NIHRDataInsights/HRCSData huggingface dataset:
Title: Improving the quality of life of people with joint pain by targeting the stress regulator FKBP51
Funder: Versus Arthritis

Abstract: Chronic pain is a hallmark of joint diseases and a significant number of people with arthritis experience severe persistent pain that is not adequately managed with current treatments. Importantly, patients with joint pain often experience symptoms such as low mood, anxiety, chronic and overwhelming tiredness and lack of energy (also called fatigue) and memory dysfunction, conditions that altogether significantly impact patients’ well-being. While the sensory aspects of joint diseases have been extensively studied in animal models, associated mood-related disorders are rarely assessed in basic research. The efficacy of pain relieving therapies in improving mood-disorders is also seldom investigated. In this proposal, we will use a battery of behavioural tests to assess, in mice with joint pain, affective- and sleep-related disorders that often affect people with arthritis and to investigate the efficacy of a novel treatment designed not only to reduce persistent pain but also to directly improve mood- and sleep-related disorders.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Developing improved mathematical tools to map the etiology of joint disease using large complex datasets
Funder: Versus Arthritis

Abstract: Omics technologies are generating large and complex datasets that require special analysis in order to mine the information buried within. Current methods for the analysis of these datasets have had some success in highlighting the most relevant pathogenic features in human joint disease, but it is recognised that improved mathematical approaches to understand these data are needed. This proposal will develop new approaches to enable more structured analysis from single datasets, develop better ways of integrating datasets from multiple omics techniques with genetic assocations and analyse temporal datasets to understand dynamic responses.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: MUSCULOSKELETAL
Title: Identifying a new treatment paradigm for osteoarthritis: targeting the ubiquitination machinery regulating inflammatory responses to injury.
Funder: Versus Arthritis

Abstract: Osteoarthritis is a disease where joint destruction arises from maladaptive responses to repetitive tissue injury. Mechanical injury to articular cartilage results in chronic inflammation, pain and predisposes to tissue damage and loss of function. There is a pressing need for disease-modifying therapies for osteoarthritis. Identifying the cellular mechanisms regulating cellular responses to injury is crucial for understanding osteoarthritis and for designing specifically-tailored therapeutic regimens. Recently, I have discovered that injury to connective tissues including articular cartilage rapidly activates the formation of Lysine 63-polyubiquitin chains that induce downstream inflammatory cascades, highlighting the critical role of ubiquitination in regulating this mechanism. Ubiquitination is a multistep reaction to add ubiquitin linkages to a protein substrate. Eukaryotic cells contain a large number of ubiquitin enzymes and the key regulators driving injury responses are currently unknown.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Bioactive Nanofibrous Sutures To Enhance Endogenous Repair Of Rotator Cuff Tears
Funder: Wellcome Trust

Abstract: Rotator cuff tendon tears are very common and are found in around 15% of 60 year olds, 25% of 70 year olds and 30% of 80 year olds. Tendon tears often cause significant pain and loss of function and present a substantial and growing social and economic burden. Many patients are unable to work effectively due to their symptoms and pain which significantly disrupts their sleep is common. Unrepaired tears grow in size and very large tears are associated with joint failure and the development of secondary osteoarthritis. In patients with persistent symptoms surgical repair is commonly performed. Professor Andrew Carr at the University of Oxford is developing is a novel suture material (Bioyarn) that is designed to stimulate repair when in contact with the torn and damaged tissue. Bioyarn is constructed of biodegradable electrospun polymeric nanofibres and is designed and manufactured to mimic the architecture of normal tendons. Studies have demonstrated that the new material stimulates cell growth and new tissue formation, and has a good safety profile. The aim is to further evaluate the technology and undertake a clinical study in humans to examine how effective the Bioyarn technology is at increasing the success of rotator cuff tendon repairs


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Engineering the new generation of biomimetic artificial muscles
Funder: Welsh Government Office for Science

Abstract: The aim of this Fellowship is the development of a physically motivated computational tool in order to assess the industrial potential of the new generation of Electro Active Polymers and Magneto Rheological Elastomers, referred to as artificial muscles, in a series of realistic applications extracted from the fields of prosthetics, soft robotics and Micro Electro Mechanical Systems. Throughout this Fellowship, a series of advancements and novelties in the fields of Physics, Computational Mechanics and Prosthetics will be crystallised: (1) the definition and benchmark of physically compliant constitutive models for these materials; (2) the development of state-of-the-art numerical techniques tailor-made for the large scale simulation of these materials; (3) the computational performance assessment of these materials in the field of prosthetics. Crucially, the nature of the investigations developed as part of this Fellowship fits the strategic priorities of the Welsh Government, Swansea University and its College of Engineering, namely Life Sciences and Health and Advanced Engineering and Materials.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: MRC Lifecourse Epidemiology Centre - Core Support
Funder: Medical Research Council

Abstract: MRC Lifecourse Epidemiology Centre: Technical Summary Overview The MRC will use lifecourse epidemiological methods to reduce the population burden of chronic musculoskeletal disease and disability. These approaches will optimize musculoskeletal health (bone, muscle and joint) through the development and testing of lifestyle, behavioural and pharmacological interventions informed by a series of observational studies; and by using these findings to influence health policy. The specific aims of the MRC Lifecourse Epidemiology Centre will be to: • Delineate the environmental influences, throughout the lifecourse, of age-related musculoskeletal diseases (osteoporosis, osteoarthritis and sarcopenia). • Use findings to develop and test population based and targeted interventions to improve musculoskeletal health throughout the lifecourse. • Maintain and develop the long-term cohorts/trials assembled in Southampton as national and international resources to explore the mechanisms underlying the developmental origins and later causes of musculoskeletal and metabolic health and disease. • Minimise the adverse impact of musculoskeletal disorders on ability to work, by undertaking a programme running alongside the Versus Arthritis-MRC Centre for Musculoskeletal Health and Work. • Provide data management and statistical support for a series of preconceptual and pregnancy-based cardiometabolic intervention studies maintained at the fore-running MRC Lifecourse Epidemiology Unit (HeLTI, TALENT, NiPPeR, EACH-B and WRAPPED). • Inform health policy and promote training, research capacity development, knowledge transfer and public engagement in lifecourse epidemiology. The aims of the MRC Lifecourse Epidemiology Centre will be delivered through three linked scientific programmes: 1. Musculoskeletal health in later life (PI: Professor Cyrus Cooper) 2. Determinants of musculoskeletal health in the mid-lifecourse (PI: Professor Karen Walker-Bone) 3. Early development and risk of adult musculoskeletal disease (PI: Professor Nicholas Harvey)


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: MUSCULOSKELETAL
Title: Programme 1: Musculoskeletal health in later life
Funder: Medical Research Council

Abstract: Summary: This programme integrates observational epidemiology and mechanistic understanding to develop novel interventions in later life aimed at optimising musculoskeletal health, in order to reduce the burden of chronic non-communicable musculoskeletal disorders, principally osteoporosis, osteoarthritis and sarcopenia. Objectives: To (a) understand better the risk factors for, and mechanisms which underlie the development of osteoporosis, sarcopenia and osteoarthritis; and (b) develop intervention studies aimed at modifying later disease risk. Research plan: Our future work will therefore focus on four key areas: (a) The Hertfordshire Cohort Study (HCS) and a novel musculoskeletal ageing cohort in Southampton, will form the basis for investigations across the lifecourse (complementing work in the Southampton Women’s Survey [SWS] with Programme 3). These will include novel intergenerational analyses as well as behaviour-focused diet and activity interventions to reduce falls and fracture risk; trajectories of musculoskeletal health in the oldest old will be characterized, with linkage to incident events via NHS Digital; (b) We will elucidate the environmental and genetic risk factors for musculoskeletal disorders such as osteoporosis, osteoarthritis and sarcopenia, accounting for multimorbidity, in cohorts including MrOS, WHI, Health ABC and UK Biobank. These findings will inform the development of the next version of the FRAX fracture risk assessment tool, as well as optimisation of primary and secondary risk assessment strategies (SCOOP and CTF); (c) We will use similar approaches to characterise the most effective integration of muscle mass, strength and physical performance, to predict falls, fractures, hospitalisation and death, in a new harmonised cohort collection (collaborator: MRC Versus Arthritis CIMA, Sheffield), in order to derive a novel outcome-based consensus definition of sarcopenia, and related risk assessment tool; and (d) We will carry out epidemiological studies to identify individuals at highest risk of requiring joint arthroplasty for osteoarthritis, and characterise outcomes of these surgeries. Impact: We will continue to link closely with Programmes 2 and 3 in the MRC LEC, to characterise relevant aetiologic factors across the lifecourse from development, through working life, into senescence. We will thereby identify novel public health approaches and evidence-based integrated care pathways, to optimise musculoskeletal health and ameliorate the burden imposed by osteoporosis, osteoarthritis and sarcopenia in late adulthood.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MUSCULOSKELETAL
Title: Programme 2: Determinants of musculoskeletal health in the mid-lifecourse
Funder: Medical Research Council

Abstract: Scientific abstract (around 400 words – max. 3,500 characters including spaces) Summary: This programme will determine how mechanical and non-mechanical environments contribute to musculoskeletal health during midlife and, in turn, determine capacity to maintain working life and to achieve healthy ageing. Objectives: To (a) reduce the disability for work caused by musculoskeletal disorders; (b) further explore the impacts of working to older ages on health and future healthy retirement; (c) prevent musculoskeletal disorders caused by work and: (d) undertake intervention studies to maximise work participation amongst people with MSDs. Research plan: Occupational aspects of the programme are complemented by the externally-funded MRC Versus Arthritis Centre of Excellence for Musculoskeletal Health and Work, which is directed by Professor Karen Walker-Bone. The programme has already contributed to policy, informing evidence presented to the Work and Pensions Select Committee about the disability employment gap, and the Green Paper “Work, health and disability: Improving Lives” (Nov 2017). Moreover, the Joint Health and Work Unit (DHSC and DWP) is taking an active interest in the Health and Employment after Fifty (HEAF) study from the policy perspective. In the last quinquennium, we have demonstrated the psychosocial determinants of work and musculoskeletal health, through investigations using the HEAF study, UK Biobank, and the HCS cohorts. A key finding from HEAF was the 30-fold increased risk of being out of employment for health reasons amongst those who fulfilled the Fried criteria for frailty between the ages of 50 and 64 years. We will assess the value of physiological measures of bone strength, muscle strength, mass and function and degenerative joint disease as predictors of impaired intrinsic capacity in order to understand which component(s) of musculoskeletal reserve are adversely impacted. Occupation constitutes one important aspect of midlife, and our work-related analyses will be undertaken alongside investigations of the role of environmental, nutritional and physical activity exposures as determinants of physical capability, body composition and musculoskeletal health in these cohorts and links with Programmes 1 and 3 through the Hertfordshire Intergenerational Study and Southampton Women’s Survey. We will investigate factors influencing successful return to work after elective surgery for osteoarthritis, and the impact of osteoarthritis in people of working age, both on their work and their wider life. Impact: Increased understanding of relationships between environmental influences (including those related to occupation) and adverse musculoskeletal outcomes will enable us to develop novel strategies, involving individuals and employers, to improve musculoskeletal health in midlife, maximise work participation and achieve optimally healthy ageing.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: MUSCULOSKELETAL
Title: Programme 3: Early development and risk of adult musculoskeletal disease
Funder: Medical Research Council

Abstract: Scientific abstract (around 400 words – max. 3,500 characters including spaces) Summary: This programme integrates observational epidemiology and mechanistic understanding to inform novel interventions in early life and thereby to reduce the risk of later diseases such as osteoporosis and sarcopenia. Objectives: To (a) elucidate risk factors for reduced bone and muscle accrual during growth and development; (b) thus identify potential early interventions aimed at optimizing musculoskeletal development, so maximising peak bone and muscle mass, and; (c) test these interventions, identifying mechanisms underlying, and markers of, factors which modify efficacy. Research plan: Our future work will therefore focus on three key areas. First, study of Southampton Women’s Survey (SWS) children in late childhood/adolescence will enable us to characterise patterns of early nutrition and growth in relation to bone mass and body composition, and specifically the potential modifying effect on the pubertal transition of the earlier growth trajectory. Where potential interventions are identified and instruments are available, studies of causal inference may be undertaken using the UK Biobank cohort to inform new randomised controlled trials. We will use novel DXA image-derived phenotypes as part of our Wellcome Trust AUGMENT Award to investigate early life influences on novel indices of adult bone health in UK Biobank. With Programmes 1 and 2, this work will be complemented by novel intergenerational studies in the Hertfordshire Cohort and SWS, assessing phenotype and health across generations. Secondly, we will investigate the replication and persistence of the finding that maternal gestational vitamin D supplementation leads to improved offspring neonatal bone mass amongst winter births, using the SPRING trial (replication) and later childhood follow-up in MAVIDOS (persistence), together with adjunctive analyses in other populations, for example in novel trials such as NiPPeR and HeLTI trials in South Africa, India and China. Lastly, using experimental medicine approaches nested within our larger intervention studies, we will delineate mechanisms by which the impact of our interventions might be maximised, in a precision medicine approach, for example elucidating the influence of genetic polymorphisms on response to vitamin D supplementation and associated bone turnover, and markers of response using epigenetic profiles. Impact: This programme will enable us to identify new public health approaches to optimise musculoskeletal development into adulthood, and characterise mechanisms underlying/modifying these early developmental influences, to ultimately reduce the burden of musculoskeletal diseases such as osteoporosis and sarcopenia in older age.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MUSCULOSKELETAL
Title: Establishment of a National Network on Musculoskeletal Ageing
Funder: Medical Research Council

Abstract: Our overall aim is to establish a new national network which will underpin a step change in musculoskeletal ageing research capacity and strategy, by identifying: key tractable research priorities; developing an integrated multi-disciplinary grouping to address the identified research gaps; providing a platform to disseminate best practice; supporting Early Career Researchers (ECRs) to build research capacity and ensure longevity to current UKRI investments; and coordinating an ongoing programme of innovative studies to identify, develop and translate findings from our discovery science to clinical impact. Crucially the network will contribute to delivering the government “Grand Challenge” target of 5 more years of independent living by 2035, by identifying approaches to maintain mobility in old age. The network will bring together the scientific excellence of the three principal applicants. Focusing on the leading chronic non-communicable disorders of bone, muscle and joint (osteoporosis, sarcopenia, rheumatoid arthritis and osteoarthritis), the integration of these groups will galvanize a truly bench to bedside approach to provide a strong evidence base for health policy, underpinning a step change in UK musculoskeletal ageing research capability/capacity, and promoting increased healthspan.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: MUSCULOSKELETAL
Title: Regulation of Contraction by the thick filaments in skeletal muscle
Funder: Medical Research Council

Abstract: Contraction of skeletal muscle is usually considered to be regulated by the intracellular calcium concentration, mediated by structural changes in the actin-containing thin filaments. However it is becoming increasingly clear that the strength, speed and metabolic cost of contraction, and the speed and timing of relaxation, are largely controlled by a separate set of regulatory mechanisms involving the myosin-containing thick filaments. Those mechanisms are poorly understood at present, although they offer a powerful new approach to the design of molecular therapies for muscle disease and weakness. The project will apply state-of-the-art time-resolved synchrotron X-ray and polarized fluorescence techniques to elucidate those mechanisms at the molecular level in the intact filament lattice of intact and demembranated cells from mammalian skeletal muscle. A key aim is to determine how thick filaments are activated following the intracellular calcium transient. Two mechanisms seem most likely: direct mechanical activation of thick filaments and inter-filament signalling by myosin binding protein-C (MyBP-C). We will determine the roles of those two mechanisms in thick filament activation, and clarify the wider role of MyBP-C in modulating muscle performance. In an analogous approach we will determine the roles of load, filament sliding and inter-filament signaling on the kinetics of muscle relaxation, and elucidate the underlying molecular mechanisms in the thick and thin filaments. Finally we will determine the structural basis of the enhancement of muscle performance following recent activity and the role of phosphorylation of the myosin regulatory light chain in that process. The results of these studies will facilitate the development of molecular targets and assays for potential therapeutic modulation of contraction in diseases of both skeletal and heart muscle.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Understanding the activities of connective tissue fibroblasts during muscle formation towards understanding disease and engineering muscle tissue
Funder: Medical Research Council

Abstract: My core objectives are to understand how tissues are constructed and how formation and maintenance of tissue integrity can go wrong in disease. Our focus is muscle tissue and specifically the action of a poorly understood population of cells called irregular connective tissue (ICT) fibroblasts. These ICT fibroblasts surround and are embedded within forming and mature muscles and have been implicated in muscle formation, repair and disease. While there is good evidence that ICT fibroblast are critical for muscle formation and disease, we do not understand how they are normally acting to control muscle formation and as a consequence, we do not know what process have been disrupted in diseases caused by malfunctioning ICT fibroblasts. We are exploiting genetic tools in the mouse to carry out screens to identify the factors produced by ICT fibroblasts that orchestrate the formation of functional muscle bundles from a cohort of nascent muscle fibres. One approach we are taking is to examine the 'scaffolding' that surrounds all cells of the body, called the extracellular matrix (ECM). This 'scaffolding' can physically support and guide cells during tissue formation and influence the way cells respond to secreted signalling molecules. We have evidence that suggests that ICT fibroblasts control the behaviours of forming muscle fibres though their action on the ECM. We will carry out studies to test this hypothesis. In parallel, using the knowledge we obtain from study of ICT fibroblasts, we will initiate efforts to engineer muscle tissue using co-culture of muscle cell and ICT precursors and study the abilities of artificial matrices to support tissue formation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL