NIHRDataInsights/HRCSData huggingface dataset:
Title: Which children develop chronic pain after a fracture? Identifying children who develop chronic pain after a fracture injury
Funder: Versus Arthritis

Abstract: A third of children will experience a fracture before they are 17 years of age. Although most children recover following acute injuries, a third of those report frequent, intense, and interrupting pain three months after their fracture injury. This long-term or chronic pain impacts their social, physical and mental health. Despite research investigating the consequences of chronic pain in childhood, we know little about which biopsychosocial risk factors are associated with developing chronic pain after injury and the recovery period. There are three goals of this proposed research: 1) to determine the biological, psychological, and social risk factors of developing chronic pain after a fracture, 2) to characterise pain and avoidance during recovery, and 3) to develop a screening measure to identify which children will develop chronic pain. I will investigate these aims through three studies, using self-report and objective measurement. Children who have a fracture will be recruited to provide a comprehensive understanding of risk factors and recovery in children and their parents. Conducting a longitudinal study over 12 months, I will identify the biopsychosocial risk factors of developing chronic pain after fracture injury. Using daily diaries and physical activity trackers, I will characterise the recovery period of children with a fracture and their parent. In a simultaneous study, parents of children with fracture will experimentally tested on how behave under different threatening conditions objectively. Finally, using findings of risk factors, I will develop and test a screening tool to identify those at risk of developing a chronic pain. Findings will identify psychosocial targets for future intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MUSCULOSKELETAL
Title: Agrin: harnessing mechanisms of limb development for joint regeneration in patients
Funder: Versus Arthritis

Abstract: Osteoarthritis is a degenerative joint disease characterised by the loss of articular cartilage. There is currently no cure of osteoarthritis and patients must ultimately undergo joint replacement surgery to regain joint function. Despite the function of the joint largely being restored, the symptoms associated with osteoarthritis rarely are. A common predisposing factor for osteoarthritis is cartilage injury, which in many cases does not heal and begins the breakdown cascade. We previously identified a molecule called agrin to possess homeostatic properties when applied to chondrocytes. Treatment with agrin resulted in enhanced cartilage formation both in vitro and in vivo, without inducing ectopic bone formation, as molecules such as BMPs have in the past. Our most recent findings uncovered that the effect of agrin is achieved by orchestrating the activation of the CaMKII/CREB pathways and simultaneous inhibition of the canonical WNT pathway. The result of this combination of events led agrin to induce the expression GDF5 in synovium derived stem cells – but not in bone marrow derived stem cells. We showed these stem cells were recruited to the site of osteochondral defects in mice and sheep and repaired the bone-cartilage architecture as well as restoring function and relieving pain. Additionally, when agrin was knocked out in the developing limb bud, only 54% of embryos were carried to term. Suggesting a major role for agrin in the limb bud stem cells. This fellowship aims to identify a molecular-signature of agrin in stem cells at different stages of their differentiation during development to ascertain which stem-cell lineage agrin affects. This molecular-signature will be screened against signature-databases of existing FDA approved drugs which could be repurposed and test these drugs (alongside agrin) in vivo in a model of osteoarthritis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: UK Paediatric North Star Network
Funder: Muscular Dystrophy UK

Abstract: Since its establishment in 2004, the UK NorthStar clinical network for DMD management and database (NSND) has been successful in establishing effective collaborative arrangements of the paediatric neuromuscular centres in UK to have a cohesive approach in DMD assessment, corticosteroid management, standards of care implementation, data collection to enable audit of clinical practice, and peer reviewed publications of natural history and disease management. This led to the successful postmarketing surveillance use of the NSND for the ataluren managed access agreement. These achievements were made possible by funding support from MDUK, and the collaborative working of doctors and therapists, and the success of this model led to the development of the adults Northstar network. The updated standards of care, the availability of novel therapies, and the need for data from the current DMD population to inform new clinical trials, together with the aim of financial sustainability, dictate the need for further evolution of the network. This evolution includes upgrading the data completion and accuracy to a higher level, ensure direct data input by patients/families, academic and industry collaboration, and a clear demonstration of the network’s ability to sustain postmarketing surveillance models. This grant application is being made to enable the step change required to achieve the above aims and especially for the ability to provide the most up-to-date accurate contemporaneous “control” / “natural history data” to inform compliance with standards of care, design clinical trials, and provide the vehicle for novel DMD treatment implementation and postmarketing surveillance.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: MUSCULOSKELETAL
Title: MICA: Synovial Fluid to Define Molecular Endotypes by Unbiased Proteomics in OA (STEpUP-OA)
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is the most common disease of joints; increasing substantially in the aged population, and in younger individuals following acute joint injury1. Once considered a disease of passive 'wear and tear', we now regard it as an actively-driven proteolytic process that is amenable to molecular targeting. Development of disease modifying drugs in OA has been challenging; the insidious nature of the disease, variable rates of progression2,3, variable treatment responses4 and lack of sensitive biomarkers5, accounts for current modest industry investment in this area. Although clinical phenotype contributes to the ability to predict progression6 this is likely to be substantially improved by recognition of distinct molecular subtypes (endotypes) of disease. Substantial investment has been made by the NIH to discover plasma/serum biomarkers of early OA diagnosis and progression. These studies have largely been small to medium scale (200 patients) and have measured candidate biomarkers (often extracellular matrix proteins1,4,7). Success has been modest. Here we propose to perform a different approach to discovery analysis using the synovial fluid (SF), the tissue with adjacency to all the diseased tissues of the joint. We will analyse 2000 OA SF samples to define molecular endotypes that are associated with disease stage, disease progression and treatment response. We will then use these to look for surrogates in systemic fluids. This project is timely; it has never been easier to perform large-scale analyses on small volume biological samples, and a recent academic collaborative agreement enables Oxford to access SomaLogic's 5000 protein Discovery Platform. Industry is poised to return to the OA area. There are agents in late stage clinical trials; NGF inhibition (Pfizer), intra-articular FGF18 (Merck) and long-acting intra-articular steroid, FX006 (Flexion Therapeutics). Stratification will greatly facilitate the adoption of new agents for OA.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: A first-in-man study to assess short-term safety of a novel osteochondral scaffold in early repair of cartilage defects
Funder: Versus Arthritis

Abstract: UCL has invented a novel biomimetic osteochondral scaffold (through support from ARUK PoC programme PCT/GB2017/050033) for the repair of large cartilage defects in patients with osteoarthritis providing a cost-effective alternative to (or delay in the use of) joint replacement. An in vivo study using a sheep condyle model has demonstrated that the scaffold is capable of achieving stable mechanical fixation through improved bone ingrowth, and led to improved cartilage fills. The applicants have recently been awarded an Innovate UK-MoST grant (no: A02872) to allow this novel osteochondral scaffold technology to be further developed, and manufactured in a GMP-compliant facility. This proposal is for a clinical trial to test short-term safety and efficacy of the developed novel osteochondral scaffold for early repair of cartilage defects in patients with osteoarthritis of the knee. In this study, we will recruit 20 eligible patients with early stage OA and treat them with the novel osteochondral scaffold implant. The patients will then be monitored for mechanical integrity, knee functions and adverse events. Data analysis will be applied to establish the safety and efficacy profile of the osteochondral scaffold. The results from this study will inform the design of a subsequent multi-centre study which, if successful, will lead to tangible and clinically relevant results from a one-step surgical procedure for the treatment of large cartilage defects. The ultimate aim is to provide clinicians with a viable treatment option in situations where the cartilage defect has progressed beyond a small defect, but where a full joint replacement could still be avoided.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Mycophenolate in limited cutaneous systemic sclerosis - external pilot (MINIMISE-Pilot)
Funder: Versus Arthritis

Abstract: Systemic sclerosis (SSc; scleroderma) has two major forms, limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets. Recent clinical trials have focused on dcSSc but the limited subset is commoner and has major unmet medical need from complications. Our long-term goal is to improve outcome in lcSSc by applying immunosuppressive treatment approaches that have become routine in dcSSc. We propose a randomized clinical trial testing whether the immunosuppressive agent mycophenolate mofetil (MMF) slows clinical progression of lcSSc. There is emerging evidence suggesting benefit from MMF for skin and lung fibrosis in dcSSc. MINIMISE-Pilot will randomly allocate patients to MMF or no-immunosuppression. The primary end-point will be “time to clinical worsening of lcSSc” defined as “development of new clinically significant pulmonary, cardiac, renal or gastro-intestinal involvement; or severe digital vasculopathy; or significant increase in modified Rodnan skin score (MRSS).” Thus, we will test the hypothesis that MMF prevents or reduces progression in lcSSc. Secondary analyses will ask whether autoantibody tests can identify lcSSc patients more likely to benefit from MMF. In this application for MINIMISE-Pilot we are proposing an external pilot trial of approximately 120 patients to confirm recruitment rates and evaluate the composite endpoint performance. This will be a collaborative trial focusing on major UK SSc centres including London, Manchester, Leeds, Liverpool, Newcastle, and Bath. Other UK Scleroderma Study Group (UKSSG) members will be key recruiting sites to maximise engagement and trial recruitment. The results of this external pilot will provide valuable information about lcSSc and, if successful, provide foundations for a future full trial which falls outside the scope of the present application. As well as providing external pilot data towards such a trial this study and the anticipated scientific substudies will be an important step towards better management of the important lcSSc subset.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Understanding the contribution of the osteoblast lineage to cartilage and joint health.
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is a major disabling disease in developed countries and with a more active and ageing population, its socio-economic impact can only increase. OA is a multifactorial disease involving many of the tissues within the joint, where damage to any of these starts a cascade of events that culminate in further deterioration of the joint. In the preliminary data I show how deletion of a single protein, PAR2, in the bone forming/sensing osteoblast lineage protects cartilage from damage during OA development, even 1 year after intervention. The data also shows that PAR2 plays an important role in bone formation and resorption. I therefore hypothesise that, signalling from the osteoblast lineage controlling bone homeostasis impacts on articular cartilage chondrocytes, thus affecting cartilage health. Therefore, this proposal is aimed at investigating how communication between cells of the osteoblast lineage and the articular cartilage chondrocytes impacts long-term cartilage maintenance and joint health. To achieve this I propose to harness PAR2 biology to dissect this relationship, allowing the identification of key pathways instrumental in sustaining long-term joint health. Specifically, I propose a combination of in vitro and in vivo studies with an intense ‘omics’ focus to address the following objectives: Examine PAR2-dependent control of bone homeostasis, to reveal the critical osteoblast lineage pathways that control cartilage maintenance. Determine the effect of the osteoblast lineage secretome on chondrocyte and articular cartilage health. Elucidate and manipulate PAR2-dependent pathways linked to osteoblast control of cartilage maintenance. This approach will provide valuable insight into the role of osteoblasts/osteocytes in cartilage maintenance, thus delivering a greater basic understanding of how the osteoblast lineage controls bone homeostasis and subsequently how it affects cartilage health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Genetic and epigenetic effects in development and disease of the human hip
Funder: Versus Arthritis

Abstract: For over a decade, genome wide association studies (GWAS) have been successfully applied to identify risk variants in common diseases, including osteoarthritis (OA) and osteoporosis (OP). However, there remains an enormous disparity between the reporting of variants and functional follow-up studies. A growing body of evidence indicates that these genetic variants lead to epigenetic changes, namely DNA methylation (DNAm), which in turn alter gene expression, leading to disease. In musculoskeletal disease, the key recurring GWAS locus is at chromosome 6p21.1. This region will be my primary research focus during this fellowship. Here, distinct variants can predispose an individual to OA, OP, and other skeletal traits. This locus harbours RUNX2, a gene encoding a transcription factor essential for skeletal mineralisation and long bone development. RUNX2 levels change in both OA and OP, due to a heritable dysregulation in gene expression. My previous studies have shown that OA-associated genetic influences affect DNAm, which can alter expression of RUNX2. I have recently made the remarkable discovery that these DNAm changes leading to age-associated disease also operate in human foetal cartilage. This indicates that the epigenetic risk of poor musculoskeletal ageing is established during development. Using state-of-the-art epigenetic technologies, including targeted Methyl-seq and dCas9 epigenome editing, I will carefully examine the role of human RUNX2 enhancers in two key hip tissues (bone and cartilage) during development and identify how this regulation becomes aberrant in common, age-associated disease. Using subnuclear proteomic profiling, I will identify the proteins binding to prioritised regulatory elements and characterise the molecular mechanisms leading to altered RUNX2 expression. Together, this innovative combination of techniques will elucidate the epigenetic regulation of RUNX2 in musculoskeletal disease and probe the developmental origins of disease risk. This will pave the way for the identification and development of novel therapies by pharmacological targeting of the epigenome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Targeting TFEB for the treatment of Osteoarthritis
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is one of the most common forms of arthritis and a leading cause of disability worldwide, with currently no effective therapy. Accumulating evidence indicates that cartilage degradation which is the main feature of OA is due to cellular senescence. We recently revealed the role of TFEB, a master regulator of autophagy and lysosomal biogenesis, the main cellular bulk degradation pathway, in immune senescence. I have shown that TFEB level decrease with age in human peripheral blood mononuclear cells, and TFEB levels can be increased by spermidine (natural polyamine) to reverse the ageing phenotype of these cells (Alsaleh et al, eLife under final revision). Paralleling the studies mentioned above, my preliminary results show that TFEB protein is decreased, while senescence is increased in chondrocytes and fibroblasts from OA patients. This is in line with reports of an age-related decline in the process of autophagy promoting OA. Moreover, I found that decreasing TFEB expression by siRNA in OA fibroblasts leads to an increase in senescence-associated markers. Excitingly, re-establishing TFEB expression prevents cartilage degradation in destabilisation of the medial meniscus (DMM) OA mouse model. Taken together, I hypothesise that the age-related decrease of TFEB in joint tissues is a major driver of OA development. To test this, I plan to: (1) Measure TFEB expression and senescence phenotype in OA synovium and cartilage cell subsets. (2) Investigate the impact of TFEB on cellular senescence in chondrocytes and fibroblasts in the joint. (3) Identify novel drug that regulates the expression of TFEB to treat OA. My proposal will (1) expand our understanding of TFEB expression and senescence phenotypes in joint cell types, (2) determine the role of TFEB in driving senescent changes and (3) identify novel agents targeting TFEB to develop effective new therapeutics for osteoarthritis that will improve patients’ quality of life.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Diagnostics of Joints Using Magic Angle Directional Imaging
Funder: Wellcome Trust

Abstract: Conventional MRI cannot accurately diagnose tissues such as ligaments, tendons and cartilage. Patients, who suffer chronic pain and seek cure, often undergo arthroscopy, a form of keyhole surgery, often without much certainty about their value. We have developed an entirely new type of MRI scanner, which enables us to obtain non-invasively detailed new information about microscopic properties, potentially providing new and safe methods for diagnosing disease or injury in joints. This scanner is open and very comfortable for claustrophobic patients. It is also significantly cheaper, very compact and much easier to install than those normally found in hospitals. In this project we will provide the evidence needed to adopt the new methods in practice, by conducting trials, first with healthy volunteers, and then with selected patients already undergoing treatment. This could lead to rapid and accurate MRI imaging as a new standard technique for diagnosing injury or disease of joints.

Lay abstract: Conventional MRI cannot accurately diagnose tissues such as ligaments, tendons and cartilage. Patients, who suffer chronic pain and seek cure, often undergo arthroscopy, a form of keyhole surgery, often without much certainty about their value. We have developed an entirely new type of MRI scanner, which enables us to obtain non-invasively detailed new information about microscopic properties, potentially providing new and safe methods for diagnosing disease or injury in joints. This scanner is open and very comfortable for claustrophobic patients. It is also significantly cheaper, very compact and much easier to install than those normally found in hospitals. In this project we will provide the evidence needed to adopt the new methods in practice, by conducting trials, first with healthy volunteers, and then with selected patients already undergoing treatment. This could lead to rapid and accurate MRI imaging as a new standard technique for diagnosing injury or disease of joints.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: A frog model for muscular ageing: Novel in vitro-virtual reality approaches to study age-related musculoskeletal degeneration
Funder: Wellcome Trust

Abstract: This project will characterise how ageing affects upper body coordination by using novel animal models and technology that our group has developed. Reaching ability degrades with age, increasing the risk of overreach, loss of balance and death. How do age-related changes in muscle properties influence the neuromuscular control of reaching? This question remains unanswered because firstly, physiologists lack tools to measure in vitro muscle behaviour in direct response to whole-limb biomechanics. Secondly, the link between age-related muscular alterations and whole-limb neuromuscular deficit is unclear. Thirdly, the role of the muscular extracellular matrix (ECM) in limb coordination and how it diminishes with fibrosis is unknown. Using our novel bio-mechatronic devices this proposal integrates muscle physiology with state-of-the-art musculoskeletal simulation to characterise how aged muscle influences limb mechanics. Aim 1 develops in vitro-Virtual-Reality allowing isolated muscle tissue to “remote control” a computer-simulated limb. Aim 2 uses in vitro-VR to determine how age-related changes in intrinsic muscle properties impair reaching. Aim 3 probes the complex and sparsely understood interplay between ECM and muscle fibres and determines how it shifts with age-related fibrosis. Outcomes will be disseminated via sharable in vitro-VR hardware/software tools and data to validate improved computational models for musculoskeletal biomechanics.

Lay abstract: I aim to understand how arm coordination degrades with age. Reaching for a glass or piano key is an exquisite orchestration of multiple nerves and muscles; this degrades with age causing overreaching, loss of balance and falling. Although we know that older muscles are stiff, we do not understand how stiffening impacts coordination because experiments are typically done "in a dish". To determine whole-body effects we must close the gap between in-a-dish (in vitro) techniques and in-the-body (in vivo) effects. To do so I will connect in vitro tissue to a computer simulation of the body as if the muscle is immersed in virtual reality. By altering software parameters we will make healthy muscle "feel" stiffer to discover how stiffening impairs coordination. My new approach could be crucial for testing treatments for age and disease-related impairments. Further, it can evaluate and improve accuracy of numerical models towards reducing animal testing.

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