NIHRDataInsights/HRCSData huggingface dataset:
Title: Endotypes of childhood wheezing after severe RSV lower respiratory tract illness in infancy in socially vulnerable Argentinian children
Funder: Medical Research Council

Abstract: Respiratory syncytial virus (RSV) lower respiratory tract illness (LRTI) is the main cause of hospitalisation in infants worldwide. Severe RSV LRTI may contribute to asthma development, but it identifying infants who will progress to chronic symptoms is not possible to date. We hypothesise that RSV LRTI causally contributes to one or more specific asthma endotypes, We further postulate that different wheezing trajectories from infancy to school age are associated with different patterns of cytokine & gene expression profiles at initial LRTI in infancy, allowing early recognition of infants at risk. We will test our hypotheses in a unique prospective study of 1,153 children in low-income region of Argentina; 419 with severe RSV LRTI in infancy, 344 with severe non-RSV LRTI, and 390 healthy controls. Extensive data has been collected through the initial hospitalisation, and biological samples from the initial episode obtained for future analyses. Participants were followed to age 3 years (retention 91%). We propose to extend follow up to age 6 years and derive subtypes of wheeze using machine learning applied to longitudinal data. In parallel, we will carry out a series of mechanistic studies in biobanked respiratory secretions to identify immunophenotypes of antiviral responses and their relationship with outcomes. Concentrations of 39 cytokines will be assessed, and machine learning used to cluster children based on their cytokine levels. We will also investigate the transcriptional response to infection in the airway and perform unbiased analyses for differentially expressed genes and pathways in severe RSV infection and infection caused by and other viruses. We will investigate developmental profiles of wheezing through childhood across clusters using longitudinal regression models. This study represents a unique opportunity to identify RSV-specific chronic wheezing endotypes and define endotype-specific indicators of progression to long-term respiratory illness.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Econometric modelling to study dynamic health behaviours at an individual, household, birth cohort a local authority level.
Funder: Medical Research Council

Abstract: The research will study smoking behaviour from a dynamic perspective, using econometric methods. Social and spatial smoking behaviour dynamics: For birth cohorts and local authority districts, we will create a pseudo panel to explore transitions and persistence in smoking behaviour among social units through time. Smoking behaviour trajectories by birth cohort and local authority district will be combined with individuals and households to understand the role of spatial and social interactions on individual's smoking decision and on the intergenerational transmission of smoking. Natural history of smoking behaviour: Using panel data models at an individual level, I will study transitions smoking state throughout an individual's life course, define patterns of smoking histories, their evolution through time as well as the role of individual, social and spatial determinants. Intergenerational transmission of smoking behaviour: Transitions will be defined in terms of the intergenerational transmission of smoking states using panel data containing information on both parent and children's smoking behaviour, accounting for the fact that parents may have experienced transitions in smoking states throughout their life course. This research will estimate the probability of passing smoking states from parents to children and how these probabilities have changed over time. Effect of tobacco control policies Use causal inference models to study the effect of tobacco control policies on smoking behaviour dynamics at individual, household, birth cohort and local authority level, exploring new matching and weighting techniques as well as time-varying exposures. Health economic modelling and extension to other unhealthy behaviours: Model health and economic outcomes associated with trends in smoking behaviour dynamics, and extend the approach to studying the association between smoking dynamics and other unhealthy behaviours using the BiB dataset.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: RESPIRATORY
Title: A statistical framework for the apportionment of particulate contaminants and their health effect determination
Funder: Medical Research Council

Abstract: Particulate matter (PM) is a complex mixture of diverse substances from anthropogenic and natural sources, which vary widely across space and time. Despite being a major public health concern, most studies have linked total PM to health outcomes, while it is now understood that contaminant mixtures deriving from different sources may have differential health effects. We propose a Bayesian nonparametric approach that, starting from measurements of a wide range of components, estimate sources of PM and evaluate their health effects, through probabilistic clustering. We will account for spatial or temporal and covariate dependency (e.g. meteorology) in the cluster allocation; the link between sources and health outcomes will be evaluated using (i) a two-stage model where the sources identification is separated from the epidemiological model and (ii) a joint model, allowing for the outcome to influence the apportionment of the sources. Our approach will provide competitive advantages over standard receptor methods, as it incorporates: (i) temporal dynamics in time-series speciation data, (ii) spatial dependence structure in multi-site contaminant data, (iii) missing data accommodation, (iv) quantification of uncertainty associated with source profiles, (v) nonlinear relationship between sources and health outcomes. We will build an extensive simulation study and consider two real case studies: (i) to identify time-varying sources of PM in Greater London and evaluate their acute effects on respiratory hospital admissions in vulnerable populations; (ii) to disentangle spatially-varying sources of PM in South East England and evaluate their respiratory chronic effects. We believe that the proposed research (i) will provide new scientific evidence of the differential health impact of air pollutant mixtures, (ii) will help understand the sources that can be controlled and (iii) will have the potential to inform policy implementation for improving UK population health.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: RESPIRATORY
Title: MICA: Defining Endotypes of Pulmonary Fibrosis by Understanding the Functional Consequences of Known, and Novel, Genetic Associations with Disease
Funder: Medical Research Council

Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease with no cure. It results from injury to genetically susceptible epithelium leading to activation of fibroblasts. Preliminary data have identified two distinct groups of prognostic biomarkers that may reflect distinct endotypes originating from either epithelial cells or fibroblasts. Our published, and preliminary, genomic data have identified a number of genes associated with mechanotransduction pathways in both cell types. Also, prior work from a number of groups has shown these pathways to be central to IPF, but their molecular details differ in these two cell types. It is possible that these differing molecular pathways may reflect endotypes that could be targeted in a drug dependant manner leading us to this hypothesis: Diverse genetic signals in mechanotransduction pathways promote the development of targetable epithelial and mesenchymal endotypes of pulmonary fibrosis. We will test this hypothesis using a range of scientific approaches across three distinct but interacting work packages (WPs). WP1: Integration of large genetic datasets to fine-map and characterise the likely causal effects of known and new genetic association signals for pulmonary fibrosis and understand the epigenetic regulation of these signals. WP2: A range of molecular techniques will be used to manipulate genes, and their function, in primary epithelial cells and fibroblasts to understand the consequences of the genetic signals that we have identified and determine whether they can be selectively targeted with available and novel anti-fibrotics. WP3: Murine and human tissue models will be used to determine whether the genes and molecular pathways identified in WP1 and 2 lead to differential endotypic responses to anti-fibrotics in whole tissue and organ systems. We will integrate the data from all three WPs to develop translational strategies to therapeutically target endotypes of pulmonary fibrosis in the clinic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: RESPIRATORY
Title: Exploration of mitochondrial-targeted hydrogen sulfide donors as novel therapeutics for fibroproliferative lung disease
Funder: Medical Research Council

Abstract: We wish to elucidate the role of hydrogen sulfide production and supplementation in the lung, and its effects on tissue injury, fibrosis and resolution, in the context of ageing. An experiment has already been performed using aged mice, demonstrating that they are more susceptible to lung injury. The broad effects of ageing on fibrosis development will be further investigated via comparison of lung samples from old and young mice in this proposal. This will include analysis of target genes of interest using QPCR and immunohistochemical approaches in mouse samples, and human PF samples (to confirm human disease relevance). Immunohistochemistry/fluorescence will be quantified on a Vectra Polaris multispectral imaging platform. The relative role of local production of hydrogen sulfide will be determined using transgenic mice where the pivotal enzyme in the hydrogen sulfide biosynthetic pathway, cystathionine gamma-lyase (CSE), is specifically knocked-out in lung fibroblasts or epithelium. We will investigate fibrotic susceptibility (and burden of cellular senescence) using the well-characterised murine model of bleomycin-induced lung injury and fibrosis (compared with littermate controls). Sophisticated imaging (micro-CT) will be used to assess disease development in these mice, in addition to standard molecular (e.g QPCR) and biochemical measures (e.g. HPLC determination of total lung collagen). In vitro correlates (effects of hydrogen sulfide administration) will be performed using primary human cells - namely fibroblasts and epithelium, to establish a role in senescence and mitochondrial function. Physiologically-relevant air-liquid interface co-cultures will be used, plus three-dimensional fibroblast organoid cultures. In vivo data will further be corroborated using ex vivo precision cut human lung slice cultures. This combination of in vivo, ex vivo/in vitro and molecular and cell biological approaches will enable us to fully exploit our data.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Delineating late foetal human lung development and maturation
Funder: Medical Research Council

Abstract: End-stage lung disease is a major global health problem and understanding normal human lung development is an essential part of regenerative medicine. At the same time, the mortality and morbidity associated with prematurity is mostly caused by lung immaturity, despite the use of antenatal corticosteroids, which do not overcome the longterm effects of prematurity on lung function. I have made various important discoveries using human embryonic and foetal lungs up to 20 weeks post-conception - notably I have developed a genetically-modifiable organoid culture system which can be used to study human lung development in vitro. My work also includes developmental immunobiology in the lung using scRNAseq and novel approaches such as CITE-seq. The period of development after 20 weeks to birth is virtually unexplored and is referred to as the "gap". In close collaboration with obstetricians and histopathologists at UCL, I have designed a tractable way of receiving fresh healthy tissue from any organ from this crucial period of in utero development. My aims are 1) to study late foetal epithelial maturation in the lung by scRNAseq, spatial transcriptomics and organoids in order to identify novel regulators in alveolar cell fate specification, 2) to study late foetal maturation of the immune system and whether the immune system in turn affects lung epithelial differentiation, 3) to study lung vascular maturation and the mechanism of endothelial-epithelial interactions to make a functioning gas exchange unit at the air-blood interface, and finally 4) to set up a late foetal tissue resource for the Human Cell Atlas, to facilitate functional work on other organs. My overall objective is to delineate late foetal human lung development and maturation, which has the potential for wide-reaching impact on the whole field of lung developmental biology, lung regeneration and neonatal medicine.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: RESPIRATORY
Title: The structural and functional basis of defective TASK1 X-Gating in a novel channelopathy associated with sleep apnoea
Funder: Medical Research Council

Abstract: KCNK3 encodes the TASK1 K2P channel and although its functional properties mean this channel has previously been implicated in sleep apnea, the evidence was incomplete. Furthermore, loss-of-function mutations in KCNK3 are currently linked to a very different (hypertensive) disorder. We now describe a new class of 'gain-of-function' mutations found in a cohort of children with developmental delay who also all have sleep apnea requiring nocturnal O2. These de novo mutations all cluster in/near the 'X-gate', a novel gating structure we recently identified in the crystal structure of TASK1. They also all render TASK1 insensitive to GPCR-mediated inhibition which further exacerbates their gain-of-function effect. Fortunately, we find that TASK1 inhibitors, including some in clinical trials, still inhibit these mutant channels thereby presenting possible therapeutic strategies. However, the way the X-gate in TASK1 opens and closes, and the way this is regulated by drugs and natural ligands remains unknown. To address this we will employ a proven multidisciplinary approach, combining detailed structural studies with electrophysiological studies of channel activity to dissect the structural and molecular mechanisms that control X-gating and GPCR inhibition. Combined with new pharmacological tools we have available this will also help us to understand the structural and molecular mechanisms underlying drug action on TASK channels. The feasibility of this project is supported by the extensive published and unpublished evidence we present, and so present a unique and timely opportunity to make a significant advance. Overall it will provide insight into the mechanisms that become defective in this disease state, and will inform both current and future therapeutic strategies for sleep apnea and for children affected by these unusual mutations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: MICA: Senolytic therapies for chronic obstructive pulmonary disease
Funder: Medical Research Council

Abstract: COPD is a common, progressive inflammatory lung disease, now the 3rd ranked cause of death globally. Current therapies are symptomatic not affecting progression or mortality. Cellular senescence in COPD peripheral lung, induced by oxidative stress (from smoking, inflammatory cells), may lead to small airway fibrosis, emphysema and comorbidities. Senescent cells release inflammatory mediators (senescence-associated secretory phenotype - SASP), similar to those found in COPD. Removal of senescent cells with senolytic therapies is effective in murine models of age-related diseases and appears to be safe in humans. Senolytic therapies have differential effects depending on cell type. We aim to study 3 types of senolytic therapy, that target cells in cell cycle arrest inducing apoptosis and clearance. We will investigate small airway epithelial cells (SAEC), small airway fibroblasts (SAF) and alveolar type 2 cells (AT2), which play key roles in the pathogenesis of COPD. We will investigate: 1) Inhibition of anti-apoptotic BCL-2 proteins (increased in COPD), using navitoclax or galactose-conjugated navitoclax to increase its therapeutic ratio. 2) Inhibition of the interaction between p53 and FOXO4 with a novel inhibitor (F7)) 3) Inhibition of p16INK4a with a novel peptide. We will study these drugs in SAEC, SAF and AT2 cells from peripheral lung of COPD patients and age-matched smoking and non-smoking controls. We will also use precision-cut lung slices to explore differential cell effects and cell interactions. We will give these drugs intratracheally (IT) in a cigarette smoke-exposed mouse model of COPD. We have data to show that a FOXO4 inhibitor selectively removes COPD SAEC and that navitoclax inhibits senescence markers and SASP mediators in COPD lung slices. In vivo studies show that IT F7 reduces senescence markers and SASP mediators in mouse lung and regeneration of AT2 cells. Senolytic therapies may be a transformative new therapeutic approach for COPD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: MICA_Multimodal analysis of the pathophysiology of bronchiectasis
Funder: Medical Research Council

Abstract: Bronchiectasis is a chronic suppurative lung disease, characterised by permanent dilatation of the bronchi and leading to persistent or repeated bacterial infections that cause progressive inflammatory lung damage and eventually respiratory failure. While cystic fibrosis (CF), primary ciliary dyskinesia (PCD), and immunodeficiencies are known to cause bronchiectasis, the majority of cases (over 200,000 in the UK) have no known aetiology, termed 'idiopathic bronchiectasis' (IB), and currently have no licensed therapies available to treat them. There is therefore a critical unmet need to define the pathophysiology of idiopathic bronchiectasis and thereby identify therapeutic targets. There are currently no in vitro or in vivo models of IB, mandating a multimodal, cross-disciplinary, and multi-scale, approach to understand this condition. Our aim therefore is to integrate genomics, single cell and spatial transcriptomics, molecular cell biology, and genetically tractable, optically transparent, functional organ models (incorporating epithelial cells, phagocytic cells, and bacteria) to define key pathways involved in the pathobiology of IB.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Stratified interventions in ARDS: EMINENT ARDS Work Package 2.
Funder: Medical Research Council

Abstract: Acute respiratory distress syndrome (ARDS) is a severe form of acute respiratory failure that affects >10% of all patients admitted to intensive care units across the world. Although in-hospital mortality remains high (35-46%), 70% of long-term survivors subsequently return to their pre-morbid employment, indicating significant potential for recovery. There is no licensed pharmacotherapy for ARDS anywhere in the world, and our understanding of ARDS disease processes remains limited. Moreover, considerable heterogeneity exists within the population of patients with ARDS. Together these factors represent a major roadblock to drug discovery. There is an urgent and unmet need to further define disease mechanisms in ARDS, and to develop tools to aid patient stratification so we can ensure the right drug is received by the right patient at the right time. Having identified multiple novel subgroups of patients with ARDS in Work Package One (WP1), we now wish to prospectively validate the presence of these groups in a new population of patients with ARDS, and determine whether the groups we identified are mechanistically discrete (end-types), or whether they represent different phases of the same pathology, as well as to determine whether the subgroups we found may be amenable to therapeutic intervention.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: MICA: Mitochondrial dysfunction in macrophages and impaired bacterial clearance in chronic obstructive pulmonary disease (COPD)
Funder: Medical Research Council

Abstract: Chronic obstructive pulmonary disease (COPD) results from small airway obstruction. No treatment halts progression. Adaption in metabolism and mitochondrial function is essential for macrophage responses to bacteria. Macrophages show impaired responses to bacteria in COPD, combined with reduced flexibility in adaption of metabolism and generation of mitochondrial reactive oxygen species (mROS). We hypothesise macrophage defects in mitochondrial antibacterial function underly COPD susceptibility. In COPD there is a systemic macrophage defect compounded by the lung environment. Therefore, we will study both monocyte-derived macrophages and alveolar macrophages (AM) in healthy volunteers (non-smokers and current smokers) and in patients with COPD. To examine findings in vivo we will use mouse models of infection and airway disease. We will identify metabolic adaptions to bacteria in mouse models of infection and healthy AM, using high-performance liquid chromatography-mass spectrometry (HLPC-MS) tracing, RNA-Sequencing and proteomics. We will repeat this approach to examine which pathways are altered in COPD macrophages and in an LPS/elastase mouse model of emphysema. Next, we will explore the kinetics and mechanisms of mROS production and mitochondrial fission following bacterial challenge and how COPD modulates these. Mechanisms will be validated using induced pluripotent stem cell derived macrophages (iPSCDM) and CRISPR/Cas9 gene editing combined with genetically modified mice or zebrafish. We will use iPSCDM from patients with genetic defects in mitochondrial functions we identify to confirm key findings. To recalibrate mitochondrial antibacterial responses in COPD we will perform a high content drug screen complemented by candidate approaches (Nrf2 agonists and BH3 mimetics). The ultimate goal will be to identify therapeutic candidates for future clinical trials to recalibrate antimicrobial responses in AM and prevent COPD progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY