NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular mechanism of the myosin motor in skeletal muscle.
Funder: Wellcome Trust

Abstract: A major obstacle to understanding how cells work, and how they fail in disease, is the difficulty of connecting detailed molecular information about one particular gene or protein to the measurable behaviour of cells and tissues, which depends on the coordinated action of huge numbers of genes and proteins. We are developing new methods to overcome this obstacle by collecting the detailed molecular information from inside a working cell. In this project we will apply these methods to discover ho w the motor protein myosin drives contraction of muscle cells. Specifically we want to discover how ATP, a small molecule that acts as an energy store in cells, can fuel muscle contraction by causing a change in the overall shape of myosin when it binds to, and is broken down by, the protein. The results will help to understand how muscle works normally, and how this goes wrong when myosin carries a particular mutation, as for example in some inherited heart diseases. The significance of the r esults extends beyond muscle cells, because muscle myosin is just one member of a large family of motor proteins that act as essential cargo transporters in many other types of cell.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Is age-related increase in bone's fragility due to bone cells' initial reduced sensitivity to mechanical strain or subsequent responses to it?.
Funder: Wellcome Trust

Abstract: Bones are only strong enough not to break during our everyday activities because the cells within them sense the amount of deformation (strain) that occurs during loading and use this information as a stimulus to adjust the mass and shape of the bones accordingly. Failure of the mechanisms involved, particularly in post-menopausal women and old men, leads to fragility and a high incidence of fracture. Forty five percent of women and 13 percent of men sustain a fragility fracture during their l ives. The experiments we propose here are designed to use short periods of artificial bone loading in experimental mice to characterise age-related changes in the adaptive response. They will also show whether exercise itself has effects on the bones adaptive response due to the bone loading which is also usually involved. We will apply strain to bone cells in culture to identify some of the possible mechanisms involved. The information derived from these studies should help identify stag es in the mechanisms involved that would be amenable to therapeutic interference to improve the effectiveness of the normal processes of loading-related adaptation. This would enable appropriate treatment to be targeted to the areas where it was needed.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Determinants of Physical Function, Frailty and Muscle Health in Later Life.
Funder: Wellcome Trust

Abstract: Health and social care services in the United Kingdom are struggling to cope with the burden of disability and disease prevalent the elderly. This problem will continue to grow as the population ages. Research has shown that the proportion of disability associated with ageing can be modified. For example, people living in the most deprived areas in Britain are expected to live twice the number of years with disability than people from the least deprived areas. We know that loss of muscle mass and strength is closely related to the onset of disability and age-related frailty. However, the factors which determine Muscle health are poorly understood. This research proposal uses the infrastructure of the European Prospective Investigation into Cancer in Norfolk population study (EPIC-Norfolk) to assess whether behavioural (in particular, diet and physical activity) and physiological factors influence physical function and Muscle health in later life. Althou gh the EPIC-Norfolk study was originally set up to investigate cancer, participants in the study suggested collecting additional data on ageing and physical function, which can now be examined. We hope to identify factors determining age-related frailty and poor muscle function. This could lead to medical and therapy based interventions to promote healthy ageing.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Engineering functional bone-soft tissue interfaces: Novel approaches to Muscle regenerative medicine.
Funder: Wellcome Trust

Abstract: Acute cartilage lesions, which can cause disability and progress to osteoarthritis, are a significant clinical problem. The poor self-healing capacity of cartilage and the lack of effective treatments to restore joint function have prompted strategies to repair damaged articulating surfaces with surgically-implantable engineered cartilage. Many approaches utilising cell-seeded scaffolds, however, have fallen short of this goal as they fail to create a tissue that replicates the native tissue b iochemically, mechanically and biologically, especially at the structurally and mechanically crucial osteochondral interface. Here, we take a new approach to osteochondral tissue engineering where innovative science in stem cell differentiation will be incorporated into a translational programme to develop treatments for cartilage lesions. Utilising hyaluronan-based hydrogels, tissue-specific growth factors, and scientific insights into the role of mechanosensing in stem cell differentiation, continuous osteochondral constructs designed to replicate the osteochondral interface and promote bone and cartilage tissue development will be created. State-of-the-art biological and materials engineering methods to characterise both the constructs and the structure-function relationship of the native tissue interface will also be undertaken to ensure functionality upon implantation. Tissue engineering strategies for osteochondral interface regeneration that are inspired by biology may hold tremendous potential for developing successful therapies for cartilage lesions.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Cell BIology: Caught in the NET: Does the capture of genes at the nuclear periphery regulate their transcriptional activity during differentiation?
Funder: Wellcome Trust

Abstract: This work will focus on the muscle-specific NET39 to determine if it mediates chromosome repositioning during myogenesis, how this occurs and what the functional consequences are for gene expression and differentiation efficiency. NET39 is induced during myogenesis (Fig 5)37 and our lab found that NET39 repositions chromosomes in undifferentiated C2C12 myoblasts (Fig 4) and can ChIP histones, suggesting a direct interaction with chromatin (Fig 2F). A NET39 role in myogenesis could be relevant to NE-linked muscular dystrophies35 that have perturbed genome organization and gene expression38-41. Specifically, we will use mouse C2C1242, 43 and human RD44 muscle differentiation systems to determine: 1. Is NET39 responsible for establishing a myogenic chromosome organization pattern? 2. Does this spatial organization pattern contribute to genome regulation? 3. What is the molecular mechanism to reposition chromosomes? Should chromosome repositioning during myoblast differentiation not correlate with the repositioning induced by NET39 in myoblasts, we will engage similar methodologies on the liver-specific NET47, where previous work (Fig 2) has shown a clear correlation during hepatic differentiation. We will begin with NET39, however, because of muscle links to NE disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Exploiting synergy in dual modality molecular imaging.
Funder: Wellcome Trust

Abstract: Stem cell therapy may hold tremendous regenerative potential for an array of chronic human afflictions, including arthritis and Muscle disease because these cells are able to repair damaged tissue. Osteoarthritis already affects 15% of the population and its impact will grow as the population ages. The introduction of stem cell-based treatments is limited by two unmet needs: first, a need to understand the contribution made to cartilage repair by different stem cell populations, so tha t the right treatment can be given to each patient; and second, the problem of determining whether given stem cell populations actively work at the site of injury. Advanced nanoparticle chemistry and imaging methods can solve both of these problems We will generate non-toxic, magnetically active multimodal nanoparticles that bind specifically to given stem cell populations. These will be visible by magnetic resonance imaging (MRI), a widely used and safe clinical technique and, additionally, by luminescence imaging (at single cell and sub-cellular levels). By introducing the particles into animals and eventually patients, and allowing them to bind to different stem cell populations, we will be able to determine which stem cell types home in on damaged tissue, and which are the most effective mediators of repair.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Characterization of low bone mass phenotypes in 3 knockout mouse strains from the Wellcome Trust Sanger Institute high throughput gene targeting pipeline
Funder: Wellcome Trust

Abstract: Half of all adults are affected by bone and cartilage disorders, which already result in a huge financial burden to the NHS. This cost will inevitably increase as the population ages and new treatments are urgently needed. We have identified three new genes (Bbx, Slc38a10 and Fam73B) not previously known to have a role in the skeleton. When these genes are deleted our preliminary studies have shown that bones develop structural abnormalities and are fragile. Based on these new findings we wi ll determine: 1) The cause of the skeletal defects resulting from deletion of Bbx, Slc38a10 and Fam73B. 2) How these defects cause bone to become fragile. 3) Whether these genes affect bone directly or cause abnormalities in other tissues that subsequently affect the skeleton. 4) Which bone cell types function abnormally when Bbx, Slc38a10 and Fam73B are absent. 5) The molecular signalling pathways responsible. These studies will advance our understanding of bone and cartilage biology a nd identify new potential drug targets for prevention and treatment of skeletal disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: In situ investigation of roles of Tmem120A in adipogenesis, lipodystrophy and obesity
Funder: Wellcome Trust

Abstract: We previously found enormous tissue differences in the nuclear envelope (NE) proteome, identified several hundred novel NE transmembrane proteins (NETs) many of which are restricted in their tissue expression, and screened these to identify NETs that affect genome and cytoskeletal organisation. Of note, certain liver-specific NETs promoted a particular chromosome organisation pattern associated with liver, this pattern is lost in liver cells if the NETs are knocked down, and gene expression cha nges resulting from expression of these NETs overlap in part with those associated with hepatic differentiation. In the first two aims we will test if these findings represent a conserved developmental mechanism that applies also to myogenesis and adipogenesis, investigating muscle and fat-specific NETs. We will determine the regions of NETs required for chromosome repositioning and identify the chromosome proteins that interact with these NET regions to enable the repositioning mechanism. In the last aims, we will characterise NETs that affected cytoskeletal organisation, determining roles of one in centrosome positioning and others in cell mechanical stability. In particular, as NE-linked muscular dystrophies are thought to reflect weakening of nucleo-cytoskeletal interactions we will sequence genes for NETs that affect the cytoskeleton in unlinked muscular dystrophy patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Nuclear envelope transmembrane protein regulation of tissue-specific genome organisation and cell cycle regulation.
Funder: Wellcome Trust

Abstract: Individual chromsomes have tissue-specific positioning patterns within the nucleus, but how this is accomplished and why is not understood. We recently identified several novel tissue-specific nuclear membrane proteins that can reposition chromosomes. We will determine how these proteins function in tissue differentiation by modulating their levels in cell culture systems that we can differentiate into fat or muscle and determine what changes occur for chromosome positioning and gene expressio n. These studies should determine if gene positioning in the nucleus contributes to gene regulation during development. We also identified several muscle-specific nuclear membrane proteins whose perturbation disrupts the cytoskeleton that confers cellular mechanical stability. Because muscle cell mechanical stability is often compromised in muscular dystrophy and several muscular dystrophies are associated with the nuclear envelope, we predict some of these might contribute to muscle diseases . We will stain for these proteins in muscle patient samples to see if their normal distribution is perturbed, sequence the genes for these nuclear envelope proteins in several patients that have not been linked to a disease gene, and directly test the mechanical stability of cells expressing any mutations that we find. Thus we hope to identify additional proteins involved in muscle disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Upregulation of early inflammation to accelerate repair of fragility fractures.
Funder: Wellcome Trust

Abstract: Strategies for accelerating fracture healing in osteoporotic bone represent a major unmet medical need. These fragility fractures pose an enormous public health problem and cost the NHS 1.7 billion in 2000. The incidence of fragility fractures increases dramatically with age and the lifetime risk of clinically significant fragility fractures is over 40%, equivalent to that for cardiovascular disease. Osteoporotic bone has a reduced healing capacity and a weak structure, resulting in high rat es of failure in surgical fixation. Patient recovery and mobilisation are limited by the time taken for the fracture to heal. This accounts for the severe morbidity and mortality seen in this vulnerable group of patients. This proposal aims to develop a clinically translatable strategy for accelerating healing of fragility (osteoporotic) fractures. Previously, we significantly enhanced fracture repair in normal (non-osteoporotic) bone by adding a key inflammatory molecule at the fracture s ite using our mouse model. My objectives are first, to determine whether this strategy applies to osteoporotic bone, and second, to elucidate upstream molecular mechanisms of bone repair to identify the most effective point for intervention as a basis for targeted drug development.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Investigating the role of siganlling in joint morphogenesis in zebrafish
Funder: Wellcome Trust

Abstract: the developmental processof joint morphogenesis is of pathogeenic relevance, as the inability of a joint to form correctly causes disorders such as a Developmental Dysplasia of the Hip (DDH). My overall aim is to investigate how joint morphogenesis occurs molecularly and genetically. I plan to use zebrafish as a model for joint development, as they offer both genetic amenability and the ability to visualise gene expression and cell movement in a spatiotemporal context.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: The contribution of gamma-delta T cells, dendritic cells and bacteria in bisphosphonate related osteonecrosis of the jaw.
Funder: Wellcome Trust

Abstract: Understanding mechanisms of Bisphosphonate-induced Jaw Disease Bisphosphonates are drugs used to stop bone loss occuring in osteoporosis and in certain cancers. An extremely unpleasant side-effect in up to I 0% of patients taking high dose hisphosphonates is jaw bone death and infection. The cause of this disease is poorly understood, difficult to treat and significantly affects the quality of life of its sufferers. This research investigates the interaction of dental plaque, immune defence cells and bisphosphonates in causing the disease. Understanding the mechanism of the disease and why it specifically targets the jaw is central in developing prevention and treatment strategies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Wellcome Trust Clinical PhD Programme at the University of Oxford: 'Restoration of dystrophin expression and function in mouse models of Duchenne muscular dystrophy using peptide-conjugated antisense oligonucleotides'.
Funder: Wellcome Trust

Abstract: Duchenne muscular dystrophy (DMD) is an incurable neuromuscular disorder that severely disables and shortens the lives of affected boys. The overall clinical goal of this project is to develop an effective treatment for DMD using RNA-directed antisense oligonucleotide technology. There are two main scientific goals. The first is to identify and develop an optimum conjugated peptide-antisense oligonucleotide compound that can be delivered systemically to dystrophin-deficient mdx mice inducing selective exon skipping in the DMD gene with restoration of dystrophin protein expression and muscle function. The compound must be effective both in cardiac and skeletal muscle. The second goal is to understand the mechanism by which such cell-penetrating peptides permit cell uptake, particularly in cardiomyocytes. This project provides many academic training goals. It will increase my knowledge of basic RNA biology, muscle biology and disease mechanisms. I will develop skills in multiple laboratory techniques including oligonucleotide engineering, RNA molecular analysis, histology, immunohistochemistry, tissue culture and functional animal studies, including imaging, in a range of mouse models of DMD. Importantly, I will gain experience of working in a pre-clinical laboratory developing a novel therapeutic agent. This training will enhance my academic career and allow me to pursue further translational research in the future.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Total Shoulder Replacement System.
Funder: Wellcome Trust

Abstract: Many people with arthritis of the shoulder would benefit from total shoulder replacement (TSR). However, its use is limited because the scapula has very little bone in which to fix the artificial joint. In addition, it is difficult for the surgeon to visualise the damaged joint, and that leads to a high prevalence of misalignment. This tendency is exacerbated by uneven loss of bone by the arthritis. The result can be failure due to instability, loosening and accelerated wear. Therefore, the key goals of this project are: 1. Design and test a scapular component which is less destructive and yet more secure when implanted; 2. Use novel bearing materials which will reduce wear rates; 3. Design and test a novel thin-walled ceramic shell for the head of the humerus, which also uses less-invasive fixation. 4. Test the novel implants in a shoulder simulator machine; 5. Develop augmented implants which allow for bone lost by arthritis; 6. Develop a system of surgical guidance, to ensure accurate alignment; 7. Develop less-invasive surgery, avoiding shoulder dislocation, to enhance rehabilitation; 8. Commence a clinical study of the novel TSR and guidance system; 9. Commercialise this package when supported by the resulting clinical evidence.


Research activity codes: 5.4 SURGERY;5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Lifecourse trajectory of muscle strength and the relationship with physical activity: exploiting the HALCyon and FALCon Cohort Consortia.
Funder: Wellcome Trust

Abstract: Our muscle strength increases during childhood and early adult life before typically declining with increasing age. We can assess muscle strength using a simple test: by measuring grip strength. Previous work has shown that people with lower grip strength in old age appear to be at greater risk of a range of health problems An important factor influencing strength seems to be how physically active people are. There is evidence that older people who are more physically active, such as those who regularly do gardening, have higher muscle strength. Less is known, however, about whether being more physically active at different stages earlier in life improves muscle strength in the future. We plan to use existing information from several cohorts (groups of individuals taking part in a study which involves measurements being taken on more than one occasion) to make an accurate model of grip strength throughout life. We will then look to see what effect being more physically active at di fferent ages has on muscle strength. We expect that the results of this research would help inform strategies for maintaining the health of our increasingly older population.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: The interplay between force and adhesion in muscle development and function.
Funder: Wellcome Trust

Abstract: In this project we aim to extend recent discoveries on the mechanotransductionpathways involving integrin extracellular matrix receptors from cell culture models to tissues within a whole organism. Our model system will be the integrin-dependent attachment of Drosophila larval muscles to the exoskeleton,via the intervening epidermal tendon cells. Mechanotransduction is of particular importance in the muscles, because they experience large changes inforce due to contraction, and increase their contractile force through an expansion in size. We will develop assays to analyse the physiological changesto muscle contraction and adhesion and the pathways involved in muscle repair.The proposed experiments employ parallel approaches to explore how muscle adhesion is correctly balanced to be able to resist the strength of muscle contraction, and to discover whether the stress fiber repair pathway plays a role in repairing muscle damage. They will give us improved understanding of how the different integrin associated protesins contribute to this remarkable force-responsive cellular machinery.


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