NIHRDataInsights/HRCSData huggingface dataset:
Title: Centre for Genetics & Genomics Versus Arthritis
Funder: Versus Arthritis

Abstract: We have established a Centre of Excellence in Genetics and Genomics of arthritic diseases with an international reputation for research identifying genetic markers of susceptibility to and outcomes of inflammatory arthritis and for training researchers of the future. We now plan to exploit that knowledge with two major programmes of research. In Translational Genetics we will translate the findings from susceptibility and outcome studies to prevent disease and it’s complications, predict treatment response and personalise treatment to the individual. In Functional Genomics, we will advance a programme of discovery science aimed at understanding exactly how genetic variants associated with inflammatory arthritis alter gene, protein and cellular function to cause dysregulation of the immune system; we believe that such a mechanistic understanding of arthritis causation is vital if we are ever to cure or prevent arthritis. By developing a pipeline to facilitate the interpretation of genome wide association studies, the impact of this programme, to inform patient stratification and personalised medicine and identify novel therapeutic targets, will reach beyond arthritis to other complex diseases. As a Centre of Excellence we will continue to deliver on currently funded research whilst leveraging new funding to support the proposed programmes. We will communicate our research findings in high impact scientific journals and to lay audiences, ensuring that clinical translation is prioritised. We will continue to collect samples for our research from our unique patient-based studies, supported by our recently established social enterprise company. We will maintain existing and build new collaborations nationally and internationally with academia and the commercial sector. Training of our own staff and students and visitors from other groups, to develop expertise in translational genetics, bioinformatics and functional genomics to establish the next generation of arthritis researchers, will remain a high priority.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL
Title: Fibromyalgia and refractory pain in rheumatic diseases
Funder: Medical Research Council

Abstract: Fibromyalgia syndrome (FMS) is a common chronic primary pain syndrome with a prevalence exceeding 2% in the general population. FMS is characterized by chronic widespread pain in combination with other neurological symptoms, such as fatigue, sleep disturbances, anxiety, depression, and memory problems. FMS is more common in women than men, and much more prevalent in patients with autoimmune rheumatological conditions. Patients report very poor scores for health-related quality of life, and the available therapies are of limited efficacy. We have recently discovered that FMS in patients without comorbidities (primary FMS) is caused by autoantibodies and that sensory, anatomical, and motor symptoms can be transferred from patients to mice by administration of IgG. These findings are likely to initiate a paradigm shift in our understanding and management of FMS and have enabled us to embark on detailed cellular and molecular investigations of FMS. Our studies of single afferents in skin-nerve preparations and current-clamp investigations of dorsal root ganglion (DRG) neurons show that FMS IgG produces neuronal hyperexcitability. Transcriptomic analysis of sensory ganglia has identified a single candidate ion channel, and the observed electrophysiological changes in DRG neurons mirror those expected to be caused by dysregulation of the candidate ion channel. About 20-30% of patients with rheumatoid arthritis, ankylosing spondylitis, and Behcet's disease meet the diagnostic criteria of FMS. While the rheumatic disease in these patients is often well-controlled clinically, FMS is typically refractory to treatment. The proposed studies will determine whether the same mechanisms that we have identified in primary FMS, are also responsible for comorbid FMS in patients with rheumatic diseases. The results of the proposed studies will expand our earlier conclusions and may establish FMS as an autoimmune disease in its own right.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL;NEUROLOGICAL
Title: Manchester Molecular Pathology Innovation Centre (MMPathIC): bridging the gap between biomarker discovery and health and wealth
Funder: Engineering and Physical Sciences Research Council

Abstract: Our aim is to establish an infrastructure: promoting biomarker discovery; translation into molecular pathology tests; NHS dissemination; and commercialisation. -Discovery builds on existing strengths in "omics" technologies (notably £13M MRC Clinical Proteomics Centre [MRC-CPC], North West Genomic Medicine Centre [NW-GenMed]); University of Manchester's (UoM) Health Economics/Biostatistics, UoM TextMining (NaCTeM); Farr Institute safe haven for data analysis; and MIMIT (Manchester Integrating Medicine and Innovative Technology) -Translation exploits the molecular pathology expertise across Central Manchester Foundation Trust's (CMFT) extensive laboratories and UoM's Experimental Molecular Pathology. -Dissemination utilises interlinked NW networks of pathology laboratories, facilitated by Greater Manchester Academic Health Sciences Network (GM-AHSN) -Commercialisation will develop around the partners' intellectual property commercialisation agents (UMI3, Trustech); commercial partners; and through Innovate's UK Precision Medicine Catapult (IUK PM Catapult) All activities benefit from Manchester Academic Health Sciences Centre's (MAHSC) £3bn healthcare economy; UoM health economists; involvement of NICE and patient groups; local educational resource; and links with other nodes. Ultimately we will produce an infrastructure for developing biomarker-based molecular pathology tests for many diseases, but initially we concentrate on key inflammatory pathways for diagnosing, stratifying and assessing therapeutic response of patients within our 3 MRC Stratified Medicine Programmes (MRC-StratMedP: MATURA £5.7M, rheumatoid arthritis [RA]; MASTERPLANS £5.1M, lupus; PSORT £5M, psoriasis) A major MMPathIC activity is developing generic pipelines encompassing discovery and translation to GCLP standards. This we will pursue in intellectual partnership and shared complimentary resources with colleagues in CRUK's Major Cancer Centre to optimise time and cost effectiveness


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;MUSCULOSKELETAL;SKIN
Title: Comparing the mechanism of skin and synovial tissue inflammation in psoriatic arthritis
Funder: Medical Research Council

Abstract: Psoriatic arthritis (PsA) is an inflammatory arthritis that affects 0.3-1% UK population and occurs in 10-30% of people with psoriasis. We hypothesise that PsA is an antigen-driven IL-17+CD8+ T cell-mediated disease and that skin and joint inflammation is linked in terms of CD8+ T cell clonality and phenotype. Few studies have directly compared immune mechanisms in the skin and the joint in PsA and no study has simultaneously compared the clonality and phenotype of T cells from the skin and the joint. Our aims are (1) to isolate mononuclear cells from paired biopsies of inflamed skin, synovial tissue and blood from patients with PsA and quantify %IL-17+CD8+ T-cells by flow-cytometry. We expect to find increased %IL-17+CD8+ T-cells at sites of inflammation compared to blood and corresponding samples from controls with osteoarthritis. (2) To perform single cell analysis of paired alpha and beta T cell receptor sequences and single cell qPCR expression of 48 genes on CD8+ T cells from inflamed skin and synovial tissue and blood from patients with PsA (n=400 cells/site, n=2 patients). We expect to find (i) clonal expansion of CD8+ T cells in inflamed tissue but not blood. (ii) Skin and synovial tissue will harbour CD8+ T cells of the same clonality. (iii) Clonally expanded CD8+ T cells will share common phenotypes with higher %clonally expanded cells expressing IL-17 compared to non-clonally expanded cells. This project will link information regarding potential antigen-specificity and T-cell ancestry with phenotype. This could identify new therapeutic targets and provide a basis for future studies to identify responsible antigens with the possibility of developing peptide-immunotherapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;MUSCULOSKELETAL;SKIN
Title: Latent enhancers - a novel mechanism for pain chronification?
Funder: Medical Research Council

Abstract: This project is concerned with the question of why painful conditions should persist over many years, despite the fact that the initial injury or disease has remitted. It is a phenomenon commonly observed in the clinic, where patients might for instance be plagued by back pain long after the initial sports injury healed. What is known is that their nervous system appears to have adopted a permanent maladaptive state as a result of an initial condition. What is unknown is what molecular mechanisms enable this maladaptive state to persist over long periods of time. This project investigates the novel hypothesis that the emergence of latent enhancers permanently alters the phenotype of the neurons and immune cells involved in nociception - ultimately turning acute pain into a lasting chronic condition. Latent enhancers are regulatory regions that emerge in the genome as a result of stimulation once cell development is complete. They have been shown to occur in immune cells, and I have recently been able to observe their appearance in mouse microglia in a model of chronic pain (Denk et al, Cell Reports, 2016). Based on this work, this proposal aims to answer the following three questions: 1. Do latent enhancers also emerge in neurons, where nociception ultimately takes place? 2. Do latent enhancers display characteristics that would allow them to act as a molecular memory? 3. Does the deposition of latent enhancers have functional consequences? Enhancer profiles ultimately determine cell identity, and post-developmental changes to these profiles could therefore affect cell function in the long term. The results of this work would help elucidate the origins of chronic pain, ultimately facilitating the search for effective prevention or treatment. They would also help uncover generic mechanisms of how the environment can impact gene function in a cell-type specific manner.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: International Collaboration On Neuroinflammation in Traumatic Brain Injury (ICON-TBI)
Funder: Medical Research Council

Abstract: There is growing acceptance that traumatic brain injury (TBI) can result in long-lasting physical, psychiatric and psychological disability. TBI may also be progressive, with worsening neuroimaging findings and neurology over months and years, and/or increased risk of late dementia. The mechanisms underpinning these late processes are uncertain, but may involve neuroinflammation, which is known to occur in acute severe TBI. However, neuroinflammation may also occur in mild TBI, and may include an adaptive immune response with autoantibody production and chronic microglial activation. These have been investigated in animal models, but there are limited clinical data. ICON-TBI will address this through complementary clinical and experimental research, involving 175 patients with a range of TBI severity. We will bank serial blood, CSF and brain microdialysis samples, obtain serial MRI (including diffusion tensor imaging), and undertake serial imaging of microglial activation with [11C]PK11195 PET in a subgroup of patients to understand the time course of and consequences of microglial activation following TBI. Peripheral and CNS immunocytes will be characterised using immunophenotyping and expression profiling, and we will measure autoantibody responses, and their modulation by the acute alarmin response, immunocyte profile, and CD8 T cell exhaustion. Clinical studies will be underpinned by studies in experimental models of diffuse and focal TBI, which will investigate the role of severity, age and gender in modulating neuroinflammation, and explore novel immunomodulatory therapies, including a selective TNFR1 antagonist. We will characterise microglial polarisation states after TBI, explore whether variations in this process could explain varying outcome impact of neuroinflammation, and examine the effect of immunomodulatory events on microglial phenotype and subsequent outcome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Systemic inflammation and the blood-brain barrier in multiple sclerosis
Funder: Medical Research Council

Abstract: BACKGROUND: Increasing evidence points to a role for systemic inflammation in driving chronic neurological disease, such as multiple sclerosis (MS). The mechanism is unknown; but evidence suggests that changes in the blood-brain barrier (BBB) may be important. Changes may be mediated by the host inflammatory response. The BBB in the diseased brain may be more susceptible. AIMS: Investigate BBB permeability during systemic inflammation in people with progressive MS and controls without neurological disease. Spontaneous urinary tract infection (UTI) is used as a common and easily-identifiable trigger of systemic inflammation. Hypotheses are that (1) UTI is associated with BBB disruption; (2) magnitude of BBB disruption correlates with magnitude of inflammatory response; (3) magnitude of BBB disruption correlates with magnitude of central nervous system symptoms; (4) BBB disruption during UTI is more marked in people with MS than controls. METHODS: PwMS (n=30) and controls (n = 30) will report symptoms of UTI, which will then be confirmed using a number of markers including pyuria. BBB change will be assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Serial scans during infection and convalescence will define BBB changes associated with UTI. Urinary neopterin and serum cytokines will be used to assess the inflammatory response. Validated assessments will be used to record symptoms. SCIENTIFIC & MEDICAL OPPORTUNITIES: This project addresses a novel hypothesis. By providing a mechanistic understanding for the relationship between systemic inflammation and MS symptoms, I will be in a position to lead clinical trials of drugs which strengthen the BBB (which our group is currently developing). Serum, peripheral blood mononuclear cells, and paired BBB permeability data from all imaging time-points will be a rich resource for further mechanistic study and unbiased screen for a BBB biomarker.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Complement in Alzheimer’s disease: from gene discovery to mechanisms and better drugs
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. Gene discovery led from Cardiff has firmly implicated innate immunity, inflammation and the complement system as drivers of pathology in AD1,2. Beyond genetic association, involvement of complement in AD is further supported by a large and growing body of evidence from animal studies, human biomarker and immunopathology findings and molecular pathway analyses3-6. Complement also overlaps with and strongly influences other gene-implicated pathways such as phagocytosis, membrane turnover and debris removal, placing it at a nexus in the disease process and flagging as a potential target for therapeutic intervention. Understanding precisely HOW complement contributes to the disease process in AD, a prerequisite for effective targeting, has been more challenging. A simplistic interpretation might be that complement activation drives pathology by amplifying inflammation, activating glia and exacerbating neuronal damage; however, there is compelling evidence that complement activation can, in some circumstances, reduce or reverse AD pathology – the double-edged sword. For example, strategies that aim to enhance amyloid clearance using antibodies or immunisation rely on complement activation to opsonise amyloid for phagocytic removal7, while in mouse AD models, complement C3 deficiency exacerbates disease in some and ameliorates in other studies8,9. Further, it is now clear that complement activation plays key roles in pruning synapses, an essential aspect of normal brain development but also a contributing factor in neurodegeneration, including in AD and glaucoma10-12. Indeed, Cardiff colleagues were among the first to describe dendritic atrophy as an early marker of disease in an AD model13.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Lupus Research - Emerging Leaders Prize First place
Funder: Medical Research Foundation

Abstract: Brain disease is a serious and common manifestation of lupus, but its molecular basis is poorly understood. As a result there are no dedicated therapies to prevent the development of brain damage, and no ongoing trial efforts. My research is dedicated to tackling this neglected field of lupus brain disease, with the aim of developing effective, personalised treatments. Type I interferon proteins, which normally protect the brain from viruses, are abnormally raised in lupus. I have shown that these proteins can directly damage the brain, in particular the small blood vessels. Interferon proteins are therefore an important potential drug target in lupus brain disease. However measuring the levels of these proteins in the blood of people with lupus has been a major obstacle since the proteins were discovered 60 years ago. We have helped solve this problem by showing that a new ultrasensitive blood test, which can detect single molecules of interferon protein in blood samples, allows interferon protein levels to be accurately measured. We have combined this technology with state-of-the-art brain scanning to allow new insights to be gained into how brain disease develops in people with lupus. These observations are informing how we can design clinical trials aimed at preventing brain damage.


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;NEUROLOGICAL
Title: Signal transduction from the antigen receptors of B and T cells
Funder: The Francis Crick Institute

Abstract: The development, activation, differentiation and survival of lymphocytes are controlled by signals from multiple receptors. We are using genetic, biochemical and imaging techniques to study signalling pathways in these processes. A key area of interest is the signals that control survival of naïve B cells. We showed that signals from BAFFR that are required for B cell survival are transduced via the B cell antigen receptor (BCR) to the SYK tyrosine kinase, demonstrating, unexpectedly, that BAFFR co-opts the BCR signaling pathway. We are now investigating the molecular mechanism by which BAFFR transduces signals using proteomics, transcriptomics and genetic screens. As an extension of this we are exploring signalling pathways controlling survival of memory B cells. Migration and adhesion of lymphocytes are critical for development, activation and differentiation of lymphocytes and hence play an essential role in regulating the adaptive immune response. We recently used a genetic screen to discover a novel pathway controlled by the WNK1 kinase, which regulates T cell adhesion and migration. Future studies aim to understand the molecular mechanisms by which this pathway regulates these cellular processes, and the role of this pathway in immune responses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Inhibition of reverse transcription in type I interferon mediated neuropathology
Funder: Medical Research Council

Abstract: Given that our cells are replete with DNA and RNA, the evolutionary adoption of viral nucleic acid recognition as the primary trigger of a type I interferon (T1I) mediated antiviral response carries with it the inherent risk of misconstruing self as non-self. Neurological disease is a major feature of the group of inborn errors of immunity referred to as the type I interferonopathies (T1IFNs), where enhanced T1I signalling is considered directly relevant to disease pathogenesis. An outstanding mechanistic question then relates to the source of self-derived nucleic acids that might drive such an inappropriate immune response in the non-infectious T1IFNs. The conceptual distinction between self and non-self breaks down when considering endogenous retroelements. Indeed, given an important body of work implicating T1IFN-related genes in nucleic acid metabolism and retroelement biology, we have obtained promising preliminary data in a clinical trial of reverse transcriptase inhibitors (RTIs) in certain T1IFN genotypes, used on the premise that blocking the reverse transcription step in the lifecycle of LINE-1 (L1) elements, the only autonomous retroelement currently active in the human genome, might limit T1I induction. In the current project we wish to extend these data, proposing to challenge T1IFN patients with individual RTIs to determine if we can reduce autoinflammation by blocking reverse transcription, thereby implying a direct role for retroelements in human inflammatory disease. In the absence of a neurological phenotype in equivalent animal models, possibly related to differences in the repertoire of active retroelements between species, experiments in the whole human organism are essential to progress our knowledge of T1IFN neuropathogenesis. Furthermore, given that T1I mediated neuropathology may be relevant in a number of other disease settings, these experiments will likely have broader significance for our understanding of neurological homeostasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Experimental medicine approach linking brain and peripheral immune mechanisms mediating sickness behaviours in people with rheumatoid arthritis
Funder: Medical Research Council

Abstract: We currently do not fully understand what underlies common, but complex, behaviours like sickness behaviour in humans. This study is focused on leveraging a mechanistic understanding of the role of one cytokine, TNF, in driving sickness behaviours. The project will use state-of-the-art neuroimaging to probe the relationship between TNF and glutamate and the related effects on brain network connectivity as well as explore the potential role of monocytes recruited from periphery to brain. To do this we will use existing, effective anti-TNF therapy (etanercept) in the context of routine clinical care for rheumatoid arthritis. We will examine glutamate biochemistry via 7T MRS and brain connectivity via 7T resting state and task-based fMRI. An exploratory component will examine the role of CD14+ monocytes recruited from peripheral blood to the brain using autologous CD14+ monocytes radiolabelled with Technetium-99m and the chelating agent HMPAO.


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