NIHRDataInsights/HRCSData huggingface dataset:
Title: Assessing the contribution of common and rare short tandem repeats (STRs) to the risk of developing idiopathic pulmonary fibrosis (IPF).
Funder: Wellcome Trust

Abstract: Idiopathic Pulmonary Fibrosis (IPF) affects around five people in every 100,000 in the UK and is amongst the most devastating of lung diseases, with a median survival time of 3 years and variable progression. Comparable disease prevalence (6.8 per 100,000 persons) has also been reported in other countries such as the USA, Italy, and Canada. About 5000 cases are detected annually in the UK, and there is rising disease prevalence globally. Despite the substantial disease burden, there is little understanding of the disease etiology, and it has a poor prognosis. Other than a lung transplant, the available drugs are not curative. The majority of cases are diagnosed in patients >50 years and males are disproportionately affected than females. Both genetic and environmental factors have been associated with IPF. The genetic mutations described so far only account for about 19% of genetic risk associated with IPF. Therefore, the analysis of other types of genetic variations is pertinent. In particular, our study will use whole-genome sequences in case-control cohorts to identify other genetic mutations associated with IPF susceptibility. Identifying risky mutations can help understand disease etiology and develop more targeted therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Genomic epidemiology of acute respiratory distress syndrome and fibrosis in patients with COVID-19
Funder: Wellcome Trust

Abstract: COVID-19 is an infectious respiratory disease with a global devastating health impact. Genetic and environmental factors influence COVID-19 susceptibility and outcomes, including the development of acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. These lung pathologies have a high mortality and there are no specific treatment options or effective prognostic methods for patients. Therefore, there is an urgent need to identify effective biomarkers of disease prognosis. The aim of this research is to perform a genomic epidemiology study of ARDS and pulmonary fibrosis in patients with COVID-19. For that purpose, we will perform genetic overlap studies that will include genetic correlation analyses, polygenic risk score approaches, and assessments of overlap of individual genetic variants, followed by fine mapping studies, bioinformatic approaches to identify the likely causal genes, and further experiments to evaluate their role in disease and their potential as drug targets. Results of these analyses will allow us to identify novel genetic risk factors and to develop risk prediction models, which could enhance COVID-19 patient stratification for those at increased risk of lung sequela. Furthermore, the project will reveal novel therapeutic strategies, which would translate into improved and more personalised clinical care for patients at risk of lung fibrosis.

Lay abstract: COVID-19 is a respiratory illness caused by a virus spread worldwide. Some patients with severe COVID-19 develop deadly lung conditions, such as acute respiratory distress syndrome (ARDS) and lung scarring (termed ‘pulmonary fibrosis’ [PF]). These conditions can lead to death or to long-term reduced quality of life of patients. Currently, there are no specific treatments or effective methods for predicting how ARDS or PF will progress, and therefore further studies are needed to better understand these fatal conditions. As genetics are known to influence susceptibility of ARDS and PF, we will study the DNA of COVID-19 patients by means of state-of-the-art genetic methods. I aim to identify those patients at higher risk of ARDS and PF and to reveal specific genes and biological processes that drive that increased risk. The findings will inform improved and more personalised care and will help identify new treatment options for patients with these conditions.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Investigating the role of TGFβ in the functional imprinting of pulmonary macrophages in health and disease
Funder: Wellcome Trust

Abstract: The goal of this project is to dissect the mechanisms that control homeostatic imprinting of pulmonary macrophages since it is these same processes that must be reinstated to restore homeostasis when macrophages behave aberrantly, such as during IPF where their behaviour underlies disease pathogenesis. Specifically, I will focus on the role of TGFb using a combination of novel macrophage-specific constitutive and inducible Cre drivers and Tgfbr1fl/fl mice to assess the role of TGFbR1 signalling in the acquisition of the niche-specific functions of pulmonary macrophage subsets. Multi-photon imaging will be used to assess the impact of Tgfbr1 deficiency on macrophage-niche interactions in real time in situ, alongside gene-expression profiling and functional assays. I will use the bleomycin-induced model of fibrosis to assess the roles of macrophage subsets in the inflammatory, fibrotic and resolution phases of fibrosis. Single cell RNA-Seq analysis will provide a comprehensive and unbiased interrogation of the heterogeneity of pulmonary macrophages and how these change during distinct phases of disease. Finally, temporal deletion of Tgfbr1 in distinct macrophage subsets will establish if TGFb plays differing roles at distinct stages of disease in distinct anatomical compartments, as well as revealing subset-specific functions of macrophages during disease.

Lay abstract: All tissues of the body are populated with a mixture of immune cells that help protect the body from invasion by microbes. In many tissues the most abundant immune cell is the macrophage. Literally meaning ‘big eater’, these macrophages capture and destroy microbial intruders, but also clear dead cells and orchestrate tissue repair following injury or infection. However, in some individuals, the tissue repair functions of macrophages can become uncontrolled leading to excessive repair, unconstrained scar formation (fibrosis) and organ dysfunction. Importantly, macrophages are very flexible cells and are easily influenced by their environment. Idiopathic pulmonary fibrosis (IPF) is an incurable, devastating, deadly disease where progressive scarring of the lung is believed to be driven by overactive macrophages. The aim of this study is to understand the signals that dictate macrophage behaviour in the normal lung and during successful tissue repair in order to promote or target these signals when macrophages begin to behave abnormally in disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: The role of epithelial cell extrusion in asthma
Funder: Wellcome Trust

Abstract: Asthma is an airway inflammatory disease, defined by bronchoconstrictive attacks that can be life-threatening. The two essential tissue components of the bronchioles are the airway epithelium and the underlying smooth muscle. In asthma, the smooth muscle is remodelled and becomes hyper-responsive, leading to excessive contractility. We have shown that epithelia are exquisitely sensitive to mechanical forces. Cell crowding triggers cell extrusion, while stretching triggers cell division. We recently discovered that the asthmatic bronchoconstrictive attack, causes excess airway epithelial extrusion and damage, compromising the barrier function, leading to inflammation. We propose that in healthy lungs, epithelia and smooth muscle communicate with each other to ensure sufficient epithelial cells numbers, essential to a tight barrier. However, in asthma, excess epithelial extrusion signals smooth muscle remodeling, actuating further rounds of more intense bronchoconstriction. This feed-forward cycle could perpetuate asthma attacks. We believe that our mechanochemical and cell biological insight into asthma will reveal novel ways to prevent it. We will investigate this hypothesis by addressing the following questions: 1) How are airways remodelled to cause an attack? 2) Do epithelia regulate constriction? 3) Does extrusion shed rhinovirus, yet trigger asthma attack

Lay abstract: Asthma is an airway inflammatory disease. Sheets of cells line these airways create a barrier that prevents pathogens and toxins from getting inside. Maintaining the proper numbers of cells is critical. We have shown that mechanical forces regulates cell numbers. Too many cells leads to crowding, causing cells to extrude out of the sheet and die. Too few cells leads to cell stretching, causing the number of cells to increase by division so no gaps form. During an asthma attack musculature constricts airways and causes excess cell crowding and extrusion, leaving gaps in the barrier that cause inflammation and infection. We propose that the compromised barrier leads to further constriction and multiple cycles of asthma attacks. Our approach to asthma focuses on the mechanics controlling cells comprising the barrier and their influence on the muscle cells that control constriction. This novel insight could lead to therapies that prevent asthma attacks.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Targeting remodelling of lung stem and niche cells: lessons from regeneration to disease
Funder: Wellcome Trust

Abstract: Lungs possess a remarkable regenerative capacity by dynamic multicellular responses following injury. However, chronic damage makes these responses persistent, leading to fibrosis. We will define the mechanisms by which productive regeneration programmes are diverted to disease remodelling, with the ultimate goal of uncovering therapeutic strategies that can treat or prevent lung fibrosis. We recently identified Damage-Associated Transient Progenitors (DATPs), a functional mediator of alveolar stem cell differentiation, emerging during lung regeneration. notably, chronic inflammation leads to accumulation of DATPs displaying defective differentiation, resulting in impaired alveolar regeneration. We aim to identify strategies to target DATPs in chronic injury by dissecting changes in them and their niche environments. Specifically, we will define (1) key DATP-niche interactions during different phases of regeneration, and how to these evolve during disease progression utilising a novel niche-labelling system; (2) transcriptional and epigenetic changes mediating damage-associated reprogramming following injury at single-cell resolutions, and key signalling modules conferring lineage flexibility of stem/niche cells; (3) conserved regenerative programmes and potential therapeutic targets in preclinical 3D human lung disease models we have developed. Our work will provide fundamental insights into defining the cellular and molecular basis of lung regeneration as well as identifying selective therapeutic targets in lung diseases.

Lay abstract: Most tissues possess the remarkable capacity to self-regenerate after injury. In the lung, a regenerative response involves recreation of alveolar air-filled sacs and restoration of tissue integrity. However, with age and in chronic disease, the regenerative response often switches to lead to fibrotic scarring, compromising lung function and leading to mortality. Therefore, a deeper understanding of the process of lung regeneration and why it becomes dysregulated following chronic damage is urgently needed. We will define the changes of stem cells and their neighbouring cells which are engaged in regeneration and establishment of disease following injury. This will allow us to identify candidate targets which we can validate in preclinical 3D human lung disease models that we have developed. Our proposed study will provide fundamental new insights into the ways regenerative programmes are regulated as well as the development of therapeutic interventions to treat lung diseases.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Efficient CPAP – solving high oxygen use and system inefficiencies in non-invasive ventilation through novel valve design
Funder: Innovate UK

Abstract: Continuous positive airway pressure (CPAP) systems offer a way elevating blood oxygen without having to resort to invasive ventilation. Air mixed with oxygen is pumped through a sealed mask which the patient breathes through. Unused air and oxygen and that which is breathed out, passes through a special PEEP valve which maintains the pressure in the system. All waste oxygen is simply vented into the room in which CPAP is being used. This is wasteful and in times of high use (such as during the COVID-19 pandemic) means oxygen supplies can run out. Hospital systems loose pressure, jeopardising everyone's treatment. There is also a substantial fire risk due to elevated oxygen levels in the treatment environment. Millfield Medical Respiration have developed a new design for CPAP, efficient CPAP, which uses a new type of valve to control oxygen flow more easily, reducing its consumption by up to 80%, while maintaining oxygen flow to the patient when it is needed. Our design should produce a CPAP which is more efficient and just as affordable as current machines, suitable for mass use, including in areas with low oxygen supplies, or high volumes of patients needing treatment.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: RESPIRATORY
Title: An in vivo genetic screen of lung function candidate genes using tissue specific RNAi in Drosophila melanogaster
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Background: Chronic Obstructive Pulmonary Disease (COPD) is a major cause of worldwide mortality and morbidity with current strategies in management dependent on accurate diagnosis, followed by appropriate treatment. However, there are no current treatment-modifying approaches in COPD apart from smoking cessation. Genome-wide association studies (GWAS) are providing an unprecedented insight into the genetic basis of human disease including respiratory diseases such as COPD. We have recently completed a large GWAS of lung function including data from 144,318 individuals and identified 68 high priority genes for COPD for further study. However, translation of GWAS findings to new biological understanding and therapeutic opportunities remains a challenge with a heavy reliance on animal studies and slow progress as individual genes are studied one by one. There is a need to rethink this approach.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: RASP (Radiological Assessment of Spontaneous Pneumothorax) study
Funder: The Academy of Medical Sciences

Abstract: Pneumothoraces are caused by air leaking through a defect in the visceral pleural, the lining covering the lung. Typically, the air leak is managed by inserting a chest drain into the pleural space, evacuating the air around the lung. The air then travels through the drain, down a pressure gradient, and is detected by presence of bubbles in an under-water seal chamber. As there are no methods for directly examining the air leak at the pleura, this detectable air leak is used as a surrogate for the air leak at underlying visceral defect. However, there are good reasons to suspect the air leak in the under-water seal chamber and the air leak at the visceral defect are not analogous. The success of conservative (non-invasive) management in a large randomised study and earlier experimental studies indicate that most visceral air leak resolved rapidly if undisturbed. Together this suggests that the chest drain system itself provokes and prolongs the air leak by inducing a pressure gradient. Using a novel radiographic technique, 3-D cine CT thoracography, Nakanishi and colleagues, visualised in real time the air leak at the visceral pleural defect for the first time. By performing this technique on patient with pneumothoraces on free drainage and then with a clamped chest drain, we propose this technique could determine whether chest drain exacerbates the air leak at the level of the pleural defect. If this hypothesis is confirmed, it would have major ramifications on management, leading to a less invasive approach.

Lay abstract: A pneumothorax is an abnormal collection of air in the space between the lung and the chest wall, causing collapse of the lung. The air escapes the lung via a hole in the lining in the lung (the pleura). Typically, doctors remove the air using a tube put into the chest, with the air passing down the tube to a water filled contained, where it forms bubbles. Doctors use these bubbles to predict whether the hole in the lining in the lung has healed and therefor whether the tube can be removed. Recently, doctors in clinical trials have successfully managed patients with a pneumothorax without a tube. This has raised the question: what if inserting the tube makes the hole in the lung less likely to heal, by encouraging air to pass through it. Until recently this has been a difficult question to answer as doctors have been unable to directly observe the air leaking out the hole in the lining in the lung. However, a new x-ray technique using a 3-dimensional CT scanner can picture the air leak as it happens. Using this new scanner, we could look at the effect a chest tube has on the air leaking through the hole in the lining of the lung and determine whether insertion of a chest tube is still an appropriate therapy. If this study showed that chest tube worsens the air leak, this would change dramatically how we manage this patient population.

Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Molecular engineering and functional analysis of cytokine trap peptides for modulation of the asthma IL-13 signalling pathway
Funder: Division for Social Care and Health Research (Wales)

Abstract: This multidisciplinary translational project builds upon our research aimed at developing anti-asthma peptide therapeutics. It brings together approaches in structural bioinformatics, computational molecular modelling and engineering, with laboratory analysis of binding of the natural cytokine, IL-13, and engineered cytokines (trapping), examining downstream effects upon the IL- 13 signalling pathway that is active in asthma. Developing peptides targeted to the blood that mimic endogenous proteins circumvents many problems encountered by other drugs with regard to delivery, degradation, toxicology and immune responses. Combinatorial sequence pattern discovery applied to the recently determined structures of the IL-13 / IL-4 ternary signalling complexes, have confirmed specific motifs and residues associated with binding either or both 1 (stimulatory) or 2 (modulating) forms of the IL-13 receptor, as well as identifying cytokine binding sites on the receptors. With our track record in the relevant computational and laboratory research, this knowledge puts us in a unique position to precisely exploit advances in peptide engineering and synthesis, and apply our expertise in computational modelling of receptor/peptide interactions to the iterative design of feasible peptide therapeutics for asthma. The project possesses potential for development of new anti-asthma drugs for sufferers in Wales and world over, represents an excellent postgraduate training opportunity for a strong local candidate and will further enhance the pharmaceutical knowledge economy in Wales.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: A randomised controlled trial of continuous positive airway pressure treatment in older people with obstructive sleep apnoea hypopnoea syndrome (PREDICT)
Funder: Department of Health (England)

Abstract: Obstructive sleep apnoea hypopnoea syndrome (OSAHS) is the name given to difficulty in breathing during sleep due to blockage of the throat. It causes patients to stop breathing which leads to disturbed sleep and excessive daytime sleepiness. OSAHS can be treated with continuous positive airway pressure (CPAP) which works by the patient breathing pressurised air through a mask (like an oxygen mask). A recent NICE review concluded that CPAP is a cost effective treatment for OSAHS in middle aged people. Unfortunately very little information is available regarding the best way to treat OSAHS in older people. We think that treating OSAHS may provide a cost effective way of improving health and optimising quality of life in older people.This study will measure the effect of treating OSAHS on daytime sleepiness in patients over 65 years. It will also tell us whether CPAP is cost effective in this age group. 278 patients will be studied. Half will receive both CPAP and a package of care called Best Supportive Care and half will receive Best Supportive Care alone. Best Supportive Care consists of guidance on sleep habits weight loss and a review of all health-related issues. Before patients agree to take part in the study it will be explained that they may be allocated to either of these two treatment approaches. This randomisation is the best way to test the effectiveness of a treatment. Each group will be monitored for 12 months. The information collected will be analysed using the standard methods of NICE. The results from this trial will establish whether or not older people with OSAHS should be offered CPAP treatment and whether it is good value for money in older people. The trial will generate the first substantial and detailed randomised data set (in any population) directly describing the health economic consequences of CPAP therapy in OSAHS.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: RESPIRATORY