NIHRDataInsights/HRCSData huggingface dataset:
Title: To delineate immune mechanisms for limiting asthma development and severity
Funder: Medical Research Council

Abstract: Asthma is a chronic, allergic inflammatory lung disease generally characterized by increased numbers of eosinophils and lymphocytes producing type 2 cytokines. However, the pathogenic mechanisms involved in the development of asthma and the regulatory mechanisms for controlling allergic immune responses in the airways are not fully understood. Further, more than 1/3 of asthma patients have an aspirin allergy or a reaction to non-steroidal anti-inflammatory drugs (NSAID), needing an improved understanding of the mechanisms behind this disease. In this CDA fellowship, I will investigate the cellular and molecular mechanisms that underpin regulation of type 2 immune responses and allergic lung inflammation in asthma and how this is controlled by prostaglandin signalling pathways that are activated in response to allergens and pathogens. Prostaglandins (PGs), especially PGE2, are produced by multiple types of lung cells (e.g. epithelial cells, macrophages and dendritic cells etc) in response to various stimuli. In this proposed project, we will study how PGs regulate group 2 innate lymphoid cells (ILC2s) and allergic lung inflammation and, conversely, how down-regulation of PG signalling by NSAIDs exacerbates allergic lung inflammation. To address these questions, we will examine the mechanistic contribution of the PGE2 pathway to the control of allergen/pathogen-induced accumulation and activation of ILC2s and asthmatic lung inflammation using acute and chronic lung inflammation models and novel transgenic animals with specific deletion of PGE2 receptors in lymphocytes. Small molecule compounds targeting the PGE2 pathway will be used for pharmacological manipulation of type 2 immune responses in vitro and in vivo. In addition, I will also develop methods to analyse the effects of PGE2 signalling on human ILC2 response from healthy individuals and asthma patients in collaboration with our clinical colleagues.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Burden of Obstructive Lung Disease Follow-up in low/middle income countries (BOLD II)
Funder: Medical Research Council

Abstract: A follow up survey of 15,000 participants from 20 sites in 15 low/middle income countries from the Burden of Obstructive Lung Disease (BOLD) study will establish, from death certificates where available and verbal autopsies everywhere, the date and cause of death of those who have died. FEV1/FVC and FVC will be measured after bronchodilation with 200 micrograms salbutamol administered through a spacer using the same equipment, same protocol and same centralised training and quality control as at the baseline survey. The influence of FVC and FEV1 on mortality will be assessed mutually adjusting for each and also adjusting for other confounders such as tobacco consumption, age and sex. Sub-analyses will assess whether any excess mortality associated with poor lung function is associated with particular causes of death including chronic lung disease and cardiovascular disease. Differences between the decline of lung function with age measured in cross-sectional and longitudinal analyses will be used to estimate the change in lung function with age that is due to differences between birth cohorts. Rate of change in lung function in individuals will be assessed against risk factors including tobacco consumption, history of tuberculosis, exposure to household air pollution, occupational history, poverty, education and diet after adjusting for age and stratifying by sex. Methods for assessing these risks will mostly be the same as those used in the baseline survey. Occupational history will be assessed more fully using a modified OSCAR protocol and dietary habits will be described using GA2LEN food frequency questionnaires designed to collect standardised dietary information from diverse food cultures. Results will be publicised locally and through national and international meetings. Information will be provided to government departments both directly by study members and through an advisory committee chaired by a senior member of WHO.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Mesenchymal stem cell-derived extracellular vesicles as a cell-free therapy for ARDS.
Funder: Medical Research Council

Abstract: Acute respiratory distress syndrome (ARDS) is a major cause of mortality in the critically ill patients with no effective pharmacological treatment. Mesenchymal Stem Cells (MSCs) hold significant therapeutic promise for this condition and are rapidly progressing to clinical trials across the world. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Exracellular vesicles are key components of the MSC secetome and were reported to recapitulate efect of MSCs in the pre-clinical models of ARDS. We have demonstrated that MSC EVs are central for MSC effect on modulation of macrophages in vivo and in vitro. Furthemore we have identified that functionally active mitochondria secreted in EVs are largely responsible for the EVs effects. In this proposal we wish to undertake feasibility studies which will lead to further focussed pre-clinical development of MSC EV-based therapy for ARDS through the MRC DPFS scheme and utimately to Phase I/II clinical trial within the next 5 years. The main goal of this proposal is to evaluate therapeutic potential of MSC EVs and investigate their mechanism of action through mitochondrial transfer in the clinically relevant in vitro and in vivo models of ARDS. We will address the following research questions: 1) To determine the efficacy of intravenous and intra-tracheal EVs administration routes; 2) To assess the efficacy of repeated EV administration vs. single dose; 3) To find the optimal therapeutic dose; 4) To establish comparative efficacy of the frozen-thawed vs. freshly isolated EVs; 5) To investigate the mechanism of EVs action via mitochondrial transfer. To answer these questions we will use murine model of E.coli-induced lung injury and primary human lung epithelial, endothelial and immune cells stimulated by pro-inflammatory cytokines. These data are essential requirement to unlock the clincal development by the regulatory bodies such as MHRA and EMA.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: RESPIRATORY
Title: Inhaled EP4 receptor agonists for the treatment of idiopathic pulmonary fibrosis
Funder: Medical Research Council

Abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal chronic fibrosing interstitial lung disease with a median survival of just 3 years. IPF is characterised by the formation of fibroblast and myofibroblast foci that excrete excessive amounts of extracellular matrix resulting in airway stiffening and loss of pulmonary function. Recent work has demonstrated a link between a decrease in prostaglandin E2 (PGE2) signalling and fibrotic diseases, and restoration of this pathway can inhibit, and in some cases reverse, remodelling processes associated with fibrosis. Studies in our lab have shown that EP4 receptor agonism potently inhibits fibroblast migration, proliferation and differentiation to a variety of disease-associated stimuli. This demonstrates that the PGE2-EP4 signalling axis has the potential to prevent further structural changes in the lungs, making EP4 an attractive target to treat IPF. EP4 receptor expression is not restricted to the lung, so we propose inhaled delivery to minimise systemic exposure and mitigate anticipated on-target side effects, such as hypotension and inflammatory pain. The immediate goal of this project is to develop lead compounds with anti-remodelling efficacy and appropriate inhaled pharmacokinetic (PK) and lung coverage. Efficacy will be assessed through inhibition of primary human lung fibroblast proliferation and fibroblast to myofibroblast transdifferentiation (FMT). Duration of lung action will be evaluated using in vitro PK and cell membrane wash-out assays, followed by in vivo lung PK studies. This design strategy is based on our previous experience developing successful long-acting inhaled GPCR agonists (e.g. indacaterol). Compounds will be developed from 2 distinct chemical series, one disclosed in literature and one novel class from which we have synthesized preliminary active examples. Selected compounds will form the basis of a future lead optimisation MRC DPFS application to deliver novel, clinical candidates to treat IPF.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: Atmospheric microplastics, their accumulation in vivo and potential toxicity.
Funder: Medical Research Council

Abstract: An estimated 8.3 billion tonnes of plastic have been manufactured since mass production began in the 1950s. Eighty per cent of this has accumulated in land fill or the natural environment. Plastic can photodegrade into particles and fibres known as microplastics (<5 mm). Microplastics have been reported in dietary sources and the air, prompting speculation about risks to public health. A solid evidence base characterising population exposure, however, is lacking. Plastic fibres have been observed in pulmonary tissue. There are several mechanisms through which harm could occur-for example, by triggering inflammation, or releasing associated priority pollutants, including monomers and additives, although no definitive studies on health effects have been conducted. During this fellowship I propose to assess the human health risks of microplastics. I will address three novel issues: WP 1. The extent and sources of atmospheric microplastic contamination. Monitoring at an urban site will be conducted. Samples will be inspected with Raman microscopy to characterise suspicious particles, including the inhalable size range. A standardised method will be established for application in contrasting environments. WP 2. Microplastic uptake and accumulation in vivo. Human pulmonary tissue will be analysed using a combination of histopathology and Raman microscopy methods to identify and characterise potential microplastics. This will indicate whether microplastic exposure occurs in vivo, whilst validating a tissue screening method. WP 3. The potential toxicity of microplastics. The toxicity associated with microplastic size, shape and type will be screened in hazard mechanism studies. Molecular changes in target tissues will be assessed to determine the potential mechanistic toxicity of exposure to and accumulation of microplastics. Identifying hazardous parameters of microplastics will guide waste management, polymer engineering and product design.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: RESPIRATORY
Title: Lung function trajectories from birth to school age in African children, and their early life determinants
Funder: Medical Research Council

Abstract: Early-life factors are crucial for lung function growth, and subsequent COPD pathogenesis. Childhood asthma and early-life LRTIs reduce lung function through childhood, leading to diminished lung function at the physiological plateau in the third decade of life. The burden and pattern of LRTIs and asthma in Africa, as well as environmental factors which affect developmental trajectories of lung function, are markedly different than in high-income countries. However, despite the high prevalence and severity of childhood asthma, high incidence of LRTIs, and many harmful environmental exposures, to date there is no data on early-life factors associated with diminished lung function in Africa. We propose to extend our work in the Drakenstein Child Health Study (DCHS), a birth cohort of 1000 South African children who have been followed from antenatal period through early childhood, to address early-life determinants of lung function in African population. Unique aspect of the study is that lung function measurements have been taken longitudinally from age 6 weeks. We collected detailed information on LRTI (including aetiology) and environmental exposures. We will bring it together with the expertise in data mapping and analytical approaches in the UK STELAR consortium. We will extend the follow-up in DCHS through age 8 years, and carry out detailed measurement of lung function. This will extend the number of time points at which clinical outcomes and lung function have been measured in an identical way, and lay foundations for longitudinal analyses, thereby creating a unique resource unparalleled anywhere in LMICs. We will identify trajectories of lung function in African children from birth through age 8 years, and determine risk factors for low lung function trajectory, to inform the development of intervention strategies to reduce the risk of low lung function and prevent multi-organ morbidity and premature death in Africa.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Anion Carriers for Channel Replacement Therapy
Funder: Medical Research Council

Abstract: Anion transporters (anionophores) are actively studied by supramolecular chemists, with the aim of discovering useful biological effects. In particular, it is hoped that anionophores might be used to bypass the malfunctioning anion channels which underlie "channelopathies" such as cystic fibrosis (CF). However, while much progress has been made on anion transport across synthetic membranes, the effects of anionophores on cells is less well studied. This proposal involves a collaboration between two supramolecular chemists (A.P. Davis and P.A. Gale) and a biophysicist (D.N. Sheppard) which aims to fulfil the biological potential of anionophores, with particular focus on the treatment of CF. In a project funded through EPSRC, we explored a range of anionophore architectures, demonstrating very high activities. We also developed an assay for anion transport in cells, finding that some agents were both highly effective and non-cytotoxic. Here we aim to progress our work to the point where clinical studies can be justified. The research will involve: (a) Identifying optimal candidates for clinical development through synthesis and testing in cells, employing a variant of the previously-developed assay; (b) Testing candidates in polarised epithelia, including the demonstration that anionophores can restore function to CF airway epithelia and promote the recovery of mucociliary transport; (c) Mechanistic studies that will lead to an improved understanding of anionophore activity in membranes, as well as distribution in cells; (d) The design, synthesis and study of anionophores with optimised selectivity, especially for chloride vs. OH-/H+; (e) The development of delivery systems that allow a greater range of agents to be studied in cells. As well as providing a platform for clinical development, the above work will serve to develop and characterise a set of selective anion transporters which can be offered to the biomedical community for use as research tools.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Mobilising epithelial stem cells for human lung regeneration
Funder: Medical Research Council

Abstract: Chronic lung disease is responsible for 6 million inpatient bed days a year in the UK. Chronic obstructive pulmonary disease (COPD; including emphysema) and idiopathic pulmonary fibrosis (IPF) are increasingly recognised as diseases of epithelial damage and failed epithelial regeneration, with no treatments that reverse lung function decline. Unfortunately, a limited amount is known about adult stem cell populations that maintain adult human lung and in particular, strategies to support or enhance epithelial regeneration do not yet exist. During prior research, with Dr Emma Rawlins (Cambridge University) on human lung developmental biology, I developed a novel cell culture system which allowed the expansion of lung stem cells for the first time. I hope to establish myself as a clinical academic group leader and develop my independent work with access to adult human clinical specimens and a multitude of murine models available between the two main centres. Aim1: I intend to develop methods to expand adult stem cells from the human lung. I will systematically evaluate the importance of individual factors within the culture medium for the expansion of adult lung stem cells. This work will be greatly facilitated by collaboration with CSCRM as the Kings Stem Cell Hotel. These experiments will define specific factors and pathways that orchestrate epithelial stem cell self-renewal and differentiation during homeostasis. Aim 2: Using the factors identified as determinants of lung stem cell behaviour, I will examine their role during lung homeostasis in living organisms such as mice. Aim 3: Finally, I will focus on whether manipulation of basal stem cells can be protective against injury. To test this hypothesis, I will use tracheal injury models (naphthalene and polidocanol) as these are most relevant to human airway regeneration.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: RESPIRATORY
Title: The effect of Chronic Obstructive Pulmonary Disease (COPD) and Exercise on DNA methylation in skeletal muscle biopsies
Funder: Medical Research Foundation

Abstract: Chronic obstructive pulmonary disease (COPD) is a condition of the lung in which the airways become inflamed and narrowed and the alveoli (air sacs) are damaged, both resulting in difficulty breathing. COPD affects over 1.2million people in the UK and kills approximately 30,000 people a year. COPD is also associated with problems distinct to the lung (comorbidities) including muscle weakness. Loss of muscle strength significantly contributes to reduced quality of life in individuals with COPD. We have performed a study to assess how an exercise regime over 8 weeks improves measures of muscle function and to understand how best that benefit is sustained. Here we are interested in understanding how "epigenetic processes" may contribute to differences in muscle cells between individuals with COPD and those without and also how exercise might alter these differences. Epigenetic processes control how and when certain parts of our genetic code are read. In other words how and when our genes are "switched on". Epigenetic processes are of particular interest to us as they can be changed by a person's contact with environmental factors, for example smoking, allergy and exercise all "trigger" epigenetic processes. One process in particular is DNA methylation. DNA methylation has been shown to be altered by exercise in individuals with Type 2 Diabetes but not previously in COPD. Here we will measure DNA methylation in individuals with and without (for comparison) COPD, at the start of the study, following 8 weeks of structured exercise and again following 4 weeks rest (week 12). We already have details of the effects of COPD and exercise on gene activity (expression) and exercise capability of the individuals included in the study so this data will add biological mechanism to these existing results.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Does a low Exhaled Nitric Oxide level exclude a clinical benefit from inhaled corticosteroids in suspected asthma; a randomised, placebo controlled trial.
Funder: Department of Health and Social Care

Abstract: Background. International literature has demonstrated that up to 40% of patients treated for asthma may not have asthma and do not require treatment with inhaled steroids [1-2]. We are just completing a feasibility study (PB-PG-1010-23145) which has shown that out of 70 patients seen 52% had no objective evidence of asthma and 48% obtained no benefit from the inhaled steroid they had been prescribed. Although this is likely to be an overestimate as some patients were referred to the study due to diagnostic uncertainty it is in keeping with previous evidence. Looking at the baseline criteria an exhaled nitric oxide level of below 27 ppb appeared to exclude a response to inhaled steroid treatment. We now wish to randomise patients with a low level of exhaled nitric oxide ( Aim. The main aim is to compare the clinical response to low dose inhaled steroid treatment and placebo in patients being considered for inhaled steroid treatment for asthma and have an exhaled nitric oxide level below 25 ppb. Our null hypothesis is that there is no difference in asthma control between low dose inhaled steroids and placebo over 3 months. Plan of Investigation. We plan to integrate research nurses into general practice in Nottingham City CCG with the aim of increasing the access of clinical research to patients. Patients believed to have asthma (by the practices own standard procedures) and require a new inhaled steroid will also have exhaled nitric oxide measured as part of their care. Those with an ExNO = or >25 ppb will continue with their GP plan but those with an No Potential benefits. Patients will hopefully benefit from this study because it will reduce the number of patients given an inappropriate diagnostic label of asthma, it will prevent a number of them receiving long term treatment with an inhaled steroid and encourage further diagnostic evaluation of their symptoms. The NHS will benefit from a reduction in inhaled steroid prescribing which is currently one of the leading drug costs in the UK.

Lay abstract: Many patients get started on inhaled steroid treatment because they have developed shortness of breath, a cough or wheeze. Although some will have asthma we, and others, have shown that many do not. Although asthma can be easy to diagnose it can be hard to exclude leading to many patients getting an incorrect diagnosis and treatment with inhaled steroids that they do not need. Although low dose inhaled steroid treatment is relatively safe, they should not be used by patients without evidence of asthma and they are now amongst the most expensive class of drugs used in the NHS. Reducing the inappropriate use of inhaled steroids would, therefore, be advantageous to individual patients and the NHS overall.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY