NIHRDataInsights/HRCSData huggingface dataset:
Title: Targeting myofibroblast mechanotransduction to prevent pulmonary fibrosis
Funder: Medical Research Council

Abstract: Idiopathic Pulmonary Fibrosis is characterised by increased myofiboblast proliferation and activity. Recent evidence suggests that mechanical forces are crucial factors controlling myofibroblast function. I have preliminary data suggesting that matrix-derived "tonic" and breathing-related "cyclical" mechanical forces are sensed via different G protein signalling pathways (G12/13 and Gq/11 respectively) and have different profibrotic effects in myofibroblasts. I will test the hypothesis that G protein signalling pathways are central mediators at the interface of mechanical forces and cellular injury in the pathogenesis pulmonary fibrosis. To test this hypothesis I will address four specific aims. 1) Assess the effect of manipulating G protein signalling on murine and human fibroblasts subjected to the profibrotic mediator Lysophosphatidic Acid (LPA). 2) Understand the role of matrix-derived "tonic" and breathing-derived "cyclical" mechanical forces on G protein mediated fibrotic pathways in transgenic murine fibroblasts grown on substrates of varying stiffness and or the Flexcell stretch system. Findings will be confirmed in diseased, or control, human cells. 3) Determine the effects of targeted deletion of Ga12/13 and/or Gaq/11 in myofibroblasts on the development of matrix stiffness and lung fibrosis using the bleomycin model in triple transgenic mice. 4) In collaboration with Dr Tager (Harvard) I will measure the elastic modulus of of matrix using in vitro and in vivo models of lung fibrosis using Atomic Force Microscopy. These studies will define the role of G protein signalling in the pathogenesis of IPF and may reveal novel therapeutic targets.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Characterising the shared and disease-specific genetic determinants of asthma and COPD
Funder: Medical Research Council

Abstract: This project aims to investigate to what extent the genetic determinants of asthma and COPD are shared or disease-specific, and to identify and characterise those shared determinants. This will involve two complementary approaches undertaken in parallel. The first will use a polygenic risk score approach in UK Biobank, a large cohort of 500,000 individuals, to identify the extent of overlap between genetic variants associated with asthma and those associated with COPD. This will use pragmatic definitions of COPD and asthma similar to those used successfully in genome-wide association studies of the two diseases to date. Sensitivity analyses will be undertaken separately in smokers and never-smokers. By varying the statistical significance thresholds for inclusion of variants in the risk score model, I will examine the contribution of SNPs showing strong association and those with weaker association (which may be rare SNPs or those with small effect size). Specific variants which meet genome-wide significance thresholds for both diseases would also be identified. The second approach will refine epidemiological definitions of asthma, COPD, and the clinical syndrome of asthma-COPD overlap (ACOS), which is associated with more rapid decline in lung function and significantly worse outcomes but lacks clear consensus on the most appropriate definition. I will explore self-reported data and electronic primary care records in up to 10,000 participants in the EXCEED study and 500,000 participants in UK Biobank to develop definitions suitable for use in genetic and epidemiological studies. I will then apply these in a genome-wide association study to identify specific genetic determinants of ACOS. Replication of any associations identified will be undertaken in independent cohorts and the functional role of variants investigated through the use of appropriate bioinformatic resources.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Preventing smoking uptake among adolescents - A primary prevention initiative for chronic lung disease in India
Funder: Medical Research Council

Abstract: Smoking is the largest avoidable cause of chronic lung diseases. In India, tobacco consumption is increasing, particularly among the rapidly growing young adult population. Preventing the uptake and perpetuation of smoking is therefore crucial to reducing the future burden of chronic lung disease. This project aims to identify the main determinants of smoking uptake among adolescents in India. We will survey a population of 45,000 students in school grades 6-8 in Udupi region, ascertaining current and susceptibility to future tobacco use; and exposure to determinants including tobacco affordability and ease of access, tobacco imagery in films and music videos and in retail displays, health warnings, anti-tobacco media campaigns, smoke-free homes and schools, and potential confounders (including age, gender, family and peer smoking, self-esteem, rebelliousness, academic grades). One year later we will re-survey the cohort, now in grades 7-9, to estimate prospectively the independent effects and attributable risks of these exposures on smoking susceptibility and uptake. We will then carry out qualitative studies of perceived appropriate policy responses to our findings among national and regional policymakers, and local groups including police, community leaders, tobacco vendors, teachers, parents and adolescents. Survey data will be analysed using descriptive statistics and logistic regression of independent effects of putative risk factors with adjustment for confounders; and the prospective data using a random effects model to allow for clustering effects at the block and school level. Qualitative data will be analysed using a framework approach. We will use our study findings, which are likely to be generalisable to other LMICs, to formulate and prioritise population and individual strategies to prevent smoking uptake in India, and to work with others to engage with policymakers and others to promote implementation.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: RESPIRATORY
Title: Muslim Communities Learning About Second-hand Smoke in Bangladesh (MCLASS II): An effectiveness-implementation hybrid study
Funder: Medical Research Council

Abstract: Second-hand smoke (SHS) is a serious health hazard costing 600,000 lives a year. Women and children in developing countries are worst affected as smoke-free laws are only partially implemented and homes remain a source of SHS exposure. There is limited evidence on interventions designed to reduce SHS exposure in homes, especially in community settings. Following a successful pilot, we plan to evaluate a community-based approach to promote smoke-free homes in Bangladesh - a country with a strong commitment to smoke-free environments but with high levels of SHS exposure in children. We aim to assess the effectiveness of a community-based intervention - Smoke Free Homes (SFH), with or without Indoor Air Quality (IAQ) feedback, in reducing non-smokers' exposure to SHS in the home. SFH and IAQ feedback are behavioural interventions designed to discourage people from smoking indoors. SFH consists of a set of messages and activities couched within mainstream Islamic discourse, delivered by faith leaders (Imams) in places of worship (mosques). IAQ feedback consists of anonymised information on indoor air quality measured by a particulate matter (PM2.5) monitor. Following adaptation of SFH and IAQ feedback for the Bangladeshi context, we will conduct a three-arm cluster randomised controlled-trial in Dhaka. We will randomise 45 mosques as follows: arm 1 - SFH and IAQ feedback; arm 2 - SFH alone; and arm 3 - usual services. We will recruit 1,800 households with at least one smoker. The primary outcome is change in household PM2.5 concentration. Secondary outcomes include frequency and severity of respiratory symptoms, healthcare service use and quality of life. A cost-effectiveness analysis and process evaluation will also be conducted. An implementation study will inform how best to scale up these approaches. The investigators' expertise and track record within the field, extensive links within the community and with policy makers are some of the strengths of the proposal


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: RESPIRATORY
Title: Implementation of COPD Case Finding and Self-Management Action Plans in Low and Middle Income Countries
Funder: Medical Research Council

Abstract: We will (1) assess the utility of a simple questionnaire to better target scarce spirometry resources thus enabling the diagnosis of COPD to be made more easily and cost-effectively, and (2) examine the feasibility of implementing supported self-management Action Plan algorithms for respiratory exacerbations in people living with COPD across three low and middle income countries (LMIC) not on regular therapy. To achieve these aims we will enrol a community sample of 10,500 adults over the age of 40 at urban and rural sites in Nepal, Peru and Uganda where we have ongoing COPD investigations. We will apply a modified 5-item questionnaire which has been validated in the US and compare scores to spirometry, which will be conducted in the field according to the ATS/ERS standards using Easy-on-PC spirometers. Assuming the prevalence of COPD is 9% in Nepal, 10% in Peru and 16% in Uganda we expect a sample of 315, 350 and 560 patients to be diagnosed with COPD in each respective country. A sub-set of those that have confirmed COPD in each country will then be randomly assigned to an intervention group versus standard of care, with COPD Action Plans implemented among the intervention group. We will modify the Living with COPD and the American Lung Association COPD Action Plan which has been validated among those with COPD to act as a guide for supported self-management of exacerbations. Community health workers will be instructed on how to utilise the Action Plan in chronic disease management of COPD as well as manage exacerbations. We will measure quality of life with the EuroQol (EQ-5D) and St. George's Respiratory Questionnaire (SGRQ) every 3 months over a period of one year. The primary end point is SGRQ at 12 months. Results of the EQ-5D will be used to calculate QALYs that will inform an analysis of the cost effectiveness and equity impacts of implementation. We will additionally assess the acceptability and feasibility of implementation in each setting.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: RESPIRATORY
Title: Lung health in Africa across the life course
Funder: Medical Research Council

Abstract: Almost half of the world's population, including 700 million people in Africa, relies on biomass fuels (animal dung, crop residues, wood) for their everyday fuel-energy requirements. These fuels are typically burned in open fires, often indoors, that emit smoke into the household environment and lead to high levels of household air pollution. Women and children, especially young children, experience high exposures to air pollution in the home; this has been linked to a range of adverse health outcomes including non communicable respiratory disease (NCD-Respiratory) in children and adults. We propose to create a multi-site multi-disciplinary pan-African platform for clinical, epidemiological and applied health research underpinned by regional and international collaborative research and delivery networks that will allow us to conduct research into the aetiology, prevention and treatment of NCD-Respiratory across the life course. We will create the foundations for internationally competitive North-South and South-South collaborative proposals in the near future by developing and sharing methodology for the measurement of NCD-Respiratory exposures and outcomes tailored to the challenges of conducting research in resource-constrained African environments and using this methodology to generate and share high quality preliminary data. Methodology development will centre around questionnaires, clinical measurements, air pollution exposures and biomarker evaluation.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: RESPIRATORY
Title: A mathematical modeling framework for tuberculosis burden estimation and economic evaluation of pharmaceutical interventions
Funder: Medical Research Council

Abstract: The aim of this study is to develop methods to better understand the global burden of tuberculosis (TB), patterns of drug-resistance to TB, and the cost-effectiveness of new pharmaceutical interventions. I will build on my age- and gender-structured model of TB transmission, including HIV/ART, coded in fortran and R, and publicly available as a package. I will use a fully Bayesian inference framework, to calibrate the model to data including notification and vital registration data, and prevalence survey data, integrating over uncertainty in poorly identified parameters. Alternative models, including regression and time-series models of the temporal autocorrelation in incidence will be considered under the same model assumptions relating incidence to measured data. Bayesian model comparison techniques will be used to formally compare the fit of alternative models, and the potential benefit of model averaging in terms of improved out-of-sample predictive accuracy assessed. The model will be fitted in a hierarchical framework and any gains in performance assessed. The relative contribution of different data sources to estimates will be analysed and value-of-information analysis undertaken to identify data types and locations that would most reduce (decision) uncertainty. I will develop Bayesian hierarchical ecological multinomial regression models of the patterns and trends in all types of drug-resistance, having compiled a database of relevant country-level variables. I will incorporate drug-resistance in our transmission model, exploring emulation techniques and pragma-based use of accelerators to make this tractable. I will apply hierarchical regression techniques to cost data and extend our model to calculate disability adjusted life years and costs. I will perform cost-effectiveness, budget impact and health impact analyses of emerging pharmaceutical interventions for TB.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Stratified interventions in ARDS (EMINENT)
Funder: Medical Research Council

Abstract: WP1: ARDS: in whom to intervene? This will involve an unbiased informatics-based analysis of existing (HARP2, REST, MOSAIC, GALAXY, ARDS.NET) and new patient cohorts to define ARDS endotypes WP2: ARDS: when to intervene? Undertake prospective analysis of trans-pulmonary cytokine, genomic/epigenomic and neutrophil and monocyte phenotyping/migration signatures, and novel imaging modalities (SPECT/CT, PET/CT) to define the optimal time for intervention in the above cohorts, and to develop rapid ('by lunchtime') diagnostic platforms. This WP will specifically test the concepts generated in well-established and highly refined animal, human lung slice and EVLP models of ALI WP3: ARDS with what to intervene? The collaborative network established above will, together with GSK, be ideally positioned to deliver Phase IIa experimental POC studies, using existing assets in the specific subtypes identified; endpoints (e.g. vascular leak, cell migration, physiological indices, biomarkers) will be determined by the endotype under study


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: The critical role of microvesicles derived from lung-marginated monocytes in ventilator-induced lung injury
Funder: Medical Research Council

Abstract: Background: Acute respiratory distress syndrome (ARDS) has a mortality of over 40%, with most deaths due to multi-organ failure (MOF) and no specific therapies available. Reducing ventilator-induced lung injury (VILI) is the only therapy proven to reduce ARDS mortality, presumably because VILI promotes propagation of lung inflammation to other organs leading to MOF. We previously showed that VILI induces pulmonary microvascular inflammation through activating lung-marginated monocytes. We hypothesise that microvesicles (MVs) from these monocytes play a key role in lung-to-periphery inflammatory propagation. Aims: Investigate MVs from lung-marginated monocytes as targets for selectively controlling propagation of lung inflammation to end organs in VILI. Objectives: 1) Investigate mechanisms of monocyte-derived MV production during VILI. 2) Identify mechanisms of uptake and cargo transfer of these MVs by remote organs, to establish their role in end organ injury. Methods: I will investigate stretch-induced MV production using our unique in vitro (cyclical stretch of lung endothelial cells co-cultured with monocytes) and ex vivo isolated perfused mouse lung VILI models, with MV production analysed by flow cytometry and confocal/electron microscopy, and MV cargoes quantified by immunoassays/RT-PCR. I will investigate MV uptake/biological effects using in vitro models and an ex vivo isolated perfused kidney model, and inject labelled MVs into intact in vivo mouse models to validate findings. I will assess biological relevance of promising pathways identified for stretch-induced MV production using in vivo VILI models with inhibitors/knockouts. MV uptake/biological effects will be evaluated by flow cytometry, immunoassays/immunohistochemistry and RT-PCR, focusing on inflammatory activation and death signalling. Opportunities: Crucial insights into mechanisms of MOF during VILI, and potential development of novel ARDS therapies targeting lung-marginated monocytes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: The role of Sox9 in pulmonary fibrosis
Funder: Medical Research Council

Abstract: Fibrosis, characterised by excessive deposition of extracellular matrix (ECM) proteins, is a common feature underlying chronic lung diseases, for which idiopathic pulmonary fibrosis (IPF) is the most common and severe. Despite significant progress in defining the molecular basis of lung fibrosis, there are currently no effective anti-fibrotic therapies for clinical use. Understanding the direct transcriptional regulation of ECM in lung fibrosis, a critical component of the disease, could pave the way for urgently needed anti-fibrotic drugs. My preliminary data suggests the transcription factor SOX9 is increased in rodent and human models of lung fibrosis and plays a central role in ECM regulation. The objective of my research is to understand the role of SOX9 in pathological matrix deposition during lung fibrosis for targeted anti-fibrotic drug development. I will interrogate this through in vitro and in vivo models of disease. This project's hypothesis is based upon developmental research and evidence of the role of SOX9 in matrix regulation other organ fibrosis. It is ambitious and exciting, backed up by pilot data that insists upon further research and supports reduction in SOX9 transcriptional activity as a method of abrogating pulmonary fibrosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Unravelling the molecular mechanisms controlling respiratory tract mucus gel formation in health and disease
Funder: Medical Research Council

Abstract: Respiratory tract mucus in lung diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis has abnormal properties that contribute to obstruction of the airways. The failure in function of mucus in airway clearance and pathogen protection leads to chronic infection and risk of death. Polymeric mucins provide the structural framework of the airway mucus gel. Mucins are packaged in a highly organised and condensed form within secretory granules inside specialised secretory cells, and after the appropriate stimulus mucins are released and expand to form mucus. MUC5B the dominant mucin in healthy airways is indispensable for transport by cilia of mucus out of the lung Paradoxically MUC5B is associated with mucus obstruction in airways disease where it has been shown to have an altered structure. The planned studies will test the hypothesis that a combination of defective packaging, defective expansion and altered interactive properties yields mucus gels with aberrant transport properties that compromise the protection of the lung. Using a combination of biochemical, biophysical and structural approaches we will investigate three interlinked questions that are key to understanding this process. (1) What is the molecular mechanism that condenses MUC5B into a packaged form in secretory granules? (2) What is the molecular mechanism that controls the transition during secretion from the condensed packaged mucin to the expanded gel form with viscoelastic flow properties? (3) What are the intra- and intermolecular interactions of MUC5B involved in its self-organisation, and its interactions with other components of the secretion and the epithelial surface? It is by unravelling the molecular mechanisms that control mucin supramolecular structure and viscoelastic properties that we will gain insight into what determines aberrant mucus gel production. This will help us identify novel ways to combat the accumulation of aberrant mucus in diseased airways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: MICA: Defining the functional modes of action, and therapeutic potential of targeting, the free fatty acid receptor FFA4 in the lung.
Funder: Medical Research Council

Abstract: Our aim is to - define the physiological and signalling modes of action of FFA4 in the lung and determine whether this receptor can be validated as a therapeutic target in human airway disease. This will be achieved by addressing the following three primary objectives; 1. To understand the physiological role and modes of signalling of FFA4 in the lung We will utilise a genetically engineered mouse line that expresses the enzyme beta-galactosidase in place of FFA4 (FFA4-KO(beta-gal)) as well as validated in-house anti-bodies to FFA4 to map the expression profile of FFA4 in the murine lung. Using a unique toolbox of FFA4 small molecule ligands together with engineered mice where the FFA4 receptor has been mutated in a manner that restricts signalling (i.e. a G protein biased FFA4 mutant) we will define the models of signalling of FFA4 in the lung. Importantly, these tools will also be employed to determine the molecular mechanism by which FFA4 mediates airway smooth muscle (ASM) relaxation in murine lung. In particular to establish if FFA4 operates directly at the level of ASM or alternatively mediates the release of a relaxation factor from lung epithelium. 2. To employ murine disease models to determine the pharmacological and signalling basis of FFA4 responses in the context of airway disease Using an array of murine disease models that show hallmarks of human inflammatory airway disease we will test the in vivo efficacy of FFA4 selective small molecule ligands as agents for symptomatic treatment and disease modification. 3. To use clinical tissue samples and primary human cell preparations to establish the therapeutic potential of targeting FFA4 in human airway disease. Access to a range of human lung tissue and primary cell lines (ASM and epithelial cells) from normal donors and patients with varying degrees of airway disease (both asthma and COPD) will allow us to investigate the potential of targeting FFA4 in the context of human lung disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY