NIHRDataInsights/HRCSData huggingface dataset:
Title: MRC Transition Support CSF John Blaikley
Funder: Medical Research Council

Abstract: Two striking phenomena were discovered during my MRC fellowship. Firstly, the amplitude of circadian oscillations are increased in fibrosis permitting otherwise arrhythmic peripheral lung tissue to come under circadian control. Secondly, disruption of circadian oscillations by knocking out BMAL1 reduced the severity of pneumococcal infection. I now plan to combine these findings by investigating the consequences of pathological circadian disruption in the lung. Aim1: Identify how circadian regulated susceptibility to pneumococcal infection is altered by the gain in circadian rhythmicity during pulmonary fibrosis. In a model of pulmonary fibrosis the effects of S.Pneumoniae given at two different times of day (ZT0 or ZT12) will be investigated. Severity of infection will be measured alongside cytokines and histology. To see if these effects are mediated via the circadian clock BMAL1 will be knocked out, stopping clock oscillations, resulting in loss of any clock dependent phenotype. Aim2: Characterise altered circadian rhythms in fibrotic macrophages via single cell analysis The main cell type responsible for time-of-day effects in pneumonia are macrophages. Therefore I will perform co-culture experiments to establish how fibrotic tissue alters the macrophage's circadian rhythm. Macrophages from PER2::luc mice will be cultured with fibrotic or normal precision-cut lung slices. PER2 oscillations will then be tracked using bioluminescence permitting changes in circadian amplitude and phase to be identified. The role of TGFbeta in mediating this effect will then be investigated using chemical inhibitors. I will also analyse circadian targets in these macrophages by observing single cell heterogeneity using single cell RNA-seq.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;RESPIRATORY
Title: Elucidating how the respiratory tract microbiota regulate immune responses to bacterial infection
Funder: Medical Research Council

Abstract: Patients with chronic obstructive pulmonary disease (COPD) are prone to developing infections by bacterial pathogens such as Streptococcus pneumoniae through unknown mechanisms. The existence of commensal bacteria (microbiota) within the lower respiratory tract has only recently been demonstrated but it is unknown if microbiota alterations ('dysbiosis') in COPD contribute to increased infection susceptibility. Current understanding is limited to descriptive human studies and a major challenge for the field is to move from correlation towards addressing causation. I will examine the hypothesis that altered respiratory microbiota in COPD contribute to dysregulated immune responses to pathogenic infection. This will be evaluated within the following aims: 1.To identify components of the anti-bacterial immune response that are controlled by respiratory microbiota and define key commensals involved. 2.To understand if commensals altered in the dysbiotic COPD airway affect responses to infection and the mechanisms through which this occurs. 3.To determine whether microbiota manipulation can reduce dysbiosis and enhance immunity to infection. Methodology: These aims will be addressed using human sample analyses in a unique longitudinal COPD cohort combined with functional studies in a novel mouse model of selective respiratory microbiota depletion that I have recently developed, employing techniques to study causal relationships such as administration of cultured commensals and manipulations to block/augment microbiota-regulated pathways. Scientific and Medical Opportunities: This study will provide new fundamental insight into how respiratory commensals regulate pulmonary immunity and identify novel pathways that govern these effects. This will facilitate development of novel non-antibiotic (microbiota-focussed) approaches to targeting dysbiosis and preventing/treating bacterial infection in COPD (urgently needed with escalating antimicrobial resistance).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION;RESPIRATORY
Title: Aspergillus and chronic lung allograft dysfunction: an immunophenotyping approach to optimise therapies
Funder: Medical Research Council

Abstract: Technical Summary Colonisation or infection with the major mould pathogen Aspergillus fumigatus occurs in up to 50% of lung transplant recipients, leading to accelerated chronic lung allograft dysfunction (CLAD) and increased mortality. Better understanding is required of when the presence of Aspergillus in the airway is promoting pulmonary inflammation, and how this relates to the development of CLAD. This is clinically important, because it is currently unclear whether patients with co-existing airway Aspergillus and CLAD require either antifungal therapy, immunosuppression, or both. In particular, as CLAD may be multifactorial, better assays to identify when this is driven by Aspergillus are needed. In order to better understand the interplay between Aspergillus, pulmonary inflammation and CLAD we will undertake a cross-sectional comparative study of lung transplant patients developing CLAD in comparison to control lung transplant recipients without CLAD, comparing subgroups with pulmonary aspergillosis, Aspergillus colonisation and no Aspergillus. We will adopt the recently developed and validated multi-parameter immunophenotyping approach developed by Prof. Hayday in order to identify immunological signatures associated with Aspergillus-driven pulmonary inflammation. To underpin these immunophenotyping studies we will also undertake Aspergillus antigen-specific T cell immunophenotyping, in order to identify where a particular inflammatory pathway is being driven by Aspergillus. Together, these studies will allow us to identify which patients with Aspergillus are developing lung inflammation, and what particular immune signatures are particularly associated with CLAD. This will allow better identification of when Aspergillus is driving CLAD, allowing us to target those individuals who clearly need to be treated with antifungals. It will also provide greater insight into what immunogical pathways may require immunotherapeutic targeting in this context.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;RESPIRATORY
Title: A live model to study mucociliary clearance in health and disease
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: A critical defence mechanism in the respiratory tract against inhaled particulates and pathogens is mucociliary clearance (MCC) in which mucus secreted by specialist cells is moved by ciliated epithelial cells. Defective MCC occurs in asthma, cystic fibrosis, chronic obstructive pulmonary disease and in primary ciliary dyskinesia leading to infection. It is important to study the respiratory epithelium to understand its function in both health and in disease with the aim of developing new therapeutic strategies for treatment. Mammalian models are widely used in respiratory research. However, studying the respiratory tract in these systems has inherent difficulties, particularly observing events in real time. This is because the lungs are located internally and studying live events requires harvesting and re-constituting the tissue in vitro, taking the tissue out of its normal context and resulting in the death of many animals. In this project, we propose the skin of the Xenopus tadpole as a model for the replacement of mammals to study mucociliary epithelia. The tadpole skin has a mucociliary surface, with both mucin-secreting cells and ciliated cells, making it ideal for live imaging of its surface and for challenge through changes in the local environment. We will use transgenic tadpoles that secrete fluorescently tagged mucins onto the skin and cilia that are also fluorescently tagged allowing study of the dynamics of MCC. The model will be challenged with agonists/antagonists of mucin secretion and cilia beating, and pathogen products. Such a live fluorescent model for MCC has the potential to replace mammalian models, particularly mice. We anticipate a diverse use of the model in fundamental research, in the testing of novel therapeutics (as well as measuring secondary impacts of other drugs on MCC) and in mimicking human disease, including those due to genetic mutations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION;RESPIRATORY
Title: Investigating the role of the pattern recognition receptor Nod2 in delayed wound healing in the elderly
Funder: Medical Research Council

Abstract: Non-healing chronic wounds in the elderly are a major cause of patient morbidity and mortality and a substantial burden on the NHS. A key problem with non-healing ulcers is persistent infection due to pathogenic bacterial colonisation. In addition, the skin has a substantial, but poorly characterised, commensal microflora that may also contribute to local inflammation. In the gut, chronic inflammation can be caused by dysregulated immune responses to both commensal microflora and pathogens. We know that the interaction of commensals with mucosa, via pattern recognition receptors (PRRs), is critical for gut barrier function and wound repair. Here we propose a similar role for specific PRRs in skin homeostasis and hypothesise that disrupted PRR function in the elderly leads to delayed skin repair due either to impaired response to commensals or exaggerated response to pathogens. To support this theory, our preliminary microarray studies of delayed skin wound healing in the elderly reveal downregulation of multiple PRRs, including nucleotide oligomerisation domain 2 (Nod2). Interestingly, Nod2, in addition to mediating recognition of bacteria, has been implicated in down-modulating the pro-inflammatory cascade initiated by the major PRR, TLR2. Moreover, human Nod2 mutations are associated with chronic inflammatory conditions of both gut and skin. Crucially, our novel pilot data reveal a pronounced delayed healing phenotype in Nod2 null mice mirroring that seen in elderly humans. Thus, we hypothesise that altered Nod2 function is an important contributing factor to delayed wound repair in the elderly. This project will elucidate the role of Nod2 in delayed skin wound healing using a combination of in vitro and in vivo anlaysis in mouse models together with validation in human samples, and experimental manipulation in a murine model of delayed human healing. Our goal is to understand the cell-type specific contribution of Nod2 to delayed healing in the elderly and explore the potential for therapeutic modulation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;SKIN
Title: Variation in consultation rates for and management of bacterial skin and soft-tissue infections and other skin conditions associated with antibiotic use: modelling primary care routine data
Funder: Division for Social Care and Health Research (Wales)

Abstract: Government policy consistently recognises that high quality primary care is key to the sustainability of the NHS, and that a robust evidence base to support clinical practice of common conditions is an essential pre-condition. There are over 2.4 million consultations in UK primary care each year for skin and soft tissue infections (SSTI), including conditions such as acne, and most of these are treated with antibiotics. While some of these antibiotic prescriptions improve outcomes, others don’t, and so simply drive antibiotic resistance, put patients at unnecessary risk of side effects, and waste resources. We don’t yet have a clear description of the frequency of different categories of SSTIs presenting in primary care, how accurately they are diagnosed, how they are treated, and what factors are associated with poor outcomes. We plan to use routinely collected primary care data to describe consultation rates and management of SSTIs. We will use statistical techniques to explore the variation in the way that doctors record diagnoses and prescribe treatments that cannot be explained by differences in the patients themselves, and therefore suggestive of non-evidence based diagnosis and inconsistency in treatment. These analyses will inform subsequent, quality of care improvement interventions.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION;SKIN
Title: The natural history and management of herpes zoster: the role of moderate immunosuppression from common diseases
Funder: Department of Health (England)

Abstract: Shingles is a common disease with very important consequences that have lead to large scale vaccination programmes being introduced in the USA and planned in the UK. This research aims to answer a number of key questions which will inform the shingles vaccination policy in the UKFirstly, this research will find out how common shingles and important complications are; including possibly risks of heart attack and stroke. Secondly, it is well known that people with suppressed immune systems, e.g. from chemotherapy, are at increased risk of shingles. However we know very little about the impact of common disorders such as obesity and diabetes which may increase risks of shingles and related problems Thirdly, this study will provide important information about patterns of use of shingles treatments and their effectiveness in clinical practice in the UK. Finally I will focus on the benefit of shingles vaccination in the population. To answer these questions, I will use very large general population cohorts in the UK and USA. Studying the American population will provide information about the how effective the shingles vaccine has been in the US population which will inform NHS planners in the early stages of vaccination in the UK.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION;SKIN
Title: Pattern recognition receptor co-stimulation and chronic fungal infection in chromoblastomycosis.
Funder: Wellcome Trust

Abstract: Fonseca pedrosoi is a fungal pathogen which causes a disease called chromoblastomycosis, a long lasting (or chronic) disfiguring disease of the skin and subcutaneous tissues which is very difficult to treat. Virtually nothing is known about the immune system s response to this organism, nor why the disease is chronic. Using animal models, we have discovered that the chronicity of this disease is due to a defect in the way the immune system sees the pathogen. We found that although the pathoge n was recognised by one molecule involved in pathogen recognition, it was not recognised by another class (the Toll-like receptors; TLR), and that this lack of dual recognition resulted in insufficient immune activation. Excitingly, infection could be cured in the animals by artificially stimulating the TLRs, suggesting a possible route for treatment of this disease in humans. In this application, we wish to verify that this form of treatment would work without undesirable side-effects in a mous e skin infection model, which would more closely resemble the human disease, and to explore the possibility of using topically applied TLR stimulators as a form of treatment. We also propose to characterise the mechanisms involved in the immune recognition of F. pedrosoi.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION;SKIN
Title: Skin and Oral Disease
Funder: Department of Health and Social Care

Abstract: Our focus is on understanding inflammation and infection in the skin and oral cavity, with a view to generating new diagnostics and therapeutics. We will focus primarily on three long-term conditions affecting the skin (psoriasis, atopic eczema and UV-induced skin damage), and on acquired changes in oral bacterial flora that drive long-term conditions (periodontitis) and potentially fatal conditions (pneumonia in the ICU). Our overarching aim is to apply unique strengths in (i) single cell methodologies and (ii) microbiome assessment, to re-define the pathogenesis of skin and oropharyngeal inflammation. These studies are expected to challenge accepted dogma and to lay foundations for the delivery of novel vaccines, biomarkers, and firstinto- man intervention studies. Therefore, in the short-term we aim to:  systematically characterise inflammatory cell profiles in our target conditions.  characterise serial changes in the microbiome of the mouth (in critical illness and periodontitis) and skin (in atopic eczema). In the medium-term we aim to:  validate diagnostic and prognostic biomarkers derived from our initial studies.  evaluate the potency of immune responses generated by intradermal vaccine delivery.  begin recruitment to clinical trials based upon high-quality stratification of patients with psoriasis and atopic eczema.  deliver studies exploring novel strategies for the prevention of periodontitis and pneumonia. In the long-term we aim to establish a novel approach to drug and biomarker discovery that yields a pipeline of trials informed by our basic science, and which is readily extended to:  other skin and oral diseases.  ageing skin.  long-term conditions in the other Research Themes.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: INFECTION;SKIN;INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining the activities of the novel inflammatory mediator, PBEF, in rheumatoid arthritis
Funder: Arthritis Research UK

Abstract: The Applicant has identified PBEF to be enhanced in the synovial fluid of RA patients and its expression is activated during arthritic episodes [Nowell et al, 2006]. Currently its contribution to arthritis progression remains unknown, however, recent findings relating to the physiological properties of PBEF indicate that this cytokine may be more than a marker for inflammation. Specifically, PBEF has been described as a novel adipocytokine, linked to diabetes, metabolic syndrome and more recently, RA. PBEF is also an enzyme involved in NAD biosynthesis, that can prevent apoptosis and promote angiogenesis. The Applicant wishes to carry out an in-depth analysis of the mode of action of PBEF in arthritis with a view of controlling its activities. This study will address the hypothesis that disregulated PBEF expression in RA affects disease pathology through controlling apoptosis and angiogenesis. This study will ascertain the therapeutic efficacy of a NAmPRT inhibitor, APO866 in experimental arthritis.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Factors leading to plantar plate (ligament) damage in rheumatoid arthritis (RA)
Funder: Arthritis Research UK

Abstract: Forefoot pain is commonly reported in patients with RA and often experienced even in those who are newly diagnosed. Forefoot pain frequently results in characteristic physical features and patient-reported symptoms such as the so-called ‘walking on pebbles’ sensation. Previous studies have reported forefoot structural changes occurring regularly in patients with RA but have not identified the factors leading to these changes. Dysfunction of periarticular structures such as the plantar plate has been widely reported to lead to structural instability and morbidity in the forefoot, but this has not been studied prospectively. This cross sectional and prospective cohort study will investigate factors contributing to plantar plate damage and the relationship between this structure and the characteristic physical features and patient reported symptoms seen in the forefoot in patients with RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Endothelial galectin-1 and the control of inflammatory arthritis
Funder: Arthritis Research UK

Abstract: Our lab has demonstrated an anti-inflammatory role for the beta-galactoside binding protein Galectin-1 in models of peritonitis. I have now produced preliminary work showing that human recombinant Galectin-1 inhibits leukocyte recruitment to endothelial cells under flow in vitro, while knockdown of the endogenous protein within endothelial cells significantly increases leukocyte recruitment. These studies have been further corroborated in Galectin-1 null mice, which exhibit increased leukocyte emigration in the inflamed cremaster compared to wild-type counterparts. I will challenge the hypothesis that Galectin-1 acts to limit leukocyte recruitment in the context of experimental arthritis. I propose to use an integrated in vitro and in vivo approach using human primary cells, Galectin-1 null mice and a model of collagen-induced arthritis. Finally, I will investigate the translational potential for this research by monitoring Galectin-1 expression in synovium from rheumatoid arthritis patients as well as conducting experiments with human synovial tissue transplanted into SCID mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A randomised, placebo controlled, dose escalating clinical trial of the novel immunomodulator BiP for the treatment of rheumatoid arthritis
Funder: Arthritis Research UK

Abstract: BiP is a stress protein that has been shown both in vitro and in vivo to have powerful anti-inflammatory effects. BiP stimulation of human peripheral blood mononuclear cells in vitro results in TH2 development, inhibition of dendritic cell differentiation and upregulation of IL-10 production. In vivo, a single dose of BiP treats collagen induced arthritis(CIA) and deviates splenocyte and lymph node cell development such that these cells are capable of treating CIA following adoptive transfer without the administration of additional BiP. BiP, therefore, appears to have a novel mode of action that may prove efficacious in the treatment of rheumatoid arthritis. This project aims to investigate firstly, safety, and thereafter effectiveness of a single escalating dose of BiP given to patients who have failed on methotrexate. Easily detectable biomarkers will allow assessment of whether BiP has altered cell function and add to our knowledge of the changes in disease pathology after treatment.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Therapy with autologous tolerogenic dendritic cells in rheumatoid arthritis: A phase I study (AuToDeCRA)
Funder: Arthritis Research UK

Abstract: Pharmacologically manipulated dendritic cells with a tolerogenic profile (tolDC) have the capacity to reprogram unwanted immunological responses. We have developed a protocol for the generation of tolDC from peripheral blood of RA patients. We now propose to administer autologous tolDC into (arthroscopically lavaged) inflamed knee joints, where we hypothesise they will down regulate the autoimmune response. TolDC will be loaded with autologous synovial fluid as a source of autoantigen and evidence of a biological effect will be sought from pre- and post-intervention synovial membrane biopsies. Our immediate priority is to perform a small pilot study (n=8), whose key goals are to test the feasibility and reliability of our GMP manufacturing process, and the feasibility and patient acceptability of the subsequent complex interventions. We will also track the fate of administered cells in a few individuals. Success in this short project will enable us to seek funding for a formal proof-of-concept trial.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM