NIHRDataInsights/HRCSData huggingface dataset:
Title: Functional, Subjective and Biomechanical Outcomes Associated with Combined Partial Knee Replacement for Multi-Compartment Arthrosis – An Alternative to Total Knee Replacement?
Funder: Dunhill Medical Trust

Abstract: Arthritis of the knee affects millions of elderly people worldwide. Total Knee Replacement (TKR) is the typical treatment. TKR is major surgery with significant risks, including infection, bleeding, blood clots and death. These risks can be very high in the frail and elderly. Sadly, many patients remain deeply unsatisfied following TKR, either due to ongoing pain; stiffness or because their knee isn’t as good as they'd anticipated. The knee can be divided into three smaller joints: the front, the inside and outside. All can develop arthritis, but rarely are all three parts affected simultaneously. TKR replaced the entire knee, whether these parts are worn or not, potentially removing healthy bone and ligaments. Partial knee replacements or ‘PKRs’ replace only the worn parts. They are much safer and less invasive, with fewer risks and higher levels of function, meaning patients can enjoy more activities after surgery. Patients experience less bleeding, lower risk of infection; heart attacks; strokes and blood clots, all of which can be fatal. Very frail patients are often deemed “unfit” for TKR due to the serious risks involved. However, following cPKR, which is smaller and safer, even the frailest patients regain their independence and are highly satisfied. However, PKRs are generally only used when one of the three parts is worn, so many patients are excluded. If, after surgery, the healthy parts of the knee begin to wear out, a further operation may be necessary, which has limited their popularity. Our senior surgeon has performed 130 procedures where two small PKRs are used in the same knee. However, we are unsure how these ‘combined’ PKRs perform compared to TKR. We hope to investigate this in several ways: Patients will be asked to complete satisfaction questionnaires and walk on a treadmill capable of measuring performance of the knee replacement. In the laboratory, we will study the strength and flexibility of the different types of knee replacement. We’ll organise a course to teach surgeons to perform PKRs. We’ll ask patients which risks of surgery they fear the most – infection, bleeding and death, for example, or the potential need for a second operation later. We’ll calculate the financial costs of each operation to determine which offers better quality of life and value for money for the NHS. With this information, we hope to understand whether small combined procedures can offer elderly patients a safer, superior, treatment for arthritis than TKR.


Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: Colour contrast sensitivity for the detection of pre-symptomatic stage of neovascular age-related macular degeneration
Funder: Dunhill Medical Trust

Abstract: It was established that maintaining sirtuin activity throughout in vitro culture is essential to the success of cell based cartilage repair protocols, but that that SIRT1 spontaneously and rapidly depletes in culture. Therefore our key findings on the optimal biochemical niche for augmenting SIRT1 expression may be implemented by existing clinical techniques such as Autologous Chondrocyte Implantation, to improve clinical outcome. Furthermore, the mechanisms revealed in this research may be built upon as a novel strategy to augment cartilage regeneration and resolve joint inflammation in vivo.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Sunlight exposure and vitamin D status in the UK's ageing population
Funder: Dunhill Medical Trust

Abstract: Sunlight exposure of skin is the major source of vitamin D, which is essential for musculoskeletal health. Skin biosynthesis of vitamin D may be reduced in older people, but we do not know how the physiological vitamin D response to sunlight of UK's growing over 65 year-olds differs from younger adults, or how their behaviour modifies outcomes. In community-dwelling 65-84 year-olds we will perform a randomised controlled intervention to low-dose ultraviolet radiation simulating national recommendations on summer exposure, comparing change in vitamin D status with that of younger adults. We will assess particpants' natural summer-peak and winter-trough vitamin D status, relating to their sun-exposure, the status achieved through the intervention, and to younger groups. Findings will address a significant information gap on biological and behavioural influencers of vitamin D status in over 65 year-olds and provide underpinning evidence for national guidance on sun-exposure and vitamin D, promoting musculoskeletal health in older adults.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MUSCULOSKELETAL
Title: MicroRNAs are key mediators of cartilage destruction in osteoarthritis: in vivo, in vitro and in silico studies
Funder: Dunhill Medical Trust

Abstract: Our hypothesis is that manipulating key microRNAs in cartilage will abrogate cartilage damage in osteoarthritis. Modulating a single miRNA (evidenced by miR-140) can impact upon the disease process in OA but the reality is that a number of miRNAs are dysregulated in disease. Our current work has uncovered key roles for miR-455, miR-29, miR-324 and a miRNA we have discovered in man, miR-3085. This Programme now seeks (i) to validate the functional role of these miRNAs in vivo and in OA models; (ii) to explore the delivery or modulation of these miRNAs in the joint as proof-of-concept therapeutically; (iii) to understand the RNA interactome in chondrocytes and build a predictive mathematical model of miRNA action in cartilage and OA to enable the identification of therapeutic targets and potential biomarkers of disease. We therefore have a clear trajectory from in vitro research, through in vivo, preclinical studies to translation into man.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Does NAD+ precursor supplementation rejuvinate skeletal muscle mitochondrial function and physical capacity in ageing humans?
Funder: Dunhill Medical Trust

Abstract: A defining feature of ageing is loss of muscle mass (‘sarcopenia’) and associated functional weakness (‘dynapenia’). A common characteristic of sarcopenia is lowered mitochondrial content and metabolic function, causing reduced aerobic capacity, increased sensations of effort and impaired lipid oxidation (with resultant glucose intolerance). Exercise training improves mitochondrial and muscle function in ageing populations, however such adaptations remain below that of young counterparts, suggesting alternative approaches are required. Pre-clinical studies show that dietary supplementation with precursors of nicotinamide adenine dinucleotide (NAD+) restore mitochondrial biogenesis and oxidative capacity in ageing rodents. However, whether NAD+ precursors rejuvenate mitochondrial capacity and, ultimately, muscle function in elderly humans is unknown. This pilot project will therefore investigate the efficacy of NAD+ precursor supplementation for increasing muscle performance in normally active elderly people, and for optimising adaptation to chronic aerobic or resistance exercise training, combined with examination of the molecular and metabolic mechanisms regulating physiological responses


Research activity codes: 6.7 PHYSICAL;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Providing a rational basis for the development of an injectable stem cell therapy for the treatment of osteoarthritis in ageing patients
Funder: Dunhill Medical Trust

Abstract: Recent clinical trials have described the injection of mesenchymal stem cells (MSCs) into the joints of ageing osteoarthritis (OA) patients, leading to a reduction in pain but no evidence of MSC engraftment into cartilage. We hypothesise that a) efficacy of MSC therapy can be enhanced by targeting the injected cells into cartilage lesions and b) the success of MSC therapy will depend on careful patient selection. We will use our new technology (Nature Communications 2015, 6:7405. doi: 10.1038/ncomms8405) to coat MSCs with peptides that target them to degrading cartilage. We will seek to optimize patient section by modeling the relationship between cell loss from cartilage in age/disease and biomechanical failure of the tissue. We will seek to determine if biomechanical failure would prevent cartilage repair. Through these studies we will further our understanding of the pathogenesis of OA and accelerate the development of MSCs as an effective therapeutic for OA.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Identifying the causes of age-related tendon injury
Funder: Dunhill Medical Trust

Abstract: Tendons connect muscle to bone, enabling us to move. Tendon injuries (tendinopathies) are extremely painful and highly debilitating, preventing patients completing simple every-day activities. Tendinopathies become increasingly common as we age, and once injured, tendon pain and debilitation frequently last for many months and can recur over even longer time periods. This affects quality-of-life most dramatically in the elderly population, where the lack of mobility can cause secondary complications (obesity, diabetes, cardiovascular disease) and also lead to devastating social isolation. Developing treatments is of the utmost importance, but scientists have been unsuccessful to date, primarily owing to poor understanding of how tendinopathy starts and develops and why it becomes more common as we age. Our research goals are therefore to establish what causes tendinopathy and why it occurs so often in the elderly, paving the way for future studies to develop treatments appropriately targeted to the causes we identify. We have been investigating tendinopathy for the last six years, and have recent, exciting data which leads us to believe that tendon injury occurs because of ageing changes within a specific part of the tendon structure called the interfascicular matrix (IFM). Tendon is like rope, where the IFM connects the rope strands. Our evidence shows that the IFM should be stretchy and lubricated to allow the rope strands to slide around relative to each other, but as we age, the IFM loses these properties. Separately, we have shown that tendon overuse causes damage and inflammation in the IFM. Combining these results, leads us to propose that the changes in the IFM with age cause damage to occur more easily to this region and this leads to tendinopathy. The primary goal of this project is to establish if this is the case, and to define how the age-related changes in tendon accelerate progression to tendinopathy. We will look at the initiation and progression of tendinopathy in a rat Achilles tendon; the most appropriate animal in which to test our hypotheses. We will compare IFM function in young and old rats, to see how ageing changes in the IFM make a tendon less resistant to loading and accelerate the progression of tendinopathy. We will identify the specific IFM changes that drive increased injury risk with ageing. This is exciting as we can then continue, in future studies, to develop treatments specifically aimed at preventing, reversing, or mitigating the effects of these changes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: A novel biomimetic osteochondral medical device to regenerate articular cartilage
Funder: Dunhill Medical Trust

Abstract: Osteoarthritis is the commonest joint disease causing painful stiff joints and loss of joint mobility. Joint pain and loss of mobility can limit daily activities causing a substantial impact on quality of life. Almost half of people over 60 have painful knee osteoarthritis. Current treatments give valuable pain relief and control of symptoms but there is no cure. Replacement of the joint with an artificial one may be necessary to restore joint movement, particularly in the knee and hip. While successful, replacement joints do not have the full range of natural movement and have a limited working life of 15-20 years. Sometimes the prosthetic joint may loosen requiring further corrective surgery. A better approach may be to extend a pain-free working life of the natural joint to delay or remove the necessity for joint replacement surgery. We are developing a novel medical implant designed to stimulate the joint surface cartilage to heal itself. Our implant is designed to attract the body’s own stem cells into the damaged cartilage and then persuade them to develop into cartilage cells that can make new cartilage tissue which will gradually replace the original implant. Our early studies have shown that the healing properties of the prototype implant are exceptional but suffered from mechanical deficiencies and required suturing in place which is technical demanding and time consuming. Therefore, we have now made modifications to the implant that have increased its toughness in laboratory tests and also enable the device to be implanted into the joint in a straightforward manner, potentially arthroscopically. The improved implant is made up of two parts: an upper part which stimulates cartilage healing and a lower part which is made of a material that mimics natural bone to 'anchor' the implant in position. The implant is designed to be surgically placed into a defective area of cartilage with the lower 'anchoring' portion inserted into the underlying bone. The only way to fully confirm that the implant is tough enough to survive in a normal weight-bearing joint and allow stem cells to migrate through the implant to begin cartilage healing is to do a small, essential animal experiment. That is the purpose of this study. This will give us the information needed to take the implant forward into full pre-clinical trials to gain information needed for regulatory approval for clinical trials


Research activity codes: 5.3 MEDICAL DEVICES;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Arthritis Research UK-MRC Centre in Reducing Workplace Disability from Musculoskeletal Disorders
Funder: Medical Research Council

Abstract: We aim to establish a world-leading centre, addressing major research questions to minimise the adverse impacts of musculoskeletal disorders in the workplace, with benefits for patients, workers, employers, and society at large. We propose an integrative, cross-disciplinary centre of excellence, which will: 1. Identify cost-effective ways to minimise the substantial adverse impacts of musculoskeletal disorders in the workplace. 2. Build capacity in employment-related research by training a future generation of researchers. 3. Establish a national resource for advice on musculoskeletal disorders and work, accessible to all stakeholders, and actively promoting best practice. Research will focus on the main musculoskeletal causes of work impairment (non-specific musculoskeletal pain, osteoarthritis and inflammatory arthritis) along with a more generic theme addressing the implications of musculoskeletal disorders for working to older ages. The Centre will be based at University of Southampton, with “spokes” at eight other institutions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Molecular machines - the bacterial cytoskeleton
Funder: Medical Research Council

Abstract: Bacterial cytoskeleton, motor proteins, filamentous proteins, bacterial cell division, plasmid partitioning, bacterial chromosome segregation, actin, tubulin, FtsZ, TubZ, MreB, ParM


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Integrative Skeletal Physiology
Funder: Medical Research Council

Abstract: Blood vessels form an integral part of the skeletal system exhibiting close interactions with different cell types present in the bone marrow microenvironment. Blood vessel growth in bone is coupled to osteogenesis during the development of the skeletal system. Blood vessels also provide different niches for the maintenance and proliferation of hematopoietic stem cells. Skeletal ageing characterised by the defective osteogenesis and haematopoiesis is associated with the changes in the bone marrow vasculature. Molecular mechanisms underlying these age-related changes in the bone vasculature and consequent changes in the BM microenvironment are not known. Recently, we identified a novel blood vessel subtype regulating osteogenesis in bone. It releases angiocrine factors to generate a specific microenvironment for bone forming osteoblasts. We also observed specific localisation of mesenchymal subsets in the stroma. Therefore, with this program, we take a completely novel approach to gain mechanistic insights into the functions of blood vessels on bone morphogenesis to understand age-related changes in the bone microenvironment, using mouse model system. First, we will investigate molecular mechanisms regulating age-related changes in the bone vasculature. We will decipher the molecular mechanisms regulating bone angiogenesis by manipulating genes in endothelial specific manner. Second, we will investigate endothelial factors regulating the status of mesenchymal cells in the bone marrow microenvironment. We are specifically interested in the angiocrine function of blood vessels that regulate age-associated changes in the bone marrow microenvironment. In this program, we will combine a wide variety of novel technologies such as high-resolution 3D imaging, intra-vital imaging and cell-specific inducible mouse genetics in an unprecedented manner to push the limits of our understanding. The study will contribute towards identifying novel therapeutic strategies for age-related bone and blood diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Life course determinants of physical capability and musculoskeletal ageing
Funder: Medical Research Council

Abstract: Maintaining physical capability (the capacity to undertake the physical activities of daily living) and musculoskeletal function for the maximal period of time as we grow older are important aspects of healthy ageing, enabling people to be active and independent for longer. Low levels or accelerated loss of capability or musculoskeletal function pose threats to independence and quality of life, are major causes of frailty, disability and death, and impact greatly on health care spending. The ultimate purpose of this programme is to provide evidence to inform the likely timing, intensity and type of future interventions to promote healthy ageing or delay functional decline. This programme takes a life course approach, investigating biological and social factors from early life that influence later life physical capability and musculoskeletal ageing in population cohorts, in particular in the MRC National Survey of Health and Development (NSHD), a birth cohort study with information on health and life circumstances from 0-65 years. Studies in NSHD and other cohorts have provided evidence that childhood socioeconomic conditions, physical growth and maturation, and motor and cognitive development affect objective measures of midlife capability, such as grip strength, standing balance and chair rise performance, in addition to the cumulative effects of adult health behaviours and socioeconomic conditions. In the next five years, this programme will capture the change in physical capability and progression to disability and frailty during the transition from midlife to old age in NSHD; and will investigate the lifetime factors (from societal to underlying biology) that drive these changes, and their consequences, for everyday life. Of particular interest for improving human health are the factors that promote the maintenance of maximal functioning, or modify the consequences of functional decline for everyday activities and social integration. Using new data recently collected or planned, this programme also aims to understand better how factors across life affect bone, muscle and joints in later life and their clinical correlates, osteoporosis and fracture risk, sarcopenia and osteoarthritis. With specialist collaborators we also aim to elucidate underlying biological mechanisms, capitalising on new genomic, epigenomic and metabolomic data in NSHD. This programme addresses the MRC strategic research priority for 2009-14 to improve the chances of living a long and healthy life by driving forward interdisciplinary research addressing health and wellbeing from childhood to older age.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: MUSCULOSKELETAL
Title: Osteoarthrtis may be treated as an environmental ciliopathy
Funder: Medical Research Council

Abstract: The primary cilium is a microtubule-based structure that functions as a centre for hedgehog, Wnt and mechanotransduction signalling. Increasing evidence suggests that primary cilia and the associated signalling pathways are critical for the health of articular cartilage and that dysregulation is involved in the pathogenesis of osteoarthritis (OA). Recently we have shown that environmental/pathological stimuli regulate primary cilia length and that this modulates cilia function. We therefore hypothesise that pathological alterations in the cartilage microenvironment regulate chondrocyte primary cilia structure leading to fundamental changes in cilia signalling which drive cartilage degradation. Human articular chondrocytes will be subjected to three types of environmental stimuli, namely mechanical trauma, exposure to inflammatory cytokines and exposure to fibroblast growth factor (FGF-2). The first two factors are associated with development of OA, whilst FGF-2 appears to be anti-catabolic and protect against cartilage degradation. Importantly all three have previously been linked to changes in primary cilia length. Cilia will be imaged using confocal/super resolution microscopy and downstream changes in cilia signalling and matrix catabolism investigated using a combination of biochemical assays, molecular biology, imaging and biomechanical evaluation. A parallel set of work packages will identify existing FDA approved small molecules which regulate primary cilia length. We will then use these to determine whether pharmaceutical modulation of primary cilia length reduces catabolic signalling and cartilage degradation in both in vitro and in vivo models. Thus by the end of the project we will have identified the role of environmental regulation of primary cilia length in cartilage degradation and determined the efficacy of a totally novel treatment for OA in the form of small molecule regulation of primary cilia structure-function


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL