NIHRDataInsights/HRCSData huggingface dataset:
Title: Bioengineering to harness the immune adjuvanting properties of reactive carbonyls
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Our preliminary data strongly support a model in which the RC adduct on the flanking regions of a peptide epitope interacts with a positively charged residue on the flank of an MHC class II molecule. This interaction is predicted to stabilise peptide-MHC binding, increasing T cell activation. To interrogate this peptides will be synthesised with RCs incorporated at specified positions using orthogonally protected lysines. Peptides will be C-terminal labelled allowing direct binding studies, allowing us to measure peptide affinity with and without targeted RC groups and relate this to T cell affinity. This approach will be extended to intact protein by site-specific RC insertion using a chemoenzymatic approach by incorporating a formylglycine-generating enzyme motif into the protein. MHC class II will be mutated in the putative interacting residue (alpha-chain lysine50) to disrupt RC-lysine interactions, and peptide binding and T cell activation will be measure to provide further evidence supporting this interaction. Peptide RC groups may interact with lysine on MHC class II by electrostatic interactions or by Schiff base formation. We will investigate possible the formation of covalent links between peptide-RC and MHC using cyanoborohydride reduction and deuterium addition followed by digestion, LC, and mass spectrometric analysis. A homogenous RC-containing peptide-MHC class II complex will be used for X-ray crystallography. Binding and structural studies will be carried out in parallel with immunological readouts to correlate biochemical and immunological outcomes. Antigen presentation analyses will be carried out in vitro using T cell hybridoma activation and in vivo by immunization of mice and subsequent analysis of the immune responses. Finally, RC groups will be incorporated into influenza HA and evidence for epitope specific enhancement of T cell responses evaluated by peptide specific proliferative responses and cytokine secretions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Dietary constituents modulate the healing response through the action of amine oxidases
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Tissue homeostasis requires a coordinated programme of inflammation, regeneration and replacement. The maintenance of homeostasis is underpinned by tightly controlled inflammatory and stromal cell responses. Dysregulation of these processes can result in loss of tissue function and integrity, and is a feature of both humans and animals suffering from chronic conditions such as progressive organ failure. There is mounting evidence that dietary factors and the composition of the gut microbiome can affect an individual's response to tissue injury and the rapidity of age-related scarring. Therefore an understanding of the dietary factors that control of inflammation and wound healing responses is critical to the development of strategies to alleviate these conditions. The amine oxidases are a group of enzymes that deaminate primary amines such as those found in the diet, or those generated as a consequence of metabolism by gut bacteria. Amine oxidases have been implicated in inflammatory and stromal responses to tissue damage through recruitment of distinct immune cell subsets, stromal cell activation and cross-linking of ECM. Whilst it is known that certain dietary amines are substrates for these enzymes their effects on tissue homeostasis are poorly understood. Furthermore the precise roles of individual members of the amine oxidase family in this process have not been fully described. This project aims to define the substrate specificity of amine oxidases and their impact on i) wound healing mediated by stromal cells and ii) the recruitment of inflammatory cells. This project will also study systemic effects of amine oxidases mediated by circulating forms of the proteins and highly reactive products of the deamination reaction such as advanced glycation end products. It is anticipated that this project will provide novel data linking diet and health through the action of amine oxidase activity, and inform future approaches to improve the healing response.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Multi-scale analysis of B cell responses in ageing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The B cell repertoire is changed with age - having a decreased diversity of Ig genes and altered subsets of B cells. The human immune response is not limited to a few specific antibodies but is diverse. However, there are some common features of Ig genes, in the CDRH3 region, that are favoured in a response regardless of the type of challenge. In naïve B cells the baseline features of Ig genes before challenge show age-related differences that might contribute to reduced efficacy of responses in old age. Our observations challenge the lock and key hypothesis of antibody binding and highlight the requirement for more complex models of antibody responses. We will investigate possible mechanisms behind age-related B cell change using data on repertoire change at the molecular and cellular levels to build and test models of repertoire responses to challenge. Since Ig gene specificity has a central role in repertoire selection a large part of our work centres on predicting and testing antibody binding characteristics. In addition we have unique access to mass cytometry in order to clarify some of the confusion that exists with respect to cellular population function and age-related changes. Each member of this team has expertise complementary to the others such that the team is uniquely placed to address this question. The unique experimental analyses of high throughput sequencing (HTS) and mass cytometry (CyTOF) have, and will, generate a large amount of data (DDW) that needs to be efficiently explored for extraction of specific age-related immune response fingerprints. Structural bioinformatics will help in the analysis and predictions of the conformational changes and binding specificity observed in the age-specific repertoire (FF). Statistical mechanics can relate end point observation to parameters controlling microscopic stochastic events, and therefore may be usefully employed to help elucidate the reasons for differences in repertoire with age (ACCC)


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the role of Lactobacillus Crispatus in healthy skin and psoriasis
Funder: British Skin Foundation

Abstract: Background: Lactobacillus Crispatus is a skin resident bacterium more abundant in healthy skin than psoriasis and correlates transcriptomically with key skin immunity pathways. Aim: Characterise the role of L. crispatus on key immunity pathways and skin inflammation Objectives 1. Determine effects of L. crispatus on immune pathway and psoriasis-relevant genes and inflammatory mediators in a human skin explant model 2. Determine effects of L. crispatus on immune pathway genes in primary keratinocyte cultures derived from healthy and psoriasis skin 3. Interrogate functional role of L. crispatus through in-vivo models of psoriasis Methodology: Whole skin explants and primary keratinocytes derived from healthy and psoriatic skin will be incubated with L. crispatus extracts. Relevant expression of immune pathway genes, core psoriasis cytokines and antimicrobial peptides will be analysed through quantitative PCR (qPCR). Whole transcriptome gene expression profiling through RNA sequencing will identify novel gene transcripts modulated by L. crispatus. In-vivo models of psoriasiform inflammation will be treated with topical L. crispatus extracts to assess the effect on psoriasis severity and immune pathway activation. In all models, severity is graded histologically and using immunohistochemistry. qPCR is performed to quantify relative immune pathway gene and psoriasis relevant cytokine expression. A humanized in-vivo model of psoriasis will also be treated with topical L. crispatus to confirm microbial anti-inflammatory effects. Medical Opportunities: We will further characterise the mechanisms controlling skin homeostasis and inflammation and how skin-resident bacteria interact with the immune system. This could lead to clinical trials of novel therapeutics (e.g. L. crispatus probiotics or immunomodulatory drugs) for psoriasis, other inflammatory dermatoses such as eczema and acne and related cross-disciplinary diseases (e.g. Crohn's disease).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Atypical chemokine receptor 2 and the restriction of inflammatory spread in arthropathies
Funder: Chief Scientist Office, Scotland

Abstract: Some people with the common skin condition psoriasis also develop inflammation in their joints, called psoriatic arthritis. We have shown that the molecule ACKR2 (Atypical Chemokine Receptor 2) can control inflammation and prevent the skin rash in psoriasis from spreading. This project will use blood, skin and joint samples from patients to determine if ACKR2 also plays a role in limiting inflammation in psoriatic arthritis. This will be compared to rheumatoid arthritis which is a different type of inflammation in the joints. The project will also screen for molecules which can increase ACKR2 levels as we think this could help controlling inflammation in patient and thus have the potential to be developed into a new treatment for these conditions.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Delineating the neural mediators of rheumatoid arithritis related fatigue
Funder: Chief Scientist Office, Scotland

Abstract: We seek to tackle the highly impactful problem of fatigue – an issue which is pervasive across the chronic disease spectrum. The causes of fatigue are poorly understood and as a consequence treatment options are limited and patients are left feeling ignored. In rheumatoid arthritis (RA), a common disorder where fatigue is considered to be especially burdensome, we have recently identified several regions of the brain that may be important in the generation and/or maintenance of fatigue. In the future we wish to alleviate fatigue by targeting such regions using non-invasive devices which can modulate relevant areas of the brain using magnetic fields or very low levels of electrical current. These devices have been successfully tested for other conditions, such as depression, where they have been found to be both safe and effective. Our current knowledge however is not yet sufficiently precise to undertake trials of these interventions for the treatment of fatigue. We therefore propose a study - embedded within an already funded clinical trial - which will apply cutting edge MRI brain scanning methods to select out those candidate brain regions which are most likely to be relevant and most suitable for future targeted interventions.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Patients’ and healthcare professionals’ perspectives on the reasons for long term follow up of coeliac disease and the manner it should take
Funder: Coeliac UK

Abstract: Guidelines set out by the British Society for Gastroenterology and the American Gastroenterological Association recommends all patients with coeliac disease should receive long-term follow-up due to the risks of complications. However, not only do follow-up practices vary, the evidence on which these guidelines are based is scarce and is reflective of the medical perspective. Whilst some clinicians support these guidelines, others argue that annual follow-up is not cost effective as it is not necessary for all patients, such as those adhering to a gluten-free diet, hence only non-adherent patients would benefit. Existing guidelines have also failed to consider patients’ views and experiences of follow-up and what they think the most optimal model should comprise, particularly given the life-long nature of the disease. Research is needed to understand a variety of coeliac patients’ experiences and views, such as those under active follow-up in secondary or primary care and those who have opted out from receiving follow-up. Interviews with patients will help unpick the perceived benefits and barriers to follow-up and allow the often overlooked views of those who do not attend to be taken into account. Collecting the accounts of healthcare professionals involved in the management and treatment of coeliac patients is equally important and thus via interviews, this study aims to explore patients’ and healthcare professionals’ views on follow-up and to identify optimal forms of follow-up. These findings will inform the development of a randomised controlled trial to test the effectiveness and cost-effectiveness of various models of follow-up identified.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The impact of changes in prescription policies of gluten free products in coeliac disease
Funder: Coeliac UK

Abstract: The only treatment for coeliac disease is a life-long gluten free diet, which is challenging due to limited availability and high costs of gluten free food. National Prescribing Guidelines allow for the prescription of gluten-free food. However, eight Clinical Commissioning Groups (CCGs) no longer follow this guidance and have withdrawn all support for both adults and children and four CCGs have partially ceased prescribing of gluten free foods, children, pregnant and breast feeding women may still receive support. There is concern that these changes may have an impact on people with coeliac disease. This study aims to gain evidence of whether, and to what extent, the change in policies for gluten free prescriptions impacts on people with coeliac disease. This mixed methods study will include a survey and qualitative interviews. The survey will be sent to 4000 Coeliac UK Members, of which approximately half will be recruited from the CCGs that have stopped prescriptions for adults and the other half from CCGs following the National Prescribing Guidelines. Additionally, participants will be recruited through adverts via online social media networks and the Coeliac UK website. Data will be analysed to detect any differences in impact between people who receive prescriptions and those who do not. Up to twenty survey participants who report poor outcomes will be recruited for a qualitative interview to gain more in-depth insight into the impact of the change in the use of prescriptions for gluten-free food.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of age-associated inflammation in moderation of alternative splicing and its impact on age-related disease
Funder: Dunhill Medical Trust

Abstract: Correct splicing of genes is integral to cellular identity and function; defects in mRNA processing are a common cause of human disease and most genes are alternatively spliced. We demonstrated recently that deregulation of splicing is a key feature of human ageing, both in vitro and in vivo. One feature commonly associated with human ageing is a heightened inflammatory response termed ‘inflammaging’. Inflammation has been associated with chronic disease and loss of physical and cognitive function in older people. Senescent cells secrete a cocktail of inflammatory components; the senescence-associated secretory phenotype (SASP). Here we aim to determine whether splicing can be affected by SASP in different cell types and to what extent possible changes in splicing could contribute to age-associated disease and loss of function. To do so we will assess splicing factor expression, splicing of disease-related genes and expression of markers of tissue-specific cell function in cardiomyocytes, astrocytes, fibroblasts and endothelial cells exposed to activators of SASP in vitro (replicative senescence, inflammatory factors, oxidative stress, DNA damage). Finally, where we identify SASP-associated isoform changes, we will relate their expression to relevant diseases and age-associated conditions by epidemiological studies in the InCHIANTI population.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Determining the non-canonical functions of telomerase involved in modulating macrophage biology and their potential implications for tissue ageing
Funder: Dunhill Medical Trust

Abstract: The number of people over the age of 65 is predicted to double within the next 50 year, accompanied by an increase in chronic-diseases, which already consume up to 80% of health-care costs. Developing therapies for chronic ageing-diseases is, therefore, an urgent priority. A major medical problem of ageing is that the different tissues in our bodies become damaged over time, in particular tissues have to be repaired all the time, such as the gut. Our immune system plays an important role in helping these tissues heal and stay healthy over our life-time, but with ageing, the immune system itself becomes less efficient. Our on-going work has identified a previously unknown reason contributing to the dysfunction of the immune system in the gut with ageing. This PhD project will explore and determine the exact reasons behind this to try and identify new therapeutic opportunities that may help maintain sensitive tissues like the gut and others, healthier for longer, aiming to improve healthy ageing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Nottingham Molecular Pathology Node (NMPN) for Integrated Multi-platform Biomarker Research and Knowledge Transfer
Funder: Engineering and Physical Sciences Research Council

Abstract: NMPN brings together pathologists, molecular biologists, clinicians, computer scientists, the Nottingham Health Science Biobank (NHSB), Nottingham University Hospitals NHS Trust (NUH), Empath, Pharma/biotech companies and electronic engineering companies. Co-localisation of expertise, an exceptional tissue repository with linked real-time stratified patient data and well-defined clinical cohorts are resources we aim to use to create a new and original infrastructure encompassing informatics, computational modelling and molecular pathology. This will allow (i) biomarker testing to reveal hidden disease strata (discovery push), (ii) testing clinically stratified patient cohorts to reveal discriminatory biomarkers (clinical pull) and (iii) robust biomarker validation enabling early clinical translation. NMPN models will integrate multi-platform data including DNA/RNA/Proteomic/Metabolomic profiles, digital image analysis, genomic profiling of pathogens as well as data from other sources (e.g. radiology) to provide clinical decision support. Our models will be tested in infection/inflammation/fibrosis and repair - disease processes with variable outcomes and treatment responses and providing an ideal template for stratification. NMPN will focus on upper & lower gastrointestinal tract, liver and respiratory tract, which feature amongst Nottingham's major research strengths. Although developed for infection/inflammation/fibrosis the models will be transferable to other diseases and easily disseminated to other nodes. We will work closely with industry and align with other nodes to transfer knowledge and ensure research is translated from bench-to-bedside. NMPN will provide in-depth training for PhD students, new Fellowships in Molecular Pathology, rotation of NHS clinical pathology trainees through the Node, and creation of a new Associate Professor post. We will deliver a distance-learning MSc course for the network and organise annual summer training schools.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Arthritis Research UK Centre for Adolescent Rheumatology at UCL, UCL Hospitals and GOSH
Funder: Great Ormond Street Hospital Children's Charity

Abstract: This proposal is to support renewal funding for the ARUK Centre for Adolescent Rheumatology at UCL, UCLH and GOSH. Adolescents with inflammatory rheumatological conditions have significant, specific unmet needs, related not only to clinical care and transition between paediatric and adult care settings, but also, of central importance for the Centre, due to lack of knowledge and prior research specific to biology, disease patterns and treatment responses in this distinct age group. Since 2012 we have built a thriving multidisciplinary Centre, and enabled establishment of a National Network, to address these unmet needs. The Centre has leveraged significant new funding, brought in key expertise through collaborations, and developed in-depth patient involvement. Our goals for the next 5 years are to drive forward research in 4 key areas: 1. Mechanisms of adolescent-related arthritis; 2. Biology of the adolescent immune system in relation to inflammatory disease; 3. Improving health care provision and enabling self-management in young people with inflammatory diseases; 4. The Barbara Ansell National Network for Adolescent Rheumatology. In parellel we will secure the next generation of researchers in this growing area, to ensure sustainability of the Centre, while enhancing patient involvement at every level of Centre activity.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM