NIHRDataInsights/HRCSData huggingface dataset:
Title: Functional Studies of Mutations in Osteoporosis Drug Targets in the Zebrafish
Funder: Wellcome Trust

Abstract: Osteoporosis is a disease which weakens bones, making individuals more prone to fractures even after a minor fall. It is a prevalent disease, affecting around 1 in 3 women and 1 in 5 men which accounts for 28 million people over the age of 50 across Europe. Individuals suffering with osteoporosis put a significant burden on health care services as they can require long term hospitalisation after surgery, as well as social care packages and physiotherapy. Current treatments aim to stop bone degradation, whereas there are few treatments available to re-build bone and thus help prevent further fractures. New bone-building drug targets can be discovered by investigating the genetic changes which cause people to have naturally high bone mass. In my project, I will use human genetic datasets for genetic changes relevant to bone metabolism to select two novel candidate genes. I will use zebrafish as a model, since their rapid life cycle and transparent bodies allow for imaging of fluorescent proteins that help us understand how the candidate genes affect bone homeostasis. Cultured zebrafish scales will be used to screen for compounds targeted to these candidate genes to test their bone-building capacity informing potential novel osteoporosis treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Muscle stem cell function in facioscapulohumeral muscular dystrophy
Funder: Wellcome Trust

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy, and involves progressive muscle weakness and wasting, beginning in muscles of the face, shoulder, upper back and lower legs. FSHD is caused by inappropriate expression of a protein called DUX4 in adult tissue. DUX4 is a transcription factor, meaning that it controls expression of other genes. DUX4 upsets the carefully orchestrated pattern of gene expression that allows muscle to function effectively, causing cells to die. However, exactly how DUX4 expression induces muscle cell death/loss are not well understood.Muscle normally repairs efficiently due to resident stem cells, but loss of muscle in FSHD indicates a compromised repair mechanism. I aim to characterize muscle stem cells in FSHD by examining protein and gene expression in muscle biopsies from FSHD patients. I also aim to explore the dynamics and effects of DUX4 expression on development and function of muscle stem cells, as well as subsequent myofiber formation and regeneration, using induced pluripotent stem cells from FSHD patients and in vivo models. This work will inform whether deficits in muscle stem cell function contribute to the muscle wasting observed in FSHD pathology, and explore potential regenerative therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The role of mononuclear phagocytes in the detection of cartilage damage and the initiation of repair
Funder: Versus Arthritis

Abstract: In the UK, one in three people aged over 45 have sought treatment for osteoarthritis, which costs £5.2 billion per year. Clinical management is currently limited for early-stage disease with few available options. By understanding the cartilage repair process, cell and molecular targets can be identified for use in the development of novel regenerative therapies. Our recent in vivo experiments have demonstrated that microfracture surgery performed in young mice can result in good quality cartilage repair at 8 weeks. Mesenchymal stem and stromal cell populations (MSCs) are key too this repair process, either directly by directly differentiating into chondrocytes to produce cartilage or via their immuno-modulatory actions. MSCs can modulate function of immune populations that are involved in the detection and response to injury. One such population are mononuclear phagocytes (MNPs) that include dendritic cells, macrophages and monocytes which are increasingly being viewed as cells that are essential for tissue repair. Despite this understanding, there are limited data that directly address the role of MNPs in the setting of cartilage repair. Our preliminary data has demonstrated that MNPs are recruited to and activated in the synovium of the microfracture directly following the microfracture surgery. Furthermore, CD11c+MNPs have been shown to be present within the microfracture site at 7 days following the surgery. This research will build on these novel observations investigating how MNPs can contribute to the detection of cartilage damage and their role in the repair process. The overall goal of this research is to characterise the different immune populations present during the repair process and understand their significance during the formation of cartilage repair tissue. This will be applied to human tissue to establish cellular and molecular targets that can be used for novel regenerative therapeutic treatment options in early-stage osteoarthritis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Nurse and Allied Health Professional internship programme
Funder: Versus Arthritis

Abstract: The focus of this grant application is about continuing to develop a national network of healthcare professional internships in rheumatology. The assembled group of applicants have an excellent track record of managing rheumatology Nurse and Allied Health Profession (AHP) internships. The proposed internship programme will select nurses and AHPs following graduation/registration (within five years). Interns will be supported by leading healthcare professionals based in universities that have successful clinical rheumatology research teams. Interns will complete an eight-week placement, followed by a two year off site mentorship. During their placement, interns will be allocated projects that are based upon patient need, patient benefit, the promotion of patient self-management, and supporting patients to improve their lifelong musculoskeletal health. The proposed scheme will demonstrate transition from previous experiences towards a patient-centred multi-professional clinical academic model, with a clearly defined overall strategic aim of improving the quality of life of people living with arthritis.


Research activity codes: 5.7 PHYSICAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL
Title: Mapping and targeting inflammatory and fibrotic changes in human osteoarthritis synovium
Funder: Versus Arthritis

Abstract: Osteoarthritis causes progressively painful and stiff joints in over 8.75 million people in the UK. OA is typically attributed to mechanical stress-driven joint damage. This includes the loss of articular cartilage as well as the involvement of other joint tissues, such as synovium. Low-grade chronic synovial inflammation (synovitis) is consistently seen in osteoarthritis, alongside synovial fibrosis. Interestingly, these changes might precede cartilage damage. Our pilot data (Mimpen et al., in preparation) and recent studies have shown that there is an expansion of pathogenic cartilage-destructive fibroblasts and tissue-resident macrophages in the osteoarthritis synovial lining layer. I hypothesize that the expansion of these two cell subsets in synovium underpins the synovitis and synovial fibrosis often observed in osteoarthritis. No effective way of inhibiting or slowing osteoarthritis-related joint damage by targeting cartilage directly has been approved for use so far. Due to limited accessibility of joint tissues outside of surgery, most research is done on end-stage osteoarthritis tissue from joint replacements, which gives limited insight into the disease development/progression. Therefore, deeper phenotyping and cellular interrogation across different stages of osteoarthritis progression is now imperative. The aim of this fellowship is to define the cellular signatures of synovium in health, after ACL/meniscal injury (at high risk developing OA), and at two different stages of osteoarthritis progression using single-cell RNA sequencing and multimodal imaging. I aim to use these signatures to identify new pharmacological targets based on bioinformatic cell-cell interaction interrogation and to test these targets in an optimised and validated synovial organoid model that accurately reflects human osteoarthritis synovium. This combinatorial approach will ensure that reference datasets of synovium throughout disease are available, and that representative in vitro model can be used to test therapeutic strategies identified in this fellowship and in the future, accelerating the translation of these much-needed treatments into the clinic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Tailored Exercise Management for People aged 80 years or older with hip/knee Osteoarthritis: programme development and testing (TEMPO).
Funder: Versus Arthritis

Abstract: Introduction: Hip and knee osteoarthritis (OA) are disabling conditions that are increasingly common with advancing age. Evidence-based guidelines recommend strength and/or aerobic exercise for all people with hip/knee OA. However, these recommendations are based on clinical trials among patients with an average age between 60 and 70 years, and these findings cannot reliably be generalised to people aged 80 or older. Tailoring exercise for this population is important as people have a broad range of capabilities at this age. Rapid loss of muscle occurs beyond 70 years of age, and older people are more likely to have other health conditions such as cardiovascular disease and diabetes contributing to mobility and functional difficulties. To optimise health outcomes, it is hypothesised that exercise should be tailored to target both hip/knee OA and comorbidities. Key goal: To develop and test the feasibility and acceptability of a tailored functional exercise programme targeting both hip/knee OA and specific comorbidities for people aged 80 or older. Methods: The tailored exercise programme will be developed using a participatory approach over four work packages including: (1) a systematic review of evidence for exercise interventions in people aged 80 or older; (2) analysis of a cohort dataset to identify common mobility/functional deficits and comorbidities among people aged 80 or older with hip/knee OA; (3) conjoint analysis methodology and a consensus group meeting to evaluate patient and clinician preferences for programme components; and (4) a randomised feasibility study with embedded qualitative evaluation to test intervention feasibility and acceptability. Outcome: This research will produce a tailored exercise programme for people aged 80 or older with hip/knee OA, developed with meaningful patient involvement. The feasibility study will inform decision-making about proceeding to a definitive randomised controlled trial to determine if the programme is clinically and cost-effective compared to best-practice usual care.


Research activity codes: 5.7 PHYSICAL
Health categories: MUSCULOSKELETAL
Title: Can novel bioceramics provide an effective bone forming scaffold and lead to bone regeneration in Charcot osteoarthropathy?
Funder: Diabetes UK

Abstract: Charcot osteoarthropathy is a devastating complication of diabetes characterised by excessive osteoclastic activity and reduced osteoblastic function and this leads to non-healing fractures and fragmentation of bone. The only treatment is prolonged immobilisation of the foot in a plaster cast, but despite this, many fractures fail to heal with subsequent joint destruction and foot deformity, resulting in ulceration, infection and amputation. A new therapeutic approach is needed as highlighted in recent NICE guidelines. We hypothesise that targeted therapy with bioceramics could provide an effective bone forming scaffold, promote bone regeneration and fracture healing. The aim of this study is to identify a suitable bioceramic material which can promote osteoblast formation and function and resist the aggressive osteoclastic activity of Charcot osteoarthropathy. We plan to culture osteoblasts and osteoclasts from patients with Charcot osteoarthropathy, and assess osteoblast formation on various bioceramics discs (dense and micro-porous hydroxyapatites, tri-calcium phosphates and biphasic calcium phosphates). We will also assess the ability of these biomaterials to resist the increased osteoclastic resorption of Charcot osteoarthropathy. A suitable material that can increase osteoblastic function and withstand osteoclastic activity could be directly administered to affected Charcot bones to act as scaffolds for the treatment of fractures.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Determining new osteo-anabolic targets using zebrafish models of human genomic study discoveries.
Funder: Versus Arthritis

Abstract: Over 3-million people in the UK have osteoporosis and suffer bone fragility due to an altered balance of bone-building osteoblast and bone-resorbing osteoclast activity. Most available therapies are anti-resorptive, targeting osteoclasts which halt bone loss, rather than building new bone. Osteo-anabolic treatments are few; new compounds are needed as our population ages and fracture numbers rise. I will exploit the rich genetic learning from two unique studies to identify novel bone regulatory pathways, amenable to therapeutic manipulation for treating osteoporosis. The evolutionarily conserved zebrafish model allows quick screening of osteo-anabolic target genes by combining efficient CRISPR-Cas9 genome-engineering, rapid skeletal development and translucency; enabling skeletal imaging with fluorescent transgenic lines. I will use the latest data from (1) UK-Biobank genome wide association study of bone mineral density (BMD) and (2) whole-exome sequencing analysis of 22 pedigrees with unexplained monogenic high bone-mass (HBM), two unique datasets which together have identified hundreds of potential novel osteo-anabolic genes. I will deploy my newly developed in-silico prioritisation pipeline to objectively select genes for functional investigation in zebrafish. Preliminary in-silico prioritisation identified DOT1L histone-H3 methyltransferase as a novel BMD factor and proof-of-concept data demonstrated a HBM phenotype in dot1l mutant zebrafish. The efficient CRISPR-Cas9 gene editing protocol will in addition generate loss-of-function mutants of several prioritised genes. These mutants will be imaged for osteoblast number, skeletal development and morphology. I will learn and deploy state-of-the-art methods to ex-vivo culture of adult zebrafish scales, containing dermal bone decorated with osteoblasts and osteoclasts. This new approach will allow investigation of responses to compounds hypothesised to affect prioritised osteo-anabolic targets and enable compound screening in a gene-specific setting. This exciting high-impact collaborative research will launch my independent scientific career, focussing on osteoblast biology in-vivo, compounds for osteo-anabolic pharmacotherapies, aiming to generate cutting-edge pre-clinical data to inform future drug trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Arthrogenic muscle inhibition and impaired function in knee osteoarthritis
Funder: Versus Arthritis

Abstract: A hallmark of knee osteoarthritis (KOA) is arthrogenic muscle inhibition (AMI) of the quadriceps, which predicts muscle function, prevents effective muscle strengthening, and occurs due to the inability of the nervous system to recruit motor units (MUs) and discharge them at a sufficient rate. The downregulation of MU activity accompanying AMI has been hypothesised to occur through spinal reflex inhibition caused by four possible mediators; pain, swelling, inflammation and joint damage (‘phenotypic markers’) that alter joint receptor discharge, but the relative contribution of each is unknown. The proposed research aims to discern the aetiology of AMI by examining the underlying MU behaviour in relation to these phenotypic markers in KOA patients. Study A will characterise AMI and MU behaviour in different KOA phenotypes with distinct levels of pain, swelling, inflammation and joint damage. It is hypothesised that AMI will vary with different KOA phenotypes, and these will be associated with specific MU phenotypes. Study B will assess AMI and the underlying MU activity before and after modulating the four hypothesised mediators of AMI through joint injections; lidocaine (minimise pain), joint aspiration (to remove swelling), and joint aspiration combined with lidocaine and corticosteroid injection (to maintain only joint damage) will be performed in KOA patients, and pain will be experimentally induced (saline injections) in healthy individuals (to isolate pain). Study C will assess the changes in AMI and underlying MU behaviour before and at 1, 2 and 6 months after partial knee joint arthroplasty. It is hypothesised that changes in AMI following the surgical intervention will parallel changes in the factors causing altered MU activity. This research will inform rehabilitation strategies that can be designed according to either specific KOA phenotypes, associated MU phenotypes, specific mechanisms, or combinations of these, and used to prevent or slow down the development of AMI.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Understanding and addressing the osteoporosis treatment gap in United Kingdom primary care: a mixed methods study.
Funder: Versus Arthritis

Abstract: Background Osteoporosis is a condition of skeletal fragility which results in propensity to fracture. Fractures may cause pain, disability, reduced quality of life and cost the NHS £4.7 billion annually. Evidence-based treatments to reduce fracture risk are recommended by national guidance, cost- and clinically-effective. However, only a third of eligible people receive osteoporosis drug treatments. The identification and management of osteoporosis is mainly enacted in primary care. Therefore, this study will examine current practice in the identification, investigation and management of osteoporosis in primary care, and the barriers to and facilitators of, implementation of evidence-based practice (EBP). Methods Using i-Parihs as an underpinning framework, three phases address three matched objectives: Phase one: To identify practice in the identification of patients with or at risk of osteoporosis and management in primary care, including care pathways and an understanding of the professional roles and processes involved. Methods: national e-survey of Primary Care Practitioners (PCPs) and a process mapping exercise with stakeholders. Phase two: To explore PCPs attitudes to osteoporosis, perceptions of their role, perceived knowledge, clinical decision making needs and barriers and facilitators to EBP. Method: semi-structured interviews with PCPs, informed by Theoretical Domains Framework. Phase three: To co-design a strategy and associated resources for knowledge mobilisation (KMb) to address the osteoporosis care gap. Method: Community of Practice, bringing together experts (including patients). Impact and dissemination The study will produce recommendations for KMb and inform development of resources which have the potential to benefit patients, PCPs and the NHS by: • Improving PCP knowledge and confidence in identifying and managing osteoporosis • Improving the ongoing care of people with osteoporosis • Increasing the number of people recommended, starting and continuing fracture prevention medication Impact and dissemination will be enhanced through collaboration with the Royal Osteoporosis Society and the National Osteoporosis Guideline Group.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: MUSCULOSKELETAL
Title: Establishing a human cartilage-synovium organ-on-a-chip: A new tool for the study of osteoarthritis pathobiology and the development of personalised orthopaedic surgeries.
Funder: Versus Arthritis

Abstract: Osteoarthritis (OA) is the most common joint disease in the world, affecting approximately 1 in 5 adults over the age of 45. There are a number of surgical treatment options for early OA, that seek to restore function, reduce symptoms and delay the need for a joint replacement, but each has an associated failure rate. Our research group has previously reported a profile of biomarkers that can identify patients that don’t respond well to surgery (non-responders). The identity of these biomarkers suggests that the articular cartilage and synovium are involved in the joint’s reaction to injury and to treatment. The purpose of the study is to increase our understanding of the interaction between the articular cartilage and synovium in the human knee at different stages of disease and how this leads to a poor response to surgeries. In the proposed basic laboratory research study, we will use ‘Organ-on-a-chip’ technology to develop a human synovium and cartilage ‘chips’ reflective of healthy, early and late OA and of individual patients at the time of surgery. These chips will be used to determine how tissues respond to simulated injury and disease and how they interact with each other helping elucidate mechanisms of OA progression, the cellular source of non-responder biomarkers and identify novel therapeutic targets. We may then be able to use these chips for the personalised screening of individual patients prior to treatment and identify combinatorial interventions (drugs with surgery) to modify and improve ‘non-responder’ profiles and outcomes. The results from this study have the potential to increase our understanding of the role played by cartilage and synovium in the knee joint’s response to AC repair surgeries and OA progression. Additionally, there is scope for direct clinical impact through the development of personalised, pre-operative screening tools and as a drug discovery platform.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL