NIHRDataInsights/HRCSData huggingface dataset:
Title: Multi-modal Discovery of Mechanistic Drivers of Pulmonary Fibrosis
Funder: Medical Research Council

Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a severe, progressive, fatal disease with no cure. The current pathogenic paradigm proposes dysregulated epithelial repair following micro-injury in genetically susceptible individuals leading perpetual, abnormal, stiffened, extracellular matrix production. Loss of normal alveolar architecture is accompanied by replacement of epithelial alveolar type 1 (AT1) and type 2 (AT2) cells with an accumulation of atypical transitional 'fibrotic' epithelial cells. Cellular extrusion is a key regulator of cell fate and epithelial barrier integrity, but it role in alveolar homeostasis or IPF pathogenesis is unknown. Strikingly, multiple signals regulating the extrusion pathway are abnormal in IPF, yet how dysregulated extrusion might impact IPF has not been explored. We propose the novel hypothesis that damage to genetically-primed alveolar cells leads to failed extrusion and a feed-forward cycle of increasing matrix deposition and stiffness, exacerbating defective extrusion instead of regenerative turnover. This hypothesis will be tested through co-creation of a human tissue-based platform exploiting human precision cut lung slices, novel lung organoids derived from patients with and without IPF combined with synthetic extracellular matrices to address three specific aims: 1) Define the role of alveolar epithelial cell extrusion in normal and fibrotic human lung. 2) Explore the effects of matrix composition on alveolar epithelial extrusion. 3) Integrate multidimensional data from Idiopathic Pulmonary Fibrosis patients to inform mechanistic studies and promote clinical translation. Our approach will develop novel ways to model, and measure, lung fibrosis and scales from reductionist biology to big data analytics. It brings together world-leading expertise in IPF pathobiology, engineering, medical physics, optical imaging and cell biology to maximise discoveries that will translate into clinical practice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Translational studies into the role of CNP and NEP inhibition in acute inflammation- a potential novel therapeutic approach to ARDS
Funder: Medical Research Council

Abstract: Acute respiratory distress syndrome (ARDS) is an acute inflammatory syndrome manifesting as diffuse pulmonary oedema and respiratory failure that cannot be explained by, but may co-exist with, left-sided heart failure. The disorder is asociated with a mortality of 24%, rising to 48% in those with the most severe respiratory failure and represents appoximately 10% of all intensive care unit admissions. ARDS results from acute inflammation affecting the alveolar-capillary membrane (ACM); the gas exchange surface of the lung. Increased permeability of the membrane is associated with the recruitment of neutrophils and other mediators of acute inflammation into the airspace, which manifests clinically as high-permeability pulmonary oedema. This contributes to profound hypoxaemia and, eventually, type 2 respiratory failure. Yet, there are no effective disease modifying treatments for ARDS, despite almost 5 decades of clinical trials. This highlights the need to improve our understanding of pulmonary endothelial biology, focusing on both fluid movement and cell flux (i.e. barrier function), and its relationship to inflammation in ARDS. C-type naitruretic peptide (CNP), is a pivotal endothelium-derived mediator that governs endothelial homeostasis. My extensive preliminary findings, in conjunction with published data, suggest that pharmacological manipulation of CNP signalling holds potential for preserving endothelial barrier function, reducing oedema and dampening inflammation in the setting of ARDS. In accord, this proposal will utilise in vitro studies in murine and human pulmonary cells, in vivo experimentation in murine models of acute lung injury (ALI; the experimental description of ARDS), and a proof-of-principle clinical trial to determine the therapeutic utility of targeting CNP in ARDS. A positive outcome could be translated to ARDS patients quickly and inexpensively since the approach I am advocating involves the re-purposing of an existing licenced medicine.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: MICA - Mechanism of action of targeted lung denervation in COPD: clinical, physiological, molecular and structural assessments
Funder: Medical Research Council

Abstract: Background: Chronic obstructive pulmonary disease (COPD) is a chronic, progressive condition characterised by fixed airway obstruction. It is the fourth leading cause of death worldwide. Despite pharmacological management, many patients suffer frequent exacerbations and debilitating symptoms, and new treatments are desperately needed. Targeted Lung Denervation (TLD) is a novel one-time bronchoscopic treatment being investigated for COPD. In phase II clinical trials it has shown promising results, improving symptoms and reducing exacerbations. Aims: To date, the mechanism of action of TLD is unknown. We plan to perform the first ever mechanistic study investigating how TLD exerts its effects. The parasympathetic nerve function to the airways becomes dysregulated in COPD, causing bronchoconstriction, bronchial hyperreactivity and mucus hypersecretion. TLD is thought to disrupt this. We will test the hypothesis that TLD will result in improvements in these parameters through alterations to cholinergic pathways and the resulting downstream effects. Methods: AIRFLOW-3 is a prospective multi-centre randomised double-blind sham-controlled trial exploring the effects of TLD in COPD. We plan to recruit 30 patients in the UK and carry out a mechanistic study alongside AIRFLOW-3. Outcome measures will include clinical, physiological, cellular, transcriptomic and structural assessments. Bronchial brushes, broncho-alveolar lavage and mucosal cryobiopsies will be taken to assess changes in airway and inflammatory and neural cells, and transcriptomics. Implications: A comprehensive understanding of the mechanism of action of TLD will delineate the pathways involved and effects. This will directly translate into patient care, generate new research directions, and may identify novel therapeutic targets, within the respiratory field and beyond. Considering the burden of COPD, this work has the potential to have a significant impact worldwide.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Rhythms in Disease- Determining Circadian Clock Mechanism in Asthma
Funder: Medical Research Council

Abstract: Asthma is highly rhythmic; asthma deaths occur at night; symptoms, airway narrowing and inflammation also peak overnight. Evidence suggests the circadian clock is important in mediating rhythmicity. Here, I will determine the mechanism controlling rhythmicity in asthma. Aim 1. Using transgenic mice, I will target the molecular clock selectively in bronchiolar epithelial cells to define how local clock function in the lung impacts severity and rhythmicity in allergic airways inflammation. To determine the role of the autonomic nervous system , pharmacological and genetic interventions (removing clock function in cholinergic neurons) in vivo, will be combined with precision cut lung slice (PCLS) cultures. Assessment of disease will involve non-invasive and invasive determination of lung function, and monitoring of physiological rhythms (e.g. temperature, activity). Aim 2. I will examine how clock function itself is impacted by lung inflammation, and identify pathways affected by time-of-day, disease state, and local loss of clock function. Using a Reverba reporter mouse, I will track Reverba expression in bronchiolar epithelial cells during airway inflammation both in vivo and in PCLS. I will analyse RNAseq profiles of laser captured microdissected airway smooth muscle cells from targeted mice at 2 times of day under normal/ disease state. Aim 3. To understand the role of the central clock in the control of lung function I will manipulate the environment to decouple the central clock from the peripheral lung clock by employing a restricted feeding schedule or an acute shift in lighting schedule. This will allow me to determine the effect of misalignment on airway function (akin to the effects of night shift work). This research provides an opportunity to discover novel therapeutic targets, use existing drugs at more efficacious times of day and inform guidelines to manage asthma in night shift workers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Targeting deubiquitinaseas as a novel therapeutic strategy for the treatment of muco-obstructive lung disease
Funder: Medical Research Council

Abstract: Regardless of underlying aetiology, a number of respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), and non-CF bronchiectasis are characterised as "muco-obstructive". Sputum production and cough are common features with airway dehydration and mucus plugging contributing further to airway obstruction. Compromised mucus transport leads to inflammation and an environment prone to infection, which exacerbates the underlying condition. As such, new therapies that hydrate the airways and restore mucus fluidity have the potential to reduce inflammation. Therapeutic approaches to improve lung clearance mechanisms have considerable potential to elicit clinical benefit across several major disorders, which may now include those recovering post-COVID. DUBs (deubiquitinating enzymes), catalyse the removal of ubiquitin from protein substrates. Since ubiquitination controls a plethora of regulatory functions including degradation, modulation of DUBs provides multiple opportunities to manipulate critical cellular processes. An emerging body of evidence highlights a role for DUBs in pulmonary biology and disease. One example is the DUBs USP2 and USP8, which if inhibited would suppress activity of the epithelial sodium channel (ENaC). ENaC blockade is widely recognised an attractive therapeutic strategy to ameliorate muco-obstructive lung diseases by improving airway hydration and mucociliary clearance rates. The role of DUBs (which comprise a family of >100 enzymes) in this area is however, very poorly understood. This secondment will combine the respiratory research expertise of the secondee (Reihill) with Almac Discovery's powerful DUB identification and CRISPR-based primary cell screening platforms to systematically determine the therapeutic value of individual DUB targeting in the context of muco-obstructive lung disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: A pharmacological approach to drive lung repair
Funder: Medical Research Council

Abstract: The lung alveoli are capable of intrinsic repair, driven at least in part by alveolar epithelial progenitor populations (AEP) which increase following injury. Although the adult lungs are capable of repair, the extent to which this occurs differs between individuals and is abnormal in many lung diseases. Importantly, we still have little knowledge about the cell biology and dynamics of alveolar repair and how the AEP cells contribute. Advances in understanding alveolar repair have been hampered by the lack of suitable models. Our group has developed methods to conduct time-lapse imaging of live lung repair in precision-cut tissue slices (PCLS) from mouse and human (the Acid-injury and repair, AIR model). PCLS are a highly versatile ex-vivo model of the lung in which all resident cell types are present in the same ratios and with the same cell-cell and cell-matrix interactions as in vivo. Using the AIR model we will test our hypothesis that the growth factor Wnt5a could be used as a pharmacological pro-repair treatment. AIM1 We will conduct 12 hr time-lapse imaging experiments of AEP in spatially injured PCLS (AIR model). We will label the AEP in live mouse PCLS with the progenitor marker TM4SF1 and track them to determine their origin, and role in repair at 12, 24, 48hr and 4,7,10 and 20 days after injury. For culture beyond 48hr, PCLS will be encased in Polyethylene glycol (PEG) hydrogel to extend their viability using an established technique. AIM2 We will examine how Wnt5a treatment of PCLS affects AEP and whether this can stimulate functional repair of lung tissue using the AIR model and imaging techniques outlined in AIM 1. AIM3 We will investigate whether Wnt5a encapsulated in alginate hydrogel could be used to drive repair of human lung tissue. We will optimise the hydrogel formulation by tracking gel stiffness and Wnt5a release dynamics. Wnt5a-hydrogel will then be added to human PCLS and we will track the magnitude of repair following acid injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Lungy: A Feasibility Study For A Responsive Smartphone Application To Monitor And Improve Breathing Function in Patients with Respiratory Disease
Funder: Department of Health and Social Care

Abstract: Respiratory disease places a huge burden on NHS services and society. Prior to COVID, the cost of respiratory illness was estimated at &pound;9.9 billion/year [1], with hospital admissions due to respiratory disease rising at 3x the rate of other admissions and 10,000 new diagnoses of lung disease in the UK every week. The prevalence of long-COVID in March 2022 was estimated to be 1.7 million people in the UK, with ~35% of sufferers experiencing shortness of breath [2]. The pandemic has created unprecedented demand and a backlog for healthcare services whilst simultaneously creating barriers for patients to access appropriate therapies and care. Lungy (https://www.lungy.app) is an accessible and scaleable app that uses smartphone sensors to recognise, track and respond to real-time breathing data. These data can be used to provide responsive feedback to the patient (and clinician) to aid self-management & telemonitoring of progress; to encourage and guide the patient through a range of breathing exercises; and to create unique and relaxing generative audiovisuals that respond to every breath. Lungy has undergone beta testing in > 50 users (TRL5), with very positive user feedback from Asthma/Lung UK, and COPD & asthma patients. This NIHR Fast grant would enable a feasibility study of this breathing management platform. A 6-month study in ~20 patients with asthma, long-COVID and COPD would be evaluated at baseline and over 2 months of using the app, measuring QOLs, compliance, and user experience. These initial data would provide a stronger case for larger funding proposals, private funding, and wider evaluation in randomised controlled trials. This novel technology must be evaluated now to ensure the NHS has a new, cost-effective therapy to supplement existing practice, reduce the burden of respiratory disease, and ensure patients have access to an innovative and beneficial technology as soon as possible.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Tailored Intervention at home for patients with moderate-very severe COPD and Co-morbidities by Pharmacists and Consultant Physicians (TICC PCP): pilot randomised controlled trial
Funder: Chief Scientist Office, Scotland

Abstract: People with moderate-to-severe chronic obstructive pulmonary disease (COPD) are so breathless that they need to stop for breath when walking at their own pace. At home, when breathing gets worse e.g. due to infection, hospitalisation often results. Frequent adjustment of medicines for COPD and other medical conditions improves breathing and reduces hospitalisations however; home-based check-ups for breathing and medicines are uncommon. Our preliminary research has shown that pharmacist home-visits, undertaken with the support of the patient’s GP and chest physician, can help ensure that patients are on the right medication and through so doing reduce the risk of a flare-up of COPD and associated hospital admission. We now want to build on this work to see if pharmacist home-visits are safe and effective for patients and the NHS. But we first need a small-scale pilot study in which some patients get pharmacist home-visits and compare this with patients who do not get home-visits. If the results are promising, and patients tell us the visits help them, we plan to run a trial big enough to test whether pharmacist home-visits improve patient outcomes and reduce hospital admissions for COPD.


Research activity codes: 5.7 PHYSICAL
Health categories: RESPIRATORY
Title: A prospective survey of Near Fatal Asthma in Children and Adolescents to inform future care bundle to reduce risk of death in this population.
Funder: Chief Scientist Office, Scotland

Abstract: Asthma is a very common health condition in Scotland, and a number of children and young people have died because of it. Asthma attacks can be different every time and for every person. There is a type of attack which makes it more likely that person will have another attack within a year, and maybe die. These are called “near fatal asthma attacks”. Depending on where they live, the care people receive after a ‘near fata asthma attack’ can be very different. We want that to change. In this study we want to find out: 1. how many people have had one of these attacks 2. what care they received after the attack 3. what happened to them in the following year We hope the results of this study will: a) improve the consistency of care people receive after a near fatal asthma attack b) reduce the number of asthma deaths


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: RESPIRATORY
Title: Development of biomarkers to identify inhaled antibiotic response in bronchiectasis
Funder: Chief Scientist Office, Scotland

Abstract: Bronchiectasis is a chronic lung condition with no proven treatments. Patients have chronic lung infection and so Inhaled antibiotics offer a promising treatment. Unfortunately, several trials of inhaled antibiotics in bronchiectasis have failed to demonstrate benefit. The reasons for this are not known. In our pilot work we believe we have identified the answer. We have re-analysed a previous “failed” trial and demonstrated that this study would have been positive if limited to patients testing positive for high levels of bacteria (called high bacterial load). We now need to confirm this critical finding in other trials and identify a way this could be implemented into the NHS. We will analyse samples and data from patients enrolled in a recent study of an inhaled antibiotic which have been gifted to the Bronchiectasis research team at Dundee University. We will use molecular techniques to measure total bacterial load and compared molecular techniques with traditional bacterial growth in the laboratory and evaluation of the “microbiome”. We hypothesise that patients with higher bacterial load will respond better in terms of symptoms and fewer exacerbations


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY
Title: A pilot study of a culturally appropriate hospital-based pulmonary rehabilitation programme among adults with functionally limiting chronic respiratory diseases in Malawi
Funder: Wellcome Trust

Abstract: Malawi suffers a substantial burden of chronic respiratory diseases (CRDs) which causes significant morbidity and loss of economic productivity, and affects patients, families and health systems alike. CRDs are a major risk factor for Coronavirus Disease 2019 (COVID-19). Pharmacotherapy for CRDs is of limited benefit and costly. Its rational use could be complemented by non-pharmacologic treatments. For chronic obstructive pulmonary disease, pulmonary rehabilitation (PR) is well established as highly effective intervention which improves symptoms, quality of life and survival. PR is comprehensive package of interventions including exercise training. PR is now sufficiently understood to obviate further randomized trials in High Income Countries (HICs). However, given the design and delivery of programmes should be adapted to patient groups and context, high-quality data are needed outside HICs. My pilot study will determine feasibility and acceptability of PR in Malawi. Specifically, I will: (1) co-design, with service users and stakeholders, a locally appropriate PR program for patients with functionally limiting CRDs in Malawi, (2) examine lung function, exercise capacity and health status of participants before and after their participation in a PR program, and (3) examine participants’ levels of attendance, participation and adherence to the programme. Keywords: chronic respiratory diseases, pulmonary rehabilitation, Malawi

Lay abstract: Chronic respiratory diseases (CRDs) are common in Malawi. Symptoms include activity-limiting chronic cough and breathlessness. CRDs expose patients to Coronavirus Disease 2019 (COVID-19). Medications (e.g., inhalers) can help, but even in developed countries, they are used together with pulmonary rehabilitation (PR). PR includes exercise training, is highly effective and can improve many Malawians’ well-being. However, most programmes were designed for high-income countries. I want to adapt these to resources and cultural environment of Malawi to benefit my patients. I will answer the questions: "What is a locally-appropriate PR programme for patients with CRDs in Malawi? What is its feasibility and acceptability in Malawi?" This “pilot” study could lead to better management of people with CRDs in Malawi. It would allow us to test the intervention on a larger scale to answer the question: “In developing countries, what is the utility of PR and how can this be programmatically delivered cost-effectively?”

Research activity codes: 6.7 PHYSICAL
Health categories: RESPIRATORY
Title: The genetic epidemiology of lung scarring
Funder: Wellcome Trust

Abstract: Idiopathic Lung Fibrosis (IPF) is a disease which leads to death three years after diagnosis in half of cases. IPF is a complex genetic disease - variants of DNA that contribute to disease risk have been identified, though we have yet to fully understand how these risk factors lead to lung scarring. A Genome-Wide Association Study (GWAS) can be used to determine which regions of DNA are associated with disease. GWAS can be used to look at individual variant sites in the DNA called Single Nucleotide Polymorphisms (SNPs). By comparing the entire DNAs (Genomes) of people with and without IPF, we can narrow down the suspected sequences that may contribute to the development of the disease to very fine resolution. Once SNPs associated with IPF are identified, we then need to understand why they are associated. Determining which SNP leads to IPF requires 1) Linking SNPs to genes, 2) finding biochemical pathways associated with these genes, and 3) finding drugs that can be used to target the biochemical pathways. These steps enable us to understand the pathology of IPF and could lead to the identification of potential drug treatments for this currently incurable disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY