NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of microRNA 29 in tendon disease.
Funder: Wellcome Trust

Abstract: Tendons are the thick fibrous cords of dense connective tissue that attach muscles to bone and transmit loads generated by muscles to stabilize joints and effect movement. Inevitably, tendons play a critical role in nearly every Muscle activity - from standing to running to writing. Tendon injuries result from a single or multiple episodes of overload, and lead to tendon degeneration and/or rupture. Treatment is poor and may involve surgery. Research into tendon diseases lags far behind other Muscle disciplines particularly at a molecular/cellular level. Small molecules called microRNAs are important in tissue thickening or fibrosis seen in other diseases. Our experiments will offer insight into how microRNA drive tendon damage and how we may reverse this. Our endpoints will inform patient care in two ways: 1. Understanding how microRNA molecules affect tendon cells at a cellular level and target further molecules that may be of interest. 2. Targeting and blo cking these molecules may allow us to reverse tendon damage and ultimately benefit the human tendon disease process. Our ultimate aim is to reduce the burden of tendon disorders in patients with Muscle disorders by offering medical treatments to avoid surgical interventions and thus improve function and reduce pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Clinical PhD Programme at the University of Edinburgh: 'Investigating the role of new genetic susceptibility loci in osteoarthritis.'
Funder: Wellcome Trust

Abstract: In the UK, osteoarthritis is the most common type of joint disease and the major cause of pain and disability in older people (19). The disease, which results in loss of the protective surfaces of joints, is poorly understood and no treatments exist to prevent the onset or progression of the disease. Medical management involves pain control until such time as the severity of the disease necessitates surgical replacement of the affected joint (20). Recent studies have identified inherited variations in peoples' genes that predispose to development of the disease. This research proposes to use a range of cutting-edge genetic and molecular laboratory techniques to determine how these disease-causing genetic variations lead to degeneration of cells of the joint surface (cartilage). This research will use joint tissues donated by patients with and without osteoarthritis to establish if expression of these genetic variations influences the behaviour of cartilage cells. Deletion or over-expression of the gene of interest will be performed in experimental animals as this is the only way to adequately analyse the effect of the gene on joint function. By determining the mechanisms by which these genetic variants cause osteoarthritis, novel medications can be developed to treat the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Repurposing anti-TNF for treating Dupuytren's disease
Funder: Wellcome Trust

Abstract: Dupuytren's disease is a very common condition that causes the fingers to curl into the palm and can be extremely debilitating. There is no approved treatment for early disease. Once patients have established deformities, the diseased tissue is removed surgically or cut using less invasive techniques such as a needle or an injection of an enzyme. However, recovery following surgery usually takes several months and recurrence rates with the non-surgical techniques are high. We have unravelled the molecular mechanisms that initiate and maintain the disease process. Based on these findings we plan to test a drug currently approved for use in patients with rheumatoid arthritis. The drug will be injected directly into the diseased tissues in the palm to maximise its effect. We will first conduct a small trial in 24 patients with established Dupuytren's disease to determine the optimal dose to inhibit the activity of the cells responsible for the disorder. Next we will assess whether the drug at this dose will prevent progression in patients with early disease. If effective, this will represent the first targeted therapy involving a simple injection for patients with early Dupuytren's disease that will preserve hand function and avoid the need for surgery.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Scottish Consortium TMaT Programme: 'Does mesenchymal stem cell-mediated synovial hyperplasia after traumatic joint surface injury affect the development of secondary osteoarthritis?'
Funder: Wellcome Trust

Abstract: When pain from joint wear and tear (osteoarthritis) becomes too much we can surgically replace the joint. Operations have risks and artificial joints do not last forever. We have not yet identified how exactly osteoarthritis develops and how we can prevent or delay its progression to save the patient's own joint for example by using medication. One of the causes of osteoarthritis is damage to the joint by a fracture through the joint. In models of osteoarthritis we found that some mice heal after injury whereas others behave like humans and develop osteoarthritis in damaged joints. We want to find out whether the swelling of the joint lining after injury, which is caused by stem cells that are naturally present in our joints, is caused by a protein called Yes-Associated Protein (YAP). YAP has been shown to cause other organs to grow. We will investigate YAP in stem cells by using samples from human joints, and using a model of osteoarthritis to study the effects of YAP on the healing of joint and the development on osteoarthritis. This will tell us whether stopping the growth of the naturally occurring stem cells is good or bad for joint healing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: A new approach for preventing DVT in THR post-operative patients using NMES
Funder: Innovate UK

Abstract: Over one hundred thousand Total Hip Replacements (THR) are performed every year in the UK. It is recognised as one of the most risky procedures for the patient to develop a Deep Vein Thrombosis (DVT). Sky Medical have developed a new technology – the gekoTM - for preventing DVT that works by gently stimulating the nerve behind the knee that causes the calf muscles to contract. This contraction pumps blood around the lower leg and body and prevents a DVT occurring. This project is designed to test this new technology on a large sample of patients that are undergoing THR and examine the ability of the gekoTM device as an effective means of DVT prevention for patients most at risk of life threatening blood clots and for whom there is curently no viable alternative.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL;BLOOD
Title: Collagen Toolkits and related triple-helical peptides.
Funder: Wellcome Trust

Abstract: The collagens are proteins which have a triple-stranded, rope-like structure. The most abundant proteins in the body, collagens impart tensile strength to skin, bone, cartilage and blood vessel wall, for example. The collagens are highly interactive, being able to bind cell surface as well as extracellular proteins, such as the components of cartilage. We have made sets of triple-helical collagen fragments that we called Toolkits, containing, together, all of the triple-helical part of collag en, and we have identified which fragments bind to which cell-surface protein or other material. This allows us to identify parts of collagen that have specific jobs in the body, and to make synthetic collagen fragments that can serve the same function. We now seek support to continue and extend this work so that we can invite other researchers interested in similar topics to bring their own collagen-binding materials to this lab. We will identify which bit of collagen binds to their materi al, make a fragment specifically for them, and so allow them to manipulate their material in a specific way. We plan to make these specific collagen fragments available to the research community as a whole, to support commercial as well as academic work.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;BLOOD
Title: Collagen (I) homotrimer in age-related fibroses and tissue degeneration: evaluation as a stem cell biomarker
Funder: Medical Research Council

Abstract: Collagen (I) is the most abundant structural protein in vertebrates. The natural form of collagen (I) is a heterotrimer that assembles into large extracellular fibrils. Abnormal homotrimeric collagen (I) is resistant to protease-mediated degradation and is synthesised by cancer cells to create pathways for metastatic tissue invasion. Embryonic cells have been reported to produce collagen (I) homotrimers and in adults homotrimeric collagen (I) is also associated with fibrosis and connective tissue pathologies. This project proposes to test the hypothesis that that pathologies spanning fibrosis, osteoarthritis and tumour metastasis share a common stem/progenitor cell-mediated molecular mechanism involving the aberrant production of type I collagen homotrimers. The relative expression from the COL1A1 and COL1A2 genes in stem and progenitor cells will be determined by qRT-PCR and correlated with the relative amount of each collagen (I) alpha chain, assessed by metabolic labeling. Pathological tissues will be screened for homotrimer production and the contribution of self-renewing cell populations to homotrimer production determined in parallel cell cultures isolated from such tissues. Tissue explants and cell cultures will be treated with a genomic demethylating agent, to determine whether COL1A2 promotor methylation is widely used to reduce COL1A2 mRNA expression and promote the formation of alpha1 homotrimers. Finally the relative expression of each of the collagen (I) genes will be assessed in model systems from foetal to mature stages of development to determine how age-related epigenetic changes could predispose to skeletal disease. This data will be important for understanding how to harness stem cells for tissue repair and regeneration, without adverse effects on tissue function. The project is also highly relevant to the development of biomarkers of age-related frailty and stiffness and to predict the development of musculoskeletal disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;CANCER AND NEOPLASMS
Title: Antisense nucleic acid splice correction therapy for Duchenne muscular dystrophy and related disorders
Funder: Medical Research Council

Abstract: Experimental nucleic acid based therapies are being intensively investigated as novel strategies for currently untreatable human disease. This Programme aims to develop a detailed molecular understanding of the chemical biological requirements for long-term, targeted, functional and phenotypic antisense oligonucleotide (AO)-mediated splice correction in mouse models of Duchenne muscular dystrophy (DMD). DMD is a fatal muscle degenerative disease and AO mediated splice correction of the DMD pre-mRNA has the potential to treat approximately 75% of DMD patients and has been shown to be well tolerated with therapeutic efficacy in two recent Phase I clinical trials. A critical challenge now in the development of this approach is the need for long-term, targeted, high efficiency systemic correction of the DMD phenotype. In this Programme beginning with state-of-the-art AO-peptide conjugates (B-PMO and B-MSP-PMO) we will study long-term correction of the muscle and cardiac physiological phenotypes following splice correction in dystrophin deficient mdx and dystrophin/utrophin deficient double knockout (DKO) mice. We will also discover and study novel transduction peptides for enhanced AO delivery and splice correction, and develop methods for targeted AO delivery to muscle and cardiac tissues including novel chimeric transduction/targeting peptides and study their mechanisms of action. AO conjugates incorporating these novel peptides will be studied over the long term in DMD animal models. Work will further include study of safety aspects including long term toxicology, tissue biodistribution/pharmacokinetics, and genome-wide off-target and splicing dysregulation effects. Finally, we will further investigate our striking recent findings related to GLUT transporter mediated AO delivery to muscle and cardiac tissues. This is a challenging and integrated programme of work with several streams of study moving from discovery and basic chemistry and chemical biology through to in vitro and in vivo studies in DMD animal models and clinical application via the PI?s participation in the UK MDEX Consortium. It will substantially advance our understanding of the requirements for successful systemic splice correction of the DMD phenotype and will have direct implications for the therapy of related neuromuscular disorders and other diseases where forced manipulation of pre-mRNA splicing and/or targeted AO delivery would be of therapeutic value.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL;CARDIOVASCULAR
Title: Targeting oxidised microRNAs as potential therapeutic against sarcopenia
Funder: Dunhill Medical Trust

Abstract: There is currently a disproportionate increase in age-related health issues, with one of the major problems being the age related loss of muscle mass and function - sarcopaenia. Redox and epigenetic factors are key regulatory pathways associated with ageing. MicroRNAs, stable RNAs with half-life >24h, regulate muscle homeostasis posttranscriptionally. Oxidative modification of microRNAs results in the regulation of non-native targets. Redox balance is disrupted during ageing and the accumulation of oxidised, most likely pathogenic, microRNAs (oxi-miRs) in muscle leads to their disrupted specificity for regulating protein content. We have validated microRNAs/mRNAs/proteins networks affected by ageing in muscle and have shown that modifying microRNA expression improves muscle function, but there is currently no research into the function of oxi-miRs in ageing. Integrating epigenetic/redox experimental approaches with functional studies, we will validate key oximiRs and targets in muscle and establish the potential of inhibiting pathogenic oxi-miRs as novel, exciting strategy against sarcopaenia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;CARDIOVASCULAR
Title: Early glycation products of collagen: a solid-state NMR spectrscopy and ultrastructural study of biological and health implications
Funder: Medical Research Council

Abstract: This project will examine the biomaterial and pathological implications of the early stages of non-enzymatic glycation of type I collagen in bones and vascular tissue (medial layer). 1. To determine in vitro the structure of EGPs in type I collagen, including the presence or otherwise of non-covalently bound sugar species. 2. To determine any effects of EGPs (and any additional collagen-bound sugar species identified and water) on collagen molecular structure and organisation, nanoarchitecture of the collagen matrix and material properties of the collagen matrix. 3. To determine if the in vitro results from objectives 1 and 2 are representative of the situation in vivo in mouse models. 4. To determine the effect of EGPs on the pathology of calcification processes in (i) vascular and (ii) bone contexts (in vitro and in animal models). The principal structural tools will be solid-state nuclear magnetic resonance (NMR) spectroscopy and electron microscopy. The project will use in vitro and mouse models, with animals being fed 13-C, 15-N enriched diets to allow advanced NMR methods to be used in examining their tissues. Results will be compared to those from (unenriched) human tissues to validate the mouse models.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;CARDIOVASCULAR
Title: Sarcomeric signalling by giant muscle M-band proteins in health and disease
Funder: Medical Research Council

Abstract: This project will use a cross-disciplinary approach using to understand the links of the sarcomeric M-band to protein kinase signalling pathways controlling the turnover of myofibrils, and how mutations in the major sarcomeric protein titin affect this interplay of cellular structure, mechanics and signalling. It will use animal models to inform us on basic biological parameters of titin kinase as well as to allow us studying models of human disease. Cardiomyocyte cultures from neonatal and adult rodents will be used as easily manipulated models for studying cellular responses to mechanical stimuli, as well as for their particular suitability for live imaging approaches, which will inform us on the temporal dynamics and interactions of the M-band components studied, and the impact of defined mutations thereon. This will be complemented by super-resolution confocal microscopy and advanced image analysis (stress maps) to visualize with resolution approaching the dimension of individual M-band components the spatial relations of these, and the changes induced by mechanical activity or genetic disruptions in anmal models or patient biopsies. An underpinning activity will be the protein biochemistry necessary to generate the enzymes and structural proteins required for functional and kinetic studies, and for the nanoscale force measurements by single-molecule force spectroscopy and optical tweezers. Similarly, the structural analysis by X-ray crystallography, small-angle X-ray scattering and electron microscopy with single-particle reconstruction will be highly dependent on our proven ability to generate highly functional proteins for these types of studies, which will not only show basic molecular principles of M-band protein interactions or enzyme structure, but reveal the mechanisms of pathogenic mutations and guide the development of small molecule compounds that could target such interaction interfaces or active sites.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;CARDIOVASCULAR
Title: The role of transforming growth factor beta superfamily members in the pathogenesis of muscle weakness associated with pulmonary arterial hypertension
Funder: Medical Research Council

Abstract: We aim to define: the site of expression and the physiological correlates of GDF-15 levels in animal models of PAH; the effects of GDF-15 on muscle cells; whether GDF-15 acts via actIIBR or TGFBIIR and if antagonism of receptor function reverses the changes seen with GDF-15 exposure in vitro and in vivo; the potential role of GDF-15 in the development of muscle weakness in PAH patients. Experimental procedures 1. The site of expression and the physiological correlates of GDF-15 in the monocrotoline and BMPRII models of PAH will be determined through the analysis of dissected tissue and blood for GDF-15 levels using qPCR and ELISA. Changes in muscle cell size, structure and intracellular signaling will also be analyzed using light microscopy, immunofluorescence, qPCR and western blotting. 2. We will expose C2C12 myoblasts to GDF-15 and analyse them for signs of atrophy and autophagy. In cell lines that respond, the intracellular signaling pathway involved will be examined through luciferase reporter assays and co-transfection with actIIBR and TGFBIIR antagonists. Next mouse tibialis anterior muscle will be electroporated with GDF-15 expression vector. Muscle size, structure and intracellular changes will be analysed. If successful expression vectors for actIIBR / TGFBIIR and follistatin will be electroporated and experiments repeated. 3. Patients with PAH will have their GDF-15 plasma levels determined and correlated with physiological parameters. Muscles biopsies will be taken in those who consent and analysed as in 1. PAH is associated with muscle weakness. Our preliminary data indicates that GDF-15 is a novel mediator of peripheral muscle weakness. Our project may confirm that GDF-15, like GDF-8, acts through the actIIBR, for which there are commercially available antagonists. We would envisage that this work would eventually lead to the development of clinical trials to test these agents in man and may be generalisable to other chronic conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;CARDIOVASCULAR
Title: Engineering Solutions for an Ageing Population with Musculoskeletal & Cardiovascular Disease. 50 more years after 50.
Funder: Wellcome Trust

Abstract: The ageing population is increasing in number and life expectancy. The population expects fifty more years after fifty with high levels of activity and quality of life. However, the musculoskeletal and cardiovascular systems age and degenerate, adversely affecting mobility, ability to work and quality of life. Advances in engineering and bioscience have created opportunities for novel devices and regenerative therapies, which utilise innovative biomaterials or biological scaffolds to guide the patient's own stem cells to repair degenerative tissues. Advances in patient imaging and diagnostics are enabling earlier disease diagnosis with opportunities to intervene earlier in the degenerative process and preserve healthy tissue, and potential to provide patient specific continuum of care. WELMEC will deliver: - Longer lasting joint replacements in the hip, knee and spine. - Novel regenerative biological scaffolds for degenerative joint tissues, dental reconstructions and cardiovascular surgery. - Advances in cell therapies using the patient's stem cells. - Advanced medical imaging to facilitate earlier diagnosis and intervention. - Novel protein biosensors for disease diagnosis and improved patient targeting. WELMEC will integrate over 200 engineering, physical science, life science and medical researchers with clinicians and industrialists to develop and deliver innovative therapies and patient services for the ageing population.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: MUSCULOSKELETAL;CARDIOVASCULAR