in order to evaluate a broad range of therapeutic strategies with the aim of curing the disease. The aims of this programme are to: (i) define the structure of the pathological polymer using biophysical analysis and cryo-electron microscopy, (ii) establish the cellular response to intracellular serpin polymers, (iii) define disease mechanism in a multicellular context and identify new therapeutic targets using a C. elegans model of antitrypsin deficiency, (iv) define the dynamics of antitrypsin polymers in vivo and their utility as a biomarker of disease, (v) develop a diagnostic technology for imaging Z antitrypsin polymers in vivo. The work is enabled by the facilities at UCL and the shared lab in which the applicants work. Indeed the preliminary data have been generated following the move of Lomas and Sattelle to UCL. The findings from this programme are likely to be applicable to a broad range of other protein conformational diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY