NIHRDataInsights/HRCSData huggingface dataset:
Title: Role of the inter-fascicular matrix in age related deterioration of tendon mechanical function
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We have preliminary evidence that the interfascicular matrix (IFM) is a key determinant of tendon failure properties and fatigue resistance. We hypothesise that injury prone energy storing tendons have an extensible IFM with minimal hysteresis, leading to a structure with improved fatigue resistance. Poor optimisation of the IFM or structural changes with age may predispose individuals to tendinopathy. This project aims to investigate the role of the IFM in modulating fatigue resistance. Using an equine model, we will compare IFM composition and mechanics between a high strain energy storing and a low strain positional tendon, correlating these data with the mechanical characteristics of the tendons. Looking specifically at the energy storing tendon, we will then establish how the IFM changes with ageing and how this influences fatigue resistance. Finally, we will use knockout models and enzymatic techniques to manipulate IFM composition, and establish how this influences our findings. The equine model proves an ideal energy storing tendon, with similar properties to the human Achilles. It is also large enough to be used for a series of experiments, enabling paired statistical analyses of the influence of IFM organisation and age on tendon function. IFM composition will be assessed using histology, immunohistochemistry, mass spectroscopy and qPCR. IFM, fascicle and tendon mechanical properties will be determined using quasi-static and cyclic fatigue tests to failure. Data will provide greater understanding of how injury and ageing influence tendon mechanics via the IFM and may provide insights into methods of limiting injury risk. This will inform treatment practices, and facilitate the design of targeted drugs or treatments for the IFM. It may also be possible to develop training protocols to encourage appropriate IFM development, with the long term goals of decreasing the incidence of tendon injury and improving recovery rate post-injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Integrating modelling and experimental approaches to investigate adventitious age-related collagen crosslinking in skeletal tissues
Funder: Biotechnology and Biological Sciences Research Council

Abstract: This multi-disciplinary project brings together expertise in molecular simulation studies, extracellular matrix biochemistry and nano-scale mechanics to address the high burden of musculoskeletal disease in the ageing population. Our main focus is on the soft connective tissues of the skeleton, specifically tendons. Our study is designed to test the hypothesis that ageing results in advanced glycation end-product (AGE) cross-link formation; specifically glucosepane, within the tendon collagenous matrix, rendering it more resistant to proteolytic degradation and thereby allowing matrix damage to accumulate and mechanical properties to deteriorate. This hypothesis is based on our recent work, which has shown that the collagenous framework in an energy storing tendon is renewed less frequently and accumulates partially cleaved collagen with advancing age, whereas tendon cell activity does not decline. It is well known that irreversible modifications of long-lived proteins accumulate during ageing and that there is an association between AGE formation and changes in properties, although little is known about the mechanisms We will investigate energy storing and positional human and equine tendons from donors with a wide age range. We will quantify and locate glucosepane cross-links using tandem mass spectrometry and molecular modelling. Levels will be correlated with susceptibility to proteolytic degradation, thermal stability using differential scanning calorimetry and nano-scale mechanics using atomic force microscopy. We will use a range of complementary computational techniques to provide atomic-level information on structure and strength of glucosepane cross-links, preferential location in potential 'hotspots' and their effect on mechanical properties of collagen. Understanding adventitious age-related modifications to proteins holds considerable scope for translation into better healthcare as levels may be modified by diet, exercise and pharmacological agents.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Structural and metabolic determinants of sarcopenia and efficacy of concentric vs. eccentric exercise training: a novel temporospatial approach
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We propose to take a human systems physiology approach that couples whole body functional, whole tissue anatomic, and sub-cellular molecular and metabolic measures to address the molecular basis of sarcopenia, the molecular basis of exercise induced muscle growth, and optimal strategies with which to use exercise to counteract sarcopenia. We have shown that sarcopenia (viewed by DXA/ MRI) is due to specific architectural changes on an individual muscle level, viz: loss of sarcomeres in series and sarcomeres in parallel (by ultrasound). To determine the basis of these changes, we will sample tissue at the muscle mid-belly (loss of sarcomeres in parallel) and close to the distal aponeurosis (loss of sarcomeres in series). Using a new tracer (D2O) approach we will measuring turnover of muscle sub-fractions (e.g. myofibrils, myoplasm, mitochondria, nuclei [satellite cells]) and correlate these with standard measures of anabolic signalling (e.g. detection of phosphorylation events in these pathways). Data from these measures will then be correlated with tissue level changes and defined by comparison to a younger group to seek age x spatial architecture/ spatial metabolic differences such to identify the dynamic metabolic underlying sarcopenia. Next, we will determine the longitudinal and spatially distinct alterations in architecture, signalling, and metabolism (as above) in response to concentric (CON) vs. eccentric (ECC) contraction by comparison to a young population to seek contraction x age x spatial architecture/ spatial metabolic differences. This will inform on (i) dynamic processes regulating distinct spatial adaptations to ECC/CON and (ii) the efficacy of ECC vs. CON in reversing spatially distinct aspects of sarcopenia. Lastly, we will measure the effect of ECC vs. CON in functional terms (e.g. strength gains, improved gait, improved balance, etc.) to determine if ECC or CON is more effective at combating the functional consequences of sarcopenia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;6.7 PHYSICAL
Health categories: MUSCULOSKELETAL
Title: A novel polymer system as a bone void filler in reconstructive revision arthroplasty.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The aim of this project is to develop a simple to use, pliable, bioactive composite for reconstruction of bone in revision joint replacement. The novel, synthetic, polymer system will have a putty-like consistency, which is malleable by the surgeon but will set to solid consistency, when placed in contact bone during Orthopaedic surgery. BBSRC Super FoF is required to develop bone void filler, to a detailed and challenging specification. We will optimise the chemistry and formulation of the composite and detailed biomechanical and in vitro biological studies will be made. We intend to prove efficacy and elucidate the biological mechanisms of the osteoinductive properties. Two pre-clinical trials are planned. The research work has the support of S+N, with a commitment to take the project (if successful) into the development of a product for use in the clinic. The benefits to patients will be; improved surgical methods to fill bone voids in revision joint replacements (hips and knees).


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Smart materials for targeted stem cell fate and function in skeletal repair
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Bone disease and injury are burgeoning in our ageing populations, leading to a high economic and social cost. Treatments for bone injury are often ineffective or inappropriate. Autograft may be limited in supply and causing morbidity at the donor site, whereas allogeneic material may be poorly osteoinductive or of unreliable efficacy and in some cases may act as an agent for the transmission of life-threatening infectious disease. To address these challenges, we propose to develop a new tissue replacement that augments bone formation through temporal and targeted delivery of chemical cues for bone induction. To achieve this we will build on an existing collaboration between the universities of Edinburgh and Southampton focused on developing a new generation of biomaterials for bone regeneration. We will first engineer polymer nanoparticles which can carry a range of chemical cues (growth factors, small molecules, nucleic acids) and which degrade at controlled, predetermined rates. We will test this by examining release of fluorophores and by measuring uptake of released dyes by cells in in vitro assays. Next, we will use couple chemistries to tether such nanoparticles to the backbone of a variety of hard and soft tissue scaffolds. In this way, the scaffolds will provide an environment for cell in growth and will provide a reservoir of heterogeneous factors that are released at the appropriate times for the appropriate cell populations. Finally we will test the efficacy of such scaffolds in ex vivo models, such as the chorioallantoic membrane of the chick egg, and in in vivo small animal defect models. We take full advantage of the high-resolution CT imaging facilites available at Southampton to track drug delivery and tissue healing. Our approach will provide a new technology for controlling - temporally and spatially - the delivery of factors from hard and soft tissue scaffolds. This will enable the controlled redevelopment of tissues following injury.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Nanoparticles and Nanotopography: A Nano-toolbox to Control Stem Cell Self-Renewal via miRNAs
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Mesenchymal stem cells (MSCs) represent a cell population with self-renewal ability and multipotent differentiation capabilities. Recent studies have shown that microRNAs (miRNAs) act as regulatory signals both in maintaining self-renewal and instigating differentiation. However, their role in MSC fate is currently poorly understood and remains to be exploited. We have developed two novel nanotopgraphies, which allow us to maintain MSC self-renewal or induce osteogenesis in a chemical free controlled environment (i.e. no changes in medium formulation or surface chemistry is required). We aim to use these topographies to culture our MSCs and build on preliminary data to determine which miRNAs are up- and down-regulated during self-renewal and osteogenesis. Our team also have expertise in using gold nanoparticle (AuNP) intracellular delivery systems with a view to gene silencing. In this project we aim to design antagomirs against the miRNAs shown to be up- and down-regulated during self-renewal and osteogenesis, and decorate AuNPs with said antagomirs with the intention of influencing MSC fate, and driving cells towards osteogenesis. Our final aim is to develop a simple in vitro niche mimic model system comprised of MSCs seeded onto our self-renewing nanotopography overlaid with a soft collagen gel (akin to the stiffness of bone marrow). Nanoparticles are excellent platforms for cell delivery in 3D tissues. Injection of the AuNPs (either by syringe or microinjection), which will be further functionalised with MSC targeting moieties, will allow us to assess the efficiency of our antagomir functionalised AuNPs at targeting MSCs in a niche-like environment. In summary, we will thus utilise both nanotopographies and nanoparticles in a synergistic study to identify key miRNAs involved in MSC renewal and differentiation (osteogenesis) and then take a step towards targeting MSCs with our particles to direct cell fate in an in vitro 'niche-mimic' environment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Uncovering mechanisms underlying the transdifferentiation of human muscle fibroblasts into adipocytes
Funder: Biotechnology and Biological Sciences Research Council

Abstract: There are number of conditions such as in sarcopenia, where muscle quality declines, becoming fatty and fibrotic. The mechanisms underlying this process are not known. Recent research in our laboratory using human primary cells cultures has demonstrated clearly that it is the fibroblast cells (identify by a range of markers including TE7, TcF4, vimentin etc.) which not only produce fibrous tissue, but also have the ability to transdifferentiate into fat cells. They accumulate large amounts of lipid, alter their morphology, lose their fibrogenic markers, and increase expression of the adipogenic transcription factors. By contrast, myogenic cells do not possess this ability. The aim of this project, undertaken in collaboration with our industrial partner, GSK, is to identify and characterise the molecules responsible for the initiation of this transdifferentiation process. We intend to undertake sensitive time course studies where, using the latest transcriptomic technologies (RNA sequencing) we will track the ebb of the fibroblast phenotype with the flow of the adipocyte phenotype as characterised by detailed immunocytochemistry and time lapse cell imaging. We will also undertake experiments using mouse models to demonstrate in vivo viability of the transdifferentiated human cells and to characterize the role of fibroblasts in endogenous fibro-fatty accumulation. The first of these will use immunocompromised mice (Rag2-/- yC-/- C5-/-) to determine the ability of these human cells to form adipocytes in vivo (forming fat pads and in muscle regeneration). The second will use a conditional fibroblast knockout mouse (TCF4CreERT2mice crossed with R26RDTA) to characterise the adipogenic potential of fibroblasts when activated in vivo in a fibro-fatty degeneration model. This research will provide the mechanistic basis for fibro-fatty transdifferentiation, opening up new avenues for the development of novel and innovative therapeutics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: The sensory role of muscle for the control of balance
Funder: Biotechnology and Biological Sciences Research Council

Abstract: It is well established that sensory information from the ankle muscles is crucial for balance. However, this information is potentially ambiguous because changes in muscle length do not directly reflect changes in ankle angle, and therefore body sway. The ambiguity of proprioceptive information is affected by the mechanical environment of the muscle, including ankle stiffness and muscle strength. We will establish how these factors affect the fidelity with which the ankle musculature tracks ankle angle, and determine the consequences for proprioceptive sensation and postural stability. In particular, we will investigate how these factors change with age. The triceps surae muscles will be measured using dynamic ultrasound during quiet stance. Image analysis will track the changes in muscle length, and this will be correlated with ankle angle. The extent of ankle-to-muscle coupling will be related to ankle stiffness and postural sway. We will also directly test the extent to which this coupling affects proprioceptive sensation at the ankle joint during a perceptual threshold task. Older adults (aged 65-85) will be compared to the young (aged 18-40), to determine how age-related changes in ankle stiffness and muscle strength affect proprioception and postural sway. In addition, we will examine the effect of artificially altering physiological parameters upon postural sway (strength, stiffness, sensory gain) using a 'fictive' standing paradigm. This will involve real-time processing of EMG signals to balance an inverted pendulum. This technique will allow us to examine the effect of changing muscle/ankle properties upon proprioception and sway, both within- and between-subjects. Specifically, we will be able to mimic the ageing phenotype in younger adults, and artificially improve function in older adults. This combined approach will provide us with a comprehensive picture of the mechanisms underlying proprioceptive control of balance, and why it degrades with age.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: The use of microRNAs and nanotopography to modulate skeletal stem cell fate and function
Funder: Biotechnology and Biological Sciences Research Council

Abstract: With an increasing ageing population the clinical requirement to replace degenerated tissues, such as musculoskeletal tissue, is a major socio-economic requirement. Skeletal (SSC) or Mesenchymal Stem Cells (MSCs) have the potential to form a variety of stromal lineages including bone, cartilage, fat and muscle and display plasticity between lineages. Lineage modulation offers significant therapeutic potential for using these cells in regenerative medicine. A key issue is an understanding of skeletal stem cell differentiation and maintenance of skeletal stem cell properties. MicroRNAs (miRNAs) are a class of endogenous non-protein-coding single-stranded RNAs, ranging from 18-25 nucleotides in length that regulate gene transcription post-transcriptionally with fundamental and diverse roles in a variety of biological and pathological processes. A number of miRNAs are specifically expressed in stem cells, control stem cell self-renewal and differentiation, while other miRNAs have been linked with disease or prognosis. We have emergent proof of concept data that miRNAs regulate skeletal stem cell fate and function. We propose that miRNAs play a critical role in the regulation of skeletal stem cell fate and function. We will determine the role of miRNAs in the maintenance of stem phenotype or enhancement of bone stem cell differentiation and mechanisms involved including cytoskeletal or epigenetic changes. We have recently shown that defined nanotopographies are capable of robustly regulating SSC fate in the absence of chemical cues. We will therefore use custom designed nanotopographies to control SSC phenotype (for instance, to induce osteogenesis or maintain SSC numbers) and examine how miRNAs affect stem cell responses through modulation of epigenetic, biochemical and biomechanical processes. This study will facilitate our understanding of the mechanisms involved in the regulation of skeletal stem cell fate and function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Do age-related changes in microRNA expression in muscle mediate sarcopenia?
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Skeletal muscle homeostasis depends on a balance between muscle regeneration, hypertrophy and atrophy. This balance is disturbed as we age. A common characteristic of ageing is sarcopenia related to myofibre atrophy and decreased muscle mass and function. Sarcopenia leads to poor balance, falls and fractures and a decreased quality of life in our ageing population. There are currently few studies showing the involvement of miRNAs in skeletal muscle ageing, although miRNAs are likely to be involved in the ageing process and particularly in sarcopenia. microRNAs (miRNAs; miRs) are novel regulators of gene expression. miRNAs control myogenesis, regeneration and cellular programming. Each miRNA is predicted to target several hundred genes and expression of numerous miRNAs is conserved between species and disrupted with age. This makes miRNA-based interventions a promising therapeutic strategy against sarcopenia. This project will test the hypothesis that changes in miRNA activity act as effectors of age-related changes in the myofibres and surrounding environment by directly contributing to muscle fibre atrophy, fibrosis and impaired regeneration. This hypothesis is built upon the applicant's preliminary data showing disrupted expression of muscle-specific miRNAs and their putative targets in muscles of old mice and their involvement in myoblast apoptosis, proliferation, differentiation and myofibre atrophy, processes related to muscle ageing. Among miRNA putative target genes are myogenesis inhibitors, chromatin remodelling factors, FGF and Wnt signalling pathway components. The findings of this project will advance our knowledge of the molecular events involved in sarcopenia and will establish the potential of miRNA-targeted interventions aiming at preventing, delaying or treating sarcopenia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Synergistic combinations of diet-derived bioactives to maintain joint health and prevent osteoarthritis
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Osteoarthritis (OA) is a degenerative disease of the joints characterised by degradation of articular cartilage, thickening of subchondral bone and osteophyte formation. It is a major cause of disability in the UK. There are no effective disease-modifying drugs to treat OA and pain relief is often insufficient. Approx 8.5 million people suffer from OA in the UK, with 71% of these in constant pain. Increasing age and obesity are major risk factors and changing demographics will lead to a large rise in incidence of OA. Many phytochemicals have been proposed to have positive benefit on joint health and OA, but predominantly these have not been studied in man. The impact of dietary compounds on the joint needs to be studied with increased rigour at scientific and clinical levels to prove efficacy. Our previous research has focused on sulforaphane (SFN), an isothiocyanate from cruciferous vegetables, where we demonstrated efficacy in vitro in cartilage cell and explant assays and in vivo in a mouse model of OA. We are currently undertaking a proof-of-concept trial in man to prove dietary SFN can impact upon the human joint. We have identified several diet-derived compounds that show efficacy in a surrogate screen of cartilage protection in human chondrocytes. Our hypothesis is that these compounds will display synergy to protect cartilage and prevent or slow the progression of OA. We propose to: (i) investigate mechanism-of-action of 11 diet-derived compounds; (ii) assay synergy between compounds, where this is more likely between compounds which act on different pathways; (iii) test key combinations of compounds in assays of cartilage destruction in vitro; (iv) test one combination in a proof-of-concept human trial to demonstrate action in the human joint. The identification of a synergistic combination of compounds will allow us to protect intellectual property and design a clinical trial to provide evidence of prevention and slowing OA progression.


Research activity codes: 5.1 PHARMACEUTICALS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MUSCULOSKELETAL