NIHRDataInsights/HRCSData huggingface dataset:
Title: A multi-scale modelling framework for airway hyper-responsiveness and remodelling in asthma
Funder: Medical Research Council

Abstract: Asthma is a chronic inflammatory disease, responsible for significant societal and economic burdens worldwide. It is characterised by airway hyper-responsiveness, inflammation and remodelling. The underlying biological mechanisms responsible for these characteristics continue to be debated. The aim of the work proposed here is to develop a novel multi-scale mathematical modelling framework that explicitly couples the molecular level interactions in the airway smooth muscle (ASM) cell to acute contractile biomechanical response at the tissue level in an airway as well as long-term airway remodelling. The theoretical models will be informed by, and validated by, findings from experimental groups that focus on cellular level observations (e.g. cytoskeletal mechanical properties in response to stretch) as well as macroscopic observations of airway calibre changes in agonist-initiated precision-cut lung slice experiments during which intracellular calcium signals can also be measured. Development of the mathematical models will require the use of a number of different theories including continuum approaches that account for the glass-like rheology of biological tissue to quantify the local stress environment of the ASM cell and response time-scales involved, non-linear dynamics and reaction-diffusion models of intracellular calcium and cross-bridge muscle mechanics within the cell to predict force generation. All of these are linked (with feedback) through the functional processes involved. Furthermore the effect of repeated stress challenges on ASM and the potential for remodelling to be initiated over long time-scales will also be accounted for within the material constitutive laws. The coupling of the different models is challenging mathematically because the biological processes and dynamics have to span multiple spatial and temporal scales with the need to transfer key information across the scales. The mathematical framework will provide an important first step towards identification of key interactions from sub-cellular to tissue level events involved in asthma. This in turn will provide the basis for a computational platform (in the long term) for the assessment of new hypotheses on the system as a whole, and allow predictions of the effect of potential new therapies.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: RESPIRATORY
Title: European Community Respiratory Health Survey III
Funder: Medical Research Council

Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are major causes of morbidity in the aging population. Generational increases in the prevalence of asthma and allergy suggest the burden of these diseases will increase in the elderly population, but our knowledge of the prognosis of allergy and asthma is limited. It is thought that asthma and allergy produce airway inflammation that leads to airway remodelling, but there are few large longitudinal studies in adults that can examine the association of asthma and IgE sensitisation with COPD over decades. The European Community Respiratory Health Survey has collected extensive information on respiratory phenotype in representative samples of more than 10000 adults on two occasions over the last twenty years. Researchers in collaborating centres wish to recontact study participants who are now aged between 40 and 65 years. The aims are to a) describe change in respiratory symptom prevalence in adults as they age b) assess change in IgE sensitisation to common allergens in adults as they age c) determine whether the prognosis of asthma is influenced by any observed change in atopic status d) assess whether atopic status and asthma as measured over a twenty year period is associated with lung function decline or the development of COPD in older adults e) describe the association of obesity and physical exercise with asthma, lung function, lung function decline and the prognosis of asthma Cohort members will be examined as in previous surveys with additional measures of fatness and post bronchodilator lung function. In the British centres samples of nasal lining fluid will be obtained and analysed for inflammatory cytokines. Serum samples will be taken for assessment of IgE to common allergens in a single laboratory. A repeat cross-sectional survey will be conducted to a) assess comparability of the survivor cohort with the current population b) identify prevalent asthma cases that will be included in the study increasing the number of asthmatics for some analyses c) increase the number of asthmatics for follow-up in the event of further follow-ups. Funds are being requested for the execution of this project in two British centres and for coordination of the multicentre study (23 centres, 11 countries, 10 language groups). This application focuses on some specific analyses but the wealth of data collected through this and previous initiatives will provide a basis for further work to examine the role of environmental and lifestyle factors with respiratory disease.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Statistical modelling of longitudinal data from cohort studies to better understand phenotypes of asthma.
Funder: Medical Research Council

Abstract: Aims & objectives: To gain a better understanding of the phenotypes of asthma by statistical modelling of multidimensional, longitudinal data and to apply these models across cohorts in different settings and with varying data sets. To examine associations between genetic variants identified through genomewide association studies of asthma with asthma phenotypes, in order to understand the biological pathways leading to different phenotypes. Design: The project will build on work that I have developed in the Avon Longitudinal Study of Parents and Children (ALSPAC) using latent class analysis to derive wheezing phenotypes using reports of wheezing from birth to age 7. Methodology: Mplus will be used to fit a multi-level model within the latent class analysis framework in order to expand the single approach based on wheezing symptoms to a multi-dimensional approach including other respiratory symptoms and objective measures of allergy and lung function. A pre-selection of most relevant variables using Principal Components Analysis is likely to be required to limit the number of parameters in the model. Cubic splines will be used to derive parametric curves representing the asthma phenotypes to account for the different number and timing of variables in each dataset. The resulting models will then be tested in cross-cohort comparisons with similar longitudinal data and outcome variables. The accuracy and generalisability of models will be validated across the independent cohorts by using deviance differences. Scientific and Medical Opportunities: The results of this study will establish whether modelling of phenotypes in complex diseases, such as asthma, is feasible across cohorts with different data acquisition methods. The ability to harmonize detailed phenotypes in consortia of large, longitudinal cohorts with complementary genetic data will increase the potential to understand how genetic and environmental influences interact to cause disease expression. Current approaches are limited to crude disease definitions. If the potential of genome wide data is to be realised to its full, large studies with comparable outcomes to enable investigation of less prevalent phenotypes will be necessary. Methods developed here will be potentially transferable to other complex, polygenic diseases. Identification of diverse biological pathways associated with variation in disease phenotype is a key step in the identification of targets for disease modification or prevention. Some of these opportunities may be overlooked if the complexity of phenotypic heterogeneity is not accounted for in genetic and association and gene-environment interaction studies.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: RESPIRATORY
Title: To investigate the causal roles of environmental factors and viruses on exacerbations of COPD
Funder: Medical Research Council

Abstract: Aims and Objectives: The aim of this study is to establish the causal roles of environmental factors and viruses on exacerbations of chronic obstructive pulmonary disease (COPD) by investigating the relationship between ambient temperature, air pollution and circulating viruses on daily symptoms and COPD exacerbations. The specific objectives are; 1. To quantify the relationship between COPD exacerbations and COPD mortality with (a) temperature and other climate factors (such as humidity and sunlight hours) and (b) air pollution 2. To investigate the impact of environmental factors (ambient temperature and air pollution) on circulating viruses 3. To quantify the relationship between circulating viral levels and COPD exacerbations and mortality 4. To apply the results from Aims 1 to 3- to the detailed symptoms, lung function measurement and viral detection data in the London COPD cohort. 5. To establish to what extent the effect of environmental factors on COPD exacerbations and mortality are mediated or explained by viral infections Methodology: Large scale work based on national computerized clinical data will be complimented by detailed work on Prof Wedzicha‘s ongoing cohort of approximately 300 COPD patients who have rich data on both symptoms and viral exposures. Meteorological and pollution data will be obtained from the national network of monitors, outcome measures will be obtained from Hospital Episode Statistics (HES), General Practice Research Database (GPRD), and the Office for National Statistics (mortality). Viral data will be obtained from the Health Protection Agency (HPA), the GPRD (flu consultations and upper respiratory tract infection consultations). Scientific and Medical Opportunities: COPD is the 4th leading cause of death and prevalence is increasing. Exacerbations (commonly caused by viruses), contribute to disease progression and mortality and are the commonest cause of medical hospital admission in the UK. The forthcoming Clinical Strategy for COPD for England highlights a need to improve the quality of COPD services and decrease health care costs. Although the relationship between environmental factors and COPD exacerbations is already being assessed (Healthy Outlook?), this work adds additional detail regarding daily symptom changes and detailed virus data from the London COPD cohort. With the future development of new antiviral agents, this information may help tailor the use of these drugs to maximal effect. As climate change results in warmer winters, understanding the relationship between environmental factors and circulating respiratory viruses will prepare us for the change in exacerbation patterns likely to occur.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: RESPIRATORY
Title: Epithelial and macrophage dysfunction in alpha1-antitrypsin deficiency
Funder: Medical Research Council

Abstract: 1-antitrypsin is the most abundant circulating protease inhibitor. The common severe Z allele (Glu342Lys) causes the protein to form ordered polymers that are retained within the endoplasmic reticulum (ER) of hepatocytes. These polymers do not activate the unfolded protein response (UPR) but lead to activation of NF-kB. This in turn causes liver disease whilst the lack of circulating 1-antitrypsin predisposes the PiZZ homozygote to early onset emphysema. Z 1-antitrypsin is synthesised and secreted by monocytes/macrophages and bronchial and alveolar epithelial cells within the lung. It is unknown whether the accumulation of polymers within these cells also activates NF-kB as they do in the liver. I propose to evaluate this with 2 specific aims: (i) to determine the effect of intracellular polymers on epithelial cells in vitro and (ii) to determine the effect of intracellular polymers on lung epithelium and monocytes/macrophages in vivo. I will firstly generate alveolar (A549) and bronchial epithelial cell lines (BEAS-2B) that conditionally express wildtype and Z 1-antitrypsin under the control of a Tet-ON promotor. I will then assess whether the expression of wildtype or Z 1-antitrypsin causes the activation of the unfolded protein response (by measuring BiP, Grp94, GADD34 and CHOP protein levels, XBP1 mRNA splicing and ATF6 reporter activation), ER calcium release (Fluo-4 fluorescence), NF- B signalling (NF- B subunit protein levels, subcellular localisation and reporter activation) and the release of inflammatory cytokines such as IL-6 and IL-8 by sandwich ELISA. In the second aim I will purify monocytes from the blood of individuals with PiZZ 1-antitrypsin deficiency and PiMM controls. I will assess whether the monocytes that express Z 1-antitrypsin show evidence of ER stress, calcium release and a greater release of inflammatory cytokines. Finally, I will bronchoscope and take bronchial biopsies from individuals with PiZZ 1-antitrypsin deficiency and PiMM controls to assess whether epithelial cells in vivo show similar changes to those see in vitro. Taken together these experiments will allow me to determine whether the accumulation of Z 1-antitrypsin causes epithelial and monocyte/macrophage dysfunction in 1-antitrypsin deficiency. If so, then this would provide novel insights into the pathogenesis of the associated emphysema.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: MRC-Asthma UK Centre in Allergic Mechanisms of Asthma
Funder: Medical Research Council

Abstract: The prevalence of allergic disease in the UK is amongst the highest in the world and that of asthma in young adults is the highest in Europe. The Centre is a partnership between the MRC, Asthma UK, Imperial, QMUL and KCL. The mission of the Centre is to understand allergic mechanisms of asthma to inform the development of new treatments; to create a high quality environment for research training; and to be an authoritative voice on allergy and asthma in the public domain. In the last five years the Centre has successfully established a critical mass of researchers working co-ordinately in an internationally competitive unit for the benefits of health care. It has established core facilities, thereby focussing resources. The Centre has provided enhanced opportunities for new collaborative programmes of work to be started with even greater potential for more competitive funding, which would not otherwise be possible. The Centre has made substantial progress in each of the domains contained in its mission statement, namely in scholarship, training and public engagement. It has brought researchers together under an integrated strategy for allergy and asthma research which is unique in the UK. The research network has facilitated the conduct of translational science from the womb to adulthood and from the gene to the community.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Defining the genetic contribution and functional role to altered lung function of genes identified by GWAS meta-analysis
Funder: Medical Research Council

Abstract: We have recently identified GSTCD, AGER and HTR4 as key genetic factors which in part determine lung function and risk of COPD at the population level. Little is known regarding the function of GSTCD, although homology searches suggest it may act either as a regulator of GST activity, a modifier of Ca2+ signalling, or as a regulator of Cl- homeostasis. The role of HTR4 in determining airway function is also unclear although it may modify either cholinergic neurotransmission or potentially epithelial function. AGER is known to be a marker of epithelial injury in the lungs, but characterisation of functional variants has not been performed to date. The key hypothesis underlying this proposal is that functional variants in genes identified by genome wide association study are an important determinant of FEV1 in both the general population and in patients with respiratory diseases such as COPD. In order to address this hypothesis the programme has four main aims: (i) to determine the key genetic variants in these 3 genes, (ii)to define the functional role for these genes in relevant airway and inflammatory cells, (iii) to identify key functional variants of GSTCD, AGER and HTR4 and (iv) to determine the contribution of variants in these genes to lung function in the general population and subjects with COPD and asthma.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Role of HIF and Prolyl-hydroxylase enzymes in ventilatory acclimatisation to hypoxia.
Funder: Medical Research Council

Abstract: The body?s supply of oxygen is managed through the controlled operation of both respiratory and cardiovascular systems The efficacy of oxygen uptake is monitored by arterial chemoreceptors which, in response to acute hypoxia, evoke a robust increase in ventilation. This response helps defend against asphyxia. With more prolonged hypoxia however there follows a further steady increase in basal ventilation and an enhancement of the acute hypoxic response which develops over a period of hours to days. This secondary response is referred to as ventilatory acclimatisation. Acclimatisation is often associated with adaptation to life at altitude but a similar process also occurs in many chronic diseases where hypoxaemia is present. We know relatively little about the mechanisms of acclimatisation but several lines of evidence indicate that it is largely due to changes in the oxygen sensitivity of peripheral chemoreceptors themselves. There is also evidence that acclimatisation only occurs in response to hypoxia, other chemoreceptor stimuli do not have the same effect. The recent discovery that a hypomorphic mutation in the von Hipple Lindau factor gene has similar effects upon ventilatory control to those of chronic hypoxia, further suggests that hypoxia inducible factor (HIF) signaling may be involved. The aim of our research therefore is to investigate the hypothesis that acclimatisation involves oxygen dependent control of gene transcription via prolyl hydroxylases and hypoxia inducible factor/s (HIF) which increases the sensitivity and/or number of oxygen sensing type-1 cells in the carotid body. In evaluating this hypothesis we aim to 1) Evaluate the functional significance of HIF signaling in ventilatory acclimatisation by using both gain and loss of function mutations in the HIF signaling pathway. These mutations will be induced acutely in adult mice and their ventilatory responses to both chronic and acute hypoxia will be measured. 2) Investigate the role of prolyl hydroxylases (PHD?s). Since PHD?s control oxygen dependent degradation of HIF we hypothesize that pharmacological inhibition, or induced genetic ablation, of PHD will mimic acclimatisation. 3) Determine the effect of chronic hypoxia and HIF signaling upon carotid body morphology. In particular we seek to establish whether hyperplasia of type-1 cells coincides with the development of acclimatisation. 4) Determine whether chronic hypoxia and HIF signaling alter the intrinsic chemosensitivity of type-1 cells. Specifically we will look at the effects of chronic hypoxia and HIF gain & loss of function mutations on stimulus evoked intracellular calcium signaling events in acutely isolated type-1 cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: MRC/ABPI COPD Consortium Work Package 1: COPD Phenotyping
Funder: Medical Research Council

Abstract: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and healthcare expenditure in the UK (#1B/annum). Worldwide, over 27,000 people died from COPD in 2004 and the WHO forecasts COPD to be the 3rd leading cause of death in the world by 2030. Current therapies are ineffective in preventing the progressive airway remodelling and emphysema, or recurrent exacerbations which are COPD hallmarks. New therapeutic approaches targeting these processes would address a major unmet need. This application will provide the patient-specific data and samples that will underpin the phenotyping effort described here and all the mechanistic studies described in the other work packages of the consortium. This MRC/ABPI COPD consortium will build on existing COPD cohorts and bio-resources from early to established disease and relevant controls. These cohorts and bio-resources include MRC funded, Industry, EU-FP7, NIH, and NIHR-led cohorts. Importantly this application provides the framework for the consortium to evolve to support its changing needs and is sufficiently flexible to allow integration with future initiatives. The available data comprise extensive clinical characterisation, standard physiological measurements, CT-scans, and biological phenotyping from genome to proteome. Additional data are available from some cohorts at exacerbation events complemented with detailed molecular microbiology and virology. In others detailed measures of co-morbidities, activity monitoring, systemic inflammation and skeletal muscle biology has been assessed. We shall harmonise the data between the cohorts and will add follow-up data, and in pre-specified subgroups innovative small airway physiology, imaging and the sampling of tissue and blood to facilitate, target validation and ex vivo modelling and potentially high throughput ?omic? analyses. These data will be used to identify biologically relevant sub-phenotypes required to support the studies outlined in the other work packages, and will be interrogated using bio-statistical modelling to identify novel phenotypes to drive future hypothesis driven mechanistic studies. This connectivity with the other work packages will undergo an iterative process of ?test? and ?validation? groups each further refining the phenotyping effort; informing the mechanistic studies and the sample sizes required for adequate statistical power. Through this integrated joint academic and industry consortium we shall provide the framework necessary to achieve a step-change in our understanding of COPD which we anticipate will lead onto improvements in the treatment of this devastating disease.


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