NIHRDataInsights/HRCSData huggingface dataset:
Title: New paradigms in fibroblast-immune cells coordination in matrix homeostasis in health and disease
Funder: Medical Research Council

Abstract: Vertebrates are ~25% by mass collagen, mostly in the form of long fibrils that provide tensile strength and tissue structures. Collagen dysregulation underpins many diseases: excess leads to incurable fibrosis, which disrupts organ functions and is associated with 45% of all deaths. Reduced collagen (in amount or fibril functionality) leads to other conditions, e.g. musculoskeletal diseases, poor wound-healing. Thus, collagen pathologies have major health consequences, and understanding the molecular control of collagen is fundamental to therapeutics development. We previously reported that fibroblast collagen homeostasis is under circadian control, and clockless fibroblasts produce abnormal collagen fibrils. I also showed that the endosome is a master regulator, directing collagen (endogenous, or exogenous that was endocytosed) to either fibril formation or monomer secretion, and that distinct machineries are involved; elevated endosomal-recycling may be a disease-mechanism in lung fibrosis. To determine the components of this monomer/fibril switch, I developed a method coupling flow cytometry to mass spectrometry that will allow me to identify collagen-trafficking proteins. I will test how these proteins contribute to the monomer/fibril switch using collagen-reporter cells, and verify their involvement in lung fibrosis using human control/patient samples. Further, an unexpected collagen-deposition role for macrophages was recently reported; I have found that immune cells synchronise and promote collagen fibril deposition in fibroblasts, and make collagen fibrils themselves, indicating an as yet-unknown immune-fibroblast coordination on collagen deposition. I will define how immune cells contribute to collagen homeostasis, either directly and/or through controlling the fibroblast circadian rhythm. These mechanistic insights will be clinically important, by establishing collagen-trafficking components and defining the role of immune cells in collagen homeostasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Does impaired adipose tissue B cell function lead to loss of natural antibody secretion and increase susceptibility to infection in obesity?
Funder: Medical Research Council

Abstract: Obesity is associated with a heightened risk of community acquired pneumonia and severe COVID-19. Natural antibodies (nAbs) are vital to fight infection. Nabs recognise conserved epitopes on pathogens through innate specificity providing early protection prior to the production of pathogen-specific antibodies. Levels of circulating nAbs are reduced in chronic conditions associated with obesity and age, possibly explaining the increased risk of infection, but no therapeutic strategy targeting the protective function of nAbs in infections has been developed. In mice, nAbs are produced by innate-like B cells (IBCs), mainly found in serous cavities and in fat-associated lymphoid clusters (FALCs) in visceral adipose tissue. FALCs enable the maintenance of IBCs and the secretion of nAbs. Data on IBCs has come almost exclusively from mice and our understanding of the mechanisms driving the emergence, maintenance and activation of IBCs in humans is limited. Our preliminary data obtained from human biopsies led us to hypothesise that IBCs are present in human adipose tissue and that their function is impaired in obesity, leading to reduced nAb production and increased susceptibility to infections. In this project we will identify the mechanisms enabling the emergence, maintenance and activation of IBCs in human FALCs. We will elucidate why IBCs are dysfunctional in obese patients, how this affects susceptibility to infection and identify a pathway that could be targeted to restore IBC function in obese individuals. We will also generate proof-of-principle evidence in mice that nAb clones with anti-microbial properties can increase resistance to infections. In future, the protective properties of nAbs could be leveraged at two levels: by identifying a drug to target IBCs that boosts nAb secretion, providing a broad shield against infection and by identifying a nAb clone with high anti-microbial properties to treat or prevent high risk infection in hospitalised patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: InSIGHT: Integrating Statistical methods, Immunology and Genomics for Healthcare Translation
Funder: Medical Research Council

Abstract: Immune-mediated diseases (IMDs) are common, chronic and incurable. They affect around 10% of the population, and include inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus (SLE). Supported by an MRC Programme Grant, we have built unique patient cohorts, spanning 6 IMDs recruited at diagnosis with pre-defined disease activity, subject to detailed genomic analysis, and followed prospectively (some for over 16 years). An analysis of a small subset of the data generated by the Programme has revealed new insights into pathogenesis, and led to a prognostic test already benefitting IBD patients in the clinic via a spin-out company PredictImmune. Patient recruitment of cohorts with IBD (Crohn's disease and ulcerative colitis), MS, SLE, ANCA- associated vasculitis (and its subsets) and idiopathic pulmonary fibrosis is complete - all have had RNASeq, and most DNA methylome, analysis performed on 16 purified cell populations. This application will support remaining proteomic, genetic and epigenetic data generation from already collected samples, and will focus on developing state-of-the-art analytic pipelines to exploit this unique platform established by the MRC. These new analytic pipelines will be an output of the programme. This approach, already demonstrated to be productive in a previous MRC Programme, will deliver prognostic, disease activity and other tests to the clinic, and will define immune pathways driving disease pathogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Resolving innate inflammatory responses to tissue injury and apoptotic cell clearance to develop novel therapeutic strategies for pulmonary diseases
Funder: Medical Research Council

Abstract: Dysregulated inflammation, frequently observed in respiratory disease, causes an enormous burden of worldwide ill health and premature death. Understanding mechanisms of immune cell recruitment to injured tissue and subsequent clearance of apoptotic cells affords a unique opportunity to identify novel targets to treat acute and chronic lung disease. Using the synergistic expertise of the applicants, we will leverage the powerful genetics and live imaging potential of the fruit fly Drosophila melanogaster married to mechanistic studies in vertebrate (zebrafish) and mammalian (mouse and human) systems. This approach will screen for, identify and dissect the molecular machinery that drives immune cell migration and mechanisms of apoptotic cell reprogramming of macrophages. Core project deliverables: 1. Examine mechanisms of immune cell wound recruitment in Drosophila, and identify novel inflammation regulating genes for further study in mammalian systems. 2. Determine if PTPN21 and MEGF11, recently identified via our Drosophila studies, represent evolutionarily conserved damage sensing and migration machinery in mammalian immune cells and their impact upon experimental lung injury. 3. Determine how sensing and uptake of dying (apoptotic) cells reprogrammes macrophage behaviour to influence their fate and function using Drosophila, mouse and human systems. 4. Use these platforms to dissect the functionality of novel targets identified from parallel CRISPR/Cas genome wide screens and transcriptomic analyses on immune cells responding to tissue injury or apoptotic cells. 5. Translate our findings made in the fly, mouse and healthy human cells into severe pulmonary inflammation (as typified by acute respiratory distress syndrome) using established pipelines and tissue biobanks. Together, these approaches will identify and test evolutionarily conserved regulators of inflammation to find much needed novel targets to treat inflammatory diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Harnessing molecular signatures to deliver personalised B-cell targeted therapies in Sjogren's syndrome
Funder: Medical Research Council

Abstract: Research question: Can a "molecular signature" or "endotype" (defined as a combination of whole blood - WB and salivary gland tissue transcriptomic signatures) be more relevant than the diagnostic label in defining unique disease characteristics? Importance: If such a preliminary "molecular signature" can be identified, this is likely to help (after further validation in larger prospective studies) better patient stratification and ultimately guide treatment selection for better SS patient outcomes. Subsequently, this will address the challenge of SS patient heterogeneity as likely contributor to many negative interventional clinical trials in SS. We propose an exploratory study to investigate this research question, focused on transcriptomic signatures, which will generate preliminary data for further validation in larger prospective studies, as well as support further investigation of other omic-signatures in the same SS cohort (such as targeted proteomics analysis based on the transcriptomic analysis generated by this proposal). Rationale: B cell targeted therapeutic strategies (Belimumab and Rituximab, alone or in combination) have been used/trialled in SS with varied results. This proposal will investigate both peripheral blood and salivary gland (SG) transcriptomic signatures associated with SS in a combined cohort of SS patients (GSK patients, n=65 matched samples at baseline and W24 and UCL patient samples n=46, total n=111). These transcriptomic signatures could provide new insight into SS disease pathogenesis in different tissue compartments and generate preliminary data for further investigation of potential predictive biomarkers for patient stratification for selection of B cell therapies


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identifying therapeutic targets to treat and prevent disease flare in rheumatoid arthritis
Funder: Medical Research Council

Abstract: Flares of immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA), are a major burden for patients. They occur unpredictably, adding to the physical and psychological burden of the condition, and contribute to joint damage and comorbidities, such as cardiovascular disease. Flares are difficult to study, precisely because of their unpredictable timing. However, we have established a human model that generates a 'synchronized' population of RA patients in clinical remission, of whom about 50% flare within 6 months, the remainder maintaining remission. In recently completed work we studied 118 patients in clinical remission for at least 6 months who were prepared to discontinue treatment. After treatment cessation patients were studied intensively, with blood sampling at weeks 2, 5, 8, 12 and 24. The proposed work will study bio-banked longitudinal samples from 10 patients who remained in remission and 10 who flared. To gain novel insights into changes in the peripheral immune compartment leading up to flare, we propose a quantitative and qualitative comparison of peripheral blood mononuclear cells (PBMC) from participants, at a single cell level. This will include parallel transcriptomics, TCR/BCR sequencing and proteomic analysis (10X Genomics) using a comprehensive immune panel of 130 surface antigens (TotalSeq-C, Biolegend). We will analyse PBMC at baseline, and at each timepoint leading up to flare, as well as in matched timepoint remission samples. The data generated will be interrogated to identify compositional changes, novel cell states, altered gene regulatory networks and alterations in T and B cell receptor repertoires in the prodrome of flare. If this pilot study provides encouraging data then we will seek further funding to perform a more focussed analysis using a larger set of samples.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identifying, characterising and evaluating antibodies in Guillain-Barré syndrome
Funder: Medical Research Council

Abstract: The acute inflammatory neuropathy Guillain-Barrè syndrome (GBS) involves devastating immune-mediated damage to peripheral nerves. Affected individuals develop progressive paralysis and sensory loss, frequently necessitating ventilatory and intensive care support. There is an urgent need to improve the current situation where non-specific and incompletely effective immunotherapies leave many patients with persistent disability. We and others have recently identified disease-causing antibodies targeting specific proteins at the node of Ranvier in a subset of patients with the rarer chronic inflammatory demyelinating polyneuropathy (CIDP). We have shown that patients with these antibodies have distinct features. Crucially, they respond poorly to standard therapies, yet can show marked and sustained improvements following treatment with CD20/B-cell targeting agents such as rituximab. However, the majority of patients with GBS are seronegative for all currently identified antibodies. Despite GBS undoubtedly encompassing a range of underlying pathologies, patients typically receive standard therapies, to which a significant proportion do not respond. Using myelinating co-cultures of human stem-cell derived sensory neurones and rat Schwann cells as an unbiased screen, we are able to detect peripheral nerve reactive antibodies in 10-20%. However, the target of these antibodies, and whether they indicate a mechanistically distinct disease process and/or influence treatment responses, is currently unclear. In this project, using an established and previously successful immunoprecipitation/mass spectrometry workflow, we will identify the relevant antigens. High throughout immunoassays will then be developed to confirm these findings and assess the frequency and clinical implications of the antibodies using established national/international neuropathy biobanks linked to detailed clinical and outcome data.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Tissue research in childhood inflammatory arthritis (TRICIA consortium)
Funder: Medical Research Council

Abstract: The primary goal of this partnership is to create the Tissue Research in Childhood Inflammatory Arthritis Consortium (TRICIA), which aims to develop the intellectual infrastructure, workflow pipelines and capacity to deliver multicentre synovial tissue-based studies in children and young people with juvenile idiopathic arthritis (JIA) in the UK. The consortium will build on an existing and funded collaborative network that supports the investigation of synovial pathology in children with JIA. We will bring together UK clinical centres with the capability to perform synovial tissue biopsies and partner with major academic centres performing advanced tissue analytics linked to clinical outcome measures (data science). Our long-term goal is to embed synovial tissue analytics within both multi-centre biopsy driven clinical trials and clinical practice. The aims of the TRICIA consortium are: 1. To build capability within UK paediatric rheumatology to perform synovial tissue research in JIA by establishing synovial biopsy programmes at new centres. 2. Provide training in minimally invasive, ultrasound-guided synovial biopsy techniques in children and young people. 3. Collect data on the acceptability, tolerability and safety of paediatric synovial tissue biopsies. 4. Establish standardised approaches to clinical and biological data capture. 5. Establish a dedicated tissue analysis pipeline with a standardised approach to synovial tissue collection, processing and analysis. 6. Deposit and present clinical and experimental data from tissue analysis studies in a common integrated platform with web-based knowledge management tools supporting data mining, analysis and hypothesis generation. The creation of TRICIA and use of harmonised data and sample collection protocols will ensure that the consortium is ideally placed to maximise the benefit from ongoing precision medicine initiatives in JIA and obtain funding for synovial tissue research in the future.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Determination of the trafficking kinetics and role of mononuclear phagocyte subsets in treatment-naive psoriatic arthritis.
Funder: Medical Research Council

Abstract: Inflammatory arthritis (IA) is characterised by abnormal leukocyte infiltrate. The mechanisms behind this across different diseases and tissues are poorly understood. Psoriatic arthritis (PsA) is a common IA and is associated with joint damage and significant sequelae. Amongst the cells recruited to inflamed joints are mononuclear phagocytes (MoPs). MoPs are a complex population comprising monocytes, macrophages and five dendritic cell (DC) subsets. MoPs lie at the interface between innate and adaptive immunity, directing the immune response by releasing cytokines (CK) and driving T-cell fate, making them prime candidates for initiation of PsA. The distinct role of MoP-subsets in PsA pathogenesis has yet to be determined. Aims I hypothesise that specific MoP-subsets are primed for preferential recruitment to PsA joints where they have subset-specific roles in disease. My aims with associated objectives are: 1. Determine if circulating MoPs have a trafficking phenotype specific to PsA. Cell abundance and MoP trafficking profile will be examined using novel flow cytometry panels to describe the MoP compartments in blood and synovium in treatment-naïve PsA and healthy persons. This will be compared against cutaneous psoriasis, osteoarthritis (OA) and rheumatoid arthritis (RA). Unique radiolabelling techniques will be used to visualise in vivo behaviour. 2. Identify MoP gene signatures that are specific to PsA. Gene-expression profiles will be explored using a combination of scRNAseq and bulk-RNA-sequencing in the blood and synovium of healthy and treatment-naïve PsA patients. This will be compared against publicly-available datasets on RA/OA to determine PsA-specific signals. 3. Define the functional properties of MoP subsets that drive PsA. Isolated populations of interest migratory properties, CK production, and T-cell polarisation will be examined in vitro. This work may lead to identification of new biomarkers to aid diagnosis and novel drug targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploring mechanisms to optimise the duration of oral immunotherapy for peanut allergy
Funder: Medical Research Council

Abstract: BACKGROUND Oral immunotherapy (OIT) for peanut allergy has proven efficacy, but is associated with frequent adverse events and longer-term data are lacking. The mechanism(s) underlying OIT - and in particular, longer term efficacy - are unclear; this limits our ability to predict outcomes and improve safety. OBJECTIVES 1) To investigate the changes in humoral responses and effector cells associated with the persistence or loss of desensitisation in children undergoing peanut-OIT 2) To evaluate how these immune changes are impacted by OIT duration, and correlate to clinical outcomes (including sustained unresponsiveness [SU]) 3) To identify predictors of longer-term efficacy that could be used to optimise a personalised approach to OIT, reducing adverse reactions and thus improve patient safety METHODS i) Define the changes in humoral responses and effector cells (basophils, mast cells) from children who have undergone up to 3 years of OIT in the BOPI study (NCT02149719). SU has been assessed by double-blind, placebo-controlled food challenge (DBPCFC) in participants after stopping peanut OIT for up to 12 weeks ii) Evaluate predictors of SU by linking laboratory data to clinical outcomes using both conventional hypothesis testing but also machine-learning approaches. iii) Assess the predictors identified in (ii) in a replication cohort of young people undergoing peanut-OIT, either using boiled or roasted peanut in the BOPI-2 study (NCT03937726) iv) Additional preliminary work to assess impact of (i) on intracellular signalling The inclusion of a challenge for sustained unresponsiveness, performed 12 weeks off treatment, presents a unique opportunity to study the immune changes that result in initial desensitisation, and also the persistence or loss of treatment effect following cessation of OIT. Interrogating both processes will provide invaluable data to increase our understanding of OIT and optimise protocols to deliver safer patient care.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Protein tyrosine phosphatases as rheostats of Jak-STAT cytokine signals and determinants of disease heterogeneity.
Funder: Medical Research Council

Abstract: 1. Define the regulation of STAT transcription factor by protein tyrosine phosphatases (PTP) We will analyse RNA-seq and ATAC-seq data from IL-6, and IL-27, stimulated naïve and effector memory CD4+ T cells from Lck-Cre:Ptpn2fl:fl and Ptpn22-/- mice (and littermate controls). ChIP-seq of STAT1, STAT3 and P300 will identify the regulation of STAT transcription factors by PTP. Archived repository datasets will enhance the bioinformatic analysis. We will also consider the relevance of this mechanism to stromal cells from the joint using synovial fibroblasts cultured from mice with antigen-induced arthritis (AIA). 2. Establish the regulatory properties of PTP activity in synovitis Histology assessments of joint pathology and bioinformatics of functional genomics will compare the induction of synovitis in Lck-Cre:Ptpn2fl:fl and Ptpn22-/- mice with corresponding data (already generated) from wild-type, Il6ra-/- and Il27ra-/- mice with AIA. Bioinformatics will establish how STAT transcription factors engage the genome during disease and reveal the action of PTP on Jak-STAT signalling. Data will identify common pathways driving synovitis and disease heterogeneity. As evidenced by our publications and pilot data, we will validate our mouse findings using clinical data from open access repositories (e.g., GEO, the accelerated medicine partnership) and our collaborators. This approach will also identify criteria for the design of future clinical studies. 3. Track the transcriptional profile of cells shaping synovial histopathology Single-cell sequencing (scRNA-seq, scATAC-seq) of synovial tissue from mice with AIA will map gene signatures, epigenetic determinants (e.g., transcription factor binding sites) and cell types affecting disease onset. Bioinformatics will provide insights into alternate cellular dynamics, cell lineages and functions responsible for disease heterogeneity in synovitis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM