NIHRDataInsights/HRCSData huggingface dataset:
Title: PI3K Signaling and Aberrant Neutrophil Function in COPD; Implications for Disease Susceptibility, Prognosis and Therapeutic Targeting
Funder: Medical Research Council

Abstract: COPD is a major cause of mortality and morbidity. Data supports a genetic basis but screening (limited to Alpha-1-antitrypsin deficiency) can detect <2% of cases. We cannot predict who else is at risk. COPD encompasses different clinical phenotypes, however it is unclear if the same disease mechanism underpins all disease pathologies. Neutrophils (PMNs) are central to the inflammation seen in all clinical phenotypes and we have demonstrated that circulating COPD PMNs have defective chemotactic and phagocytic responses. This is seen in all disease severities, including early disease, is not present in other pulmonary conditions and is associated with abnormal Phosphoinositide3 kinase (PI3K) signaling. We hypothesise that aberrant PI3K signaling causes chemotactic and phagocytic defects which contribute to COPD pathogenesis. We will address the following questions: Does the aberrant PMN phenotype predict the onset or progression of COPD? Is the chemotactic defect due to aberrant PI3K signaling? What is the molecular basis of the defect? We will study PMNs from patients with COPD, across disease phenotypes, compared to healthy smoking controls to determine if the cell phenotype bridges all clinical phenotypes or is limited to specific pathologies. We will study circulating and bronchoalveolar lavage PMNs to assess if migration to the tissues modulates the chemotactic phenotype. Crucially, we will study family members of index cases to assess if the PMN phenotype is preserved across families, providing evidence of a genetic association for both COPD and cell behavior. We will study PI3K signaling using immunohistology, phase, DIC and confocal microscopy, cell sorting, mass spectrometry, selective inhibitors and PCR to identify the protein signals involved, their role in cell functions, the sites of their activities and their individual molecular signatures. Identified targets will be tested across COPD families to determine if they are a signal of risk.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Biomass Reduction and Environmental Air Towards Health Effects in Africa - BREATHE partnership
Funder: Medical Research Council

Abstract: The BREATHE Africa Partnership will bring together experts in indoor air pollution in order to achieve maximum benefit from several large currently funded interventions in Africa by sharing data and plans and by learning from the study teams of previous studies which reduced indoor smoke exposure elsewhere. We will initiate, develop, link and manage themed projects which share major well-resourced study sites and research teams focused on improving health by reducing biomass fuel smoke exposure. We have identified knowledge gaps and translational opportunities in this field themed as (1) Exposure and Biomarkers, (2) Health Effects, (3) Mechanisms and (4) Interventions. Each Theme has an expert Lead, a team of Partners with PhD students and opportunity to engage more research trainees at an Annual Meeting including a substantial Research Capacity Development cross-cutting programme. The specific objectives, which are common to each Theme, are to (a) harmonise trial design to ensure that exposure monitoring and health effect evaluation are comparable among active trials and that new studies benefit from past experience, (b) undertake mechanistic work, including testing of new biomarkers, using resource made accessible by current trials but not yet funded by those studies, (c) engage African trainees in new studies by a bottom-up approach offering mentored research training and new projects in the context of large, regionally relevant research projects. The BREATHE Africa Partnership is a platform to allow new, collaborative grants to be submitted by international teams with close engagement at important African field sites. The Partnership includes members from the African trials, previous trials published outside of the region, the Global Alliance for Clean Cookstoves and experts from the World Health Organisation, American Thoracic Society and Pan African Thoracic Society. It is set to be a "game changer" in the field of household air pollution.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: RESPIRATORY
Title: Understanding the physiology of pneumothorax and clinical predictors of outcome
Funder: Medical Research Council

Abstract: Aims & objectives - Determine whether digitally measured air leak and its evolution over initial (3 days) treatment, can predict short term clinical trajectory in patients with primary spontaneous pneumothorax (PSP), focussed on clinically relevant outcomes: requirement for prolonged drainage and need for surgical intervention. - Establish whether radiological surrogates (on CT scanning) of emphysema-like change and markers of lung inflammation can predict long term outcome (recurrence rate over 1 year follow-up). - Investigate the histopathological basis of PSP by examining histological specimens from patients requiring surgical intervention for evidence of lung inflammation, and correlation with clinical and radiological evidence of inflammation. - Investigate the physiology of PSP: comparing dynamic pulmonary function testing, with novel techniques: laser gas analyser and Xenon enhanced MRI. Methodology 120 patients from Oxford and four pleural UK centres will be recruited for detailed physiological and radiological investigation, and close clinical follow up based on protocolised management: including method of drain insertion, daily treatment regime and objective outcome criteria. Based on observed event rates, 120 patients retains sufficient power to validate four objective clinical parameters for a prediction model for patient relevant outcomes (prolonged air leak, need for surgery) from reproducible and robust criteria. Opportunities This study will provide novel insights in to an under-investigated and common respiratory problem, both from the scientific and physiological perspective and for clinical decision-making. If prediction parameters are demonstrated to be robust, with an estimated 3000 PSP per year there are opportunities for significant improvement in patient experience as well as cost savings to the NHS, which will be the subject of future research areas and applicable to other areas (traumatic pneumothorax, post-thoracic surgery).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Mesenchymal Stem Cell (MSC) regulation of pulmonary macrophage populations in Acute Respiratory Distress Syndrome (ARDS).
Funder: Medical Research Council

Abstract: Acute Respiratory Distress Syndrome (ARDS) is a major cause of acute respiratory failure in critically ill patients, with no effective treatment. The main characteristic of ARDS is excessive pulmonary inflammation. Lung macrophages play an important role in the pathogenesis and resolution of ARDS by orchestrating immune responses. As shown in several preclinical animal studies Mesenchymal Stem Cells (MSC) have strong protective effect in the ARDS and might constitute novel approach to therapy for this devastating disease. However, to develop a new therapy based on MSC, we need a better understanding of the mechanisms mediating their protective effect. Prior publications and our preliminary data suggest that MSC may have a role in promoting alternative activation of macrophages/monocytes, which play an important role in the resolution of ARDS. In this project we propose to study the mechanistic alterations in lung macrophages, induced by MSC in the clinically relevant in vitro and in vivo models of ARDS. This work is important because it will determine the mechanisms and importance of MSC-macrophage interactions in experimental ARDS which is critical for rationale development of MSC-based therapy for these condition, broaden our knowledge about MSC and macrophage biology and could point to new molecular therapeutic targets, with implications for other conditions with macrophage driven pathophysiology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: COPE: Characterisation of COPD Exacerbations using Environmental Exposure Modelling
Funder: Medical Research Council

Abstract: The research will incorporate an extended cohort monitoring campaign, validation of an existing exposure model and development of a predictive model for COPD exacerbations evaluated against historical electronic health records. A miniature personal sensor unit will be manufactured for the study from a prototype developed at the University of Cambridge. The units will monitor GPS position, temperature, humidity, CO, NO, NO2, O3, PM10 and PM2.5. Three 6-month cohort monitoring campaigns will be carried out, each including of 65 COPD patients. Patients will be asked to carry the sensor at all times, take peak flow measurements each morning and fill out a diary card noting any exacerbations or worsening of symptoms. Measurements from each monitor will be collated into a central database and undergo a series of QA/QC checks and scaling processes. Pollutant ratios will be used to characterise specific pollution sources and patient activities. Statistically significant associations will be explored relating environmental exposure to exacerbations and symptoms. The field campaign dataset will be used to validate a time-activity exposure model developed at King's College London. Modelled estimates of personal environmental exposure will be compared to measured pollutant exposure and performance for different pollutants and micro-environments assessed. Improved health associations will be combined with the validated exposure model to create a predictive model for COPD exacerbations across London. Spatial and temporal patterns of recorded exacerbations extracted from historical CPRD, HES and ONS records will be compared to model risk estimates, with the aim of deriving predictive algorithms for future hospitalisations. The findings of the study will be adapted for application on a national scale and disseminated to healthcare providers. The predictive algorithms will facilitate the development of a validated national COPD forecasting system.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Interactions of mechano-transduction and inflammatory pathways in asthmatic airway remodelling: in silico, in vivo and in vitro models.
Funder: Medical Research Council

Abstract: Inflammation has long been considered the main process by which airway remodelling in asthma occurs, supported by in vitro and animal studies. We, and others have shown that, instead, bronchoconstriction can promote airway remodelling independent of inflammation. These findings motivate the need to better understand how the mechanisms of inflammation and bronchoconstriction might be intertwined. Our recent work in computational airway biology leads to our central hypothesis: while airway remodelling might be initiated by inflammatory cytokines, it is perpetuated by mechanical factors. Our aim is thus to investigate the combined effect of repeated, short term, inflammatory episodes and associated mechanical forces arising from ASM contraction on long-term airway remodelling. The complexity of the bio-chemical and mechanical processes involved, over many space and time-scales, precludes identification of dominant interactions from experiments on isolated processes. We will therefore develop a quantitative modelling framework accounting for biochemical and mechanical processes at cell and tissue levels, informed by appropriate in vitro and in vivo studies. This unprecedented approach will combine mechanisms hitherto neglected in investigations of airway remodelling. In particular we will address:(i) The role of TGF-beta signalling on ASM/ECM structural changes;(ii) The role of mechanical factors in long-term structural changes; (iii) Accurate quantification of rates of apoptosis, proliferation, migration, inflammation resolution within the in vivo micro-mechanical environment. A vital aspect of this work will be an iterative process in which data from sophisticated experiments will enable refinement of models and models will influence experimental design, leading to synergistic evolution of both. The proposed work will result in a systems biology toolset that will be of benefit to the medical community in finding effective anti-remodelling therapies for asthma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: RESPIRATORY
Title: Modification of the host lipidome by Rhinovirus infection
Funder: Medical Research Council

Abstract: This project aims to examine the effects of Rhinoviruses (RV) upon lipid metabolism in human primary bronchial epithelial cells (BECs) isolated from four distinct healthy individuals. BECs will be infected in triplicate at a high MOI of HRV16 under optimised conditions that give maximal and synchronised infection. A 6 point time course will be performed and the lipids extracted and identified and quantified by HPLC-MS/MS thereby determining the cellular lipidomes, including the signalling lipids. Bioinformatic analysis will identify virally-induced changes in individual lipid molecular species and further through pathway analysis we will identify which enzyme activities have been affected. Since many of these changes will affect cellular membranes, effects upon the secretory pathway will be examined using cell biological methodologies. Using this data we will identify candidate host targets we believe to be important for viral replication and the host inflammatory response. These will be validated by siRNA knockdown, overexpression or the use of small molecule inhibitors where available. As part of our ongoing studies we can analyse samples and data from human healthy and asthma volunteers infected with RV to confirm pathway involvement.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: MICA: Finding new treatments for failed resolution of inflammation using zebrafish models.
Funder: Medical Research Council

Abstract: Diseases of failed inflammation resolution such as COPD are major causes of morbidity and mortality. Currently no therapies target the key effector cell, the neutrophil, to drive inflammation resolution. Targeting neutrophil recruitment leaves tissues unprotected against infection, and new approaches are needed to remove unwanted neutrophils without impacting host defence. We are in the midst of a revolution in neutrophil biology, in which neutrophils are recognised to be more long-lived, with active roles in programming adaptive immunity and regulating immune homeostasis. Neutrophils are now recognised to have a number of potential fates in addition to apoptosis. Neutrophils can reverse transmigrate back into the circulation in humans and mice, they can be lost into exudates in the mammalian lung or they can reverse migrate within tissues to dissipate the inflammatory burden - shown in zebrafish and with human neutrophils. I hypothesise that neutrophils are retained at inflammatory sites by "retention signals" that delay reverse migration, and that neutrophil sensitivity to these signals is mediated through a pathway requiring Serum and Glucocorticoid-regulated Kinase-1 (SGK1) and Kalirin, providing a series of new targets for drug discovery. In this Programme, I will identify the nature of retention signals and how these overlap with survival signals, then explore the molecular mechanism of action of Tanshinone IIA (identified by drug screening in my lab) which drives reverse migration. I will define the functional neutrophil kinome and exploit novel kinase inhibitors and kinase targets for the selective removal of inflammatory neutrophils, using SGK1 as a prototypic downstream signal important in retention signalling. Finally, I will define the role of Kalirin (identified by genetic screening in my lab), as a regulator of neutrophil retention signalling.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Expansion of state-of-the-art MR imaging infrastructure for pulmonary disease stratification: POLARIS
Funder: Medical Research Council

Abstract: The unique combination of expertise in technology development and the proven ability to translate new technologies into pioneering clinical studies at the University of Sheffield forms the basis of this application for funding. We have long-standing high-level collaborations with both Hospital Trusts in Sheffield (Sheffield Teaching Hospital and Sheffield Children's Hospital) that allow us to apply our developments in all age groups. This has established Sheffield as a national clinical referral centre for image based understanding of lung diseases, but our work has also enabled other centres within the UK to roll out the methods for the benefit of a much wider group of patients. This application is particularly timely with the award of the NIHR Research Professorship to Jim Wild in 2013, which will facilitate the national uptake of the technology at other centres. The expansion of our gas polarisation facilities enabled by this grant will have many benefits for our collaborating centres including creation of a national distribution facility for hyperpolarised gases for those centres that don't have their own polarisation facilities. The ongoing methodological research, clinical evaluations and work with drug companies performed on the planned new state-of-the art 1.5T scanner will ensure that the UK becomes the leading nation in this important area of diagnostic medicine.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: RESPIRATORY
Title: MICA: Fundamental Role of Phosphoinositide 3-kinase delta in Infection and Immunity: Insights from a Novel Primary Immune Deficiency Syndrome, APDS
Funder: Medical Research Council

Abstract: Background Respiratory infections account for more than 6% of the global burden of disease, causing more morbidity and mortality than all cancers combined. We have recently described a novel combined immune deficiency characterised by severe recurrent respiratory bacterial infections, viral infections and a marked predisposition to B cell lymphoma; this condition is caused by an activating mutation (E1021K) in the gene encoding the catalytic subunit of PI3 kinase delta (p110delta) and has been termed 'Activated PI3 kinase Delta Syndrome' (APDS). We wish to elucidate precisely how augmented p110delta function compromises lymphocyte and myeloid immune cell function, and to explore the potential therapeutic applications of p110delta inhibitors in our patients. Scientific Objectives. We wish to establish the importance of augmented p110delta function in susceptibility to infection, to ascertain precisely how increased p110delta-dependent signalling perturbs lymphocyte and myeloid cell function, and to explore the role of p110delta inhibitors in the prevention/treatment of respiratory infection in APDS. Plan of Investigation We have generated a transgenic mouse model of the human disease and will use this to explore immune cell function, susceptibility to bacterial and viral infection, and protection from such infections by administration of p110delta inhibitors. In addition, we will undertake an experimental medicine study using a novel inhaled p110delta inhibitor to establish the ideal profile of inhibition needed to restore aberrant immune cell function; this strategy will be guided and monitored by means of a number of biomarkers including sputum PIP3 levels. Potential Future Applications This work will generate improved understanding of infection susceptibility at the genetic, biochemical and cellular levels, and will help to clarify the role of p110delta inhibitors in prophylaxis and treatment of infections in APDS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION;6.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Unified probabilistic latent variable modelling strategies to accelerate endotype discovery in longitudinal studies
Funder: Medical Research Council

Abstract: Aim: To determine a unified probabilistic latent variable modelling strategy for integrating immunological, molecular, biological and clinical phenotypes for endotype discovery in longitudinal studies. Objectives: 1. To build a unified graphical model that represents a broad range of important variables associated with asthma and allergic disease. 2. To use innovative computational statistical latent variable modelling methods to discover novel subtypes of childhood asthma and allergy across multiple cohorts. 3. To extend these graphical models to generate novel insights into a systems modelling framework that is able to upscale in order to integrate clinical data, immunological data, genetic data and epigenetic data. 5. To extend this unified graphical modelling framework to explore principled methods for using probabilistic latent variable models to deal with missing variables in the context where not all variables are available at every time-point. 6. To formally assess the strengths and weakness of Bayesian and Frequentist methods within a longitudinal birth cohort setting. Methods: The proposal will use data from the STELAR consortium for clinical endotype discovery and data from MAAS for extending graphical models to a systems biology framework. Current Bayesian machine learning and classical-statistical probabilistic modelling approaches will be extended to identify latent disease subtypes. Dimensionality reduction techniques will be developed and explored to understand the latent space which best describes high-dimensional clinical and immunological data - considering viral and bacterial stimuli-cytokine responses separately. Scientific and Medical Opportunities: It is hoped that more refined endotype discovery will lead to understanding their underlying biological mechanisms and therefore lead to more targeted treatment and management strategies. This is applicable not just to asthma and allergy, but is generalizable to other diseases.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: RESPIRATORY