NIHRDataInsights/HRCSData huggingface dataset:
Title: Thick filament-based mechanisms for the dynamic regulation of contraction and relaxation in the heart
Funder: Wellcome Trust

Abstract: Recently it has become clear that, whilst the canonical calcium/thin filament-based pathway provides a start signal for contraction in skeletal muscle, its strength and speed are largely controlled by structural changes in the myosin-containing thick filaments. I now propose to test the hypothesis that thick filament regulation plays a similar key role in the dynamic control of contractility in heart muscle, by adapting and extending the methods I successfully applied to study thick filament-based regulation in skeletal muscle. I will use a fluorescence-based approach to characterise the structural dynamics of thin and thick filaments during activation and relaxation of isolated cardiac trabeculae and cardiac myofibrils. I will investigate the role of thick filament regulation and mechanical stress in determining the physiological rate of force generation and of relaxation in the heart, and how these rates are modulated in response to its functional requirements, including the stronger contraction observed after increased venous filling (the Frank-Starling law of the heart). The results of these studies are likely to lead to a new paradigm for the physiological control of contractility in the heart that will underpin future studies of the changes in that control in heart disease and potential therapeutic corrections.

Lay abstract: During each heartbeat the myosin motors on the thick filament use ATP as a fuel to generate force and shortening by interacting with overlapping actin filaments, while during heart filling the myosin motors are switched OFF to inhibit their ATP consumption. Dynamic regulation of the number of motors in the OFF or ON state is essential for the graded control of strength and duration of contraction of the cardiac muscle. Defects in this dynamic regulation lead to reduced cardiac output and, ultimately, to heart failure. My research is focused on the regulatory systems in the thick filament that control the ON/OFF state of the myosin motors during the heartbeat. I will use structural techniques at cellular and sub-cellular level to elucidate how the dynamic regulation of the myosin motors in the ON or OFF state control the speed of contraction and relaxation in cardiac muscle.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Horizon Scanning
Funder: Duchenne UK

Abstract: Horizon scanning of DMD global therapeutic landscape both clinical and preclinical; to inform research activities and strategy


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: MUSCULOSKELETAL;CONGENITAL DISORDERS
Title: Exploring the emotional and behavioural difficulties experienced in Duchenne Muscular Dystrophy (DMD)
Funder: Duchenne UK

Abstract: This project aims to understand how boys and young men with DMD and their parents might be experiencing behavioural and emotional difficulties, by giving them the chance to provide their own perspective. So far, DMD research has focused on the motor-related difficulties associated with the disease. This study aims to have novel information on behavioural, emotional and learning challenges from both a parent’s and child’s perspective. Involving parents and young people will help us understand a. what are the most common emotional and behavioural problems experienced by children and young men with DMD; b. what is the impact of such challenges on their daily life (e.g. at home, at school etc.); c. to explore the current support received for such challenges; d. understand what kind of support is needed by these families in relation to such behavioural and emotional challenges. This information will also be crucial in informing how to provide better care and support for them in their everyday lives.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MUSCULOSKELETAL;CONGENITAL DISORDERS
Title: Assisted reproduction for expediting canine Duchenne Muscular Dystrophy translational researc
Funder: Duchenne UK

Abstract: Using the deltaE50-MD dog model of DMD which has a mutation that is more similar to the human mutation.

Lay abstract: Generating a dog colony via IVF

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;CONGENITAL DISORDERS
Title: DMD Heart Protection
Funder: Duchenne UK

Abstract: Almost all boys with Duchenne muscular dystrophy develop a progressive cardiomyopathy. The multicentre, randomized, placebo controlled, Heart-Protection Study tested whether starting perindopril and bisoprolol in combination before evidence of ventricular dysfunction could delay the onset of cardiomyopathy. The study ended in 2018 after 75 boys had been studied for three years. Although LV-dysfunction did occur in some participants, there was not a group benefit for active therapy in the primary endpoint (ie: change in LVEF% from baseline). This may be explained by the fact that most participants were also getting the benefits of maintenance steroids and this, combined with inter-patient variability in age of cardiomyopathy onset, meant that longer follow_x0002_up was needed to show outcome differences. This proposal aims to reanalyse change in LVEF% between groups from baseline after adding 2-3 years of data, obtained from normal NHS-review, to the original data-set. No additional testing or hospital visits are required. International experts and patient group advocates agree on the importance of longer follow-up of this patient-cohort to determine the role of prophylactic heart therapy in young boys with DMD. The project can be completed within 10-months. Preparatory work is complete to facilitate the start - subject to securing funding.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;CONGENITAL DISORDERS;CARDIOVASCULAR
Title: Unravelling the role of NBAS in skeletal development: towards treatment for NBAS-related human phenotype
Funder: Medical Research Council

Abstract: During studies to identify genes associated with rare osteogenesis imperfecta (OI) phenotypes, I discovered that the same mutations in NBAS (Neuroblastoma Amplified Sequence) known to be associated with acute liver failure in infants were responsible for skeletal abnormalities in patients with OI. This work was published as a novel cause of bone fragility. This discovery provides me the opportunity to use tractable animal (zebrafish) research to advance understanding of the mechanisms by which NBAS exerts its effects, develop a fish model that accurately mimics human disease and identify potential new treatments. This would be beneficial to patients with both bone and liver manifestations of disease and could inform on a wider front regarding cell membrane trafficking and effects on collagen processing and secretion. Patients with NBAS are subjected to a lifetime of recurrent fractures, repeated episodes of acute liver failure needing recurrent hospital admissions and immune deficiency. Developing druggable targets towards making this condition better would have a positive impact on quality of life for patients. I plan to have potential druggable targets elucidated from this study that as part of future Fellowship/ Programme grant will be used to translate into clinical practice. My long-term career goal is to become a translational clinician scientist focused on patient-oriented research in bone fragility and establish a dynamic, cutting-edge bone genetics research group within University of Sheffield. In order to progress efficiently towards this goal, my short-term objectives are to obtain further training on practical laboratory skills in bone biology, and animal modelling, which this present application will provide. This is impossible at present with my full time clinical commitments. This application will provide me a unique combination of practical skills and scientific knowledge to help me achieve independence and prepare for my long-term goal.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;CONGENITAL DISORDERS;ORAL AND GASTROINTESTINAL
Title: The Epidemiology of NSAID Use: Trends, Outcomes and the Impact of Patient Characteristics and Clinical Guidelines.
Funder: Department of Health (England)

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed pain-killers. Serious side-effects have been identified; however most information currently available comes from clinical trials and may not apply to usage in the community. Using UK GP data, we will describe current NSAID use and how this has changed over time as new guidelines are published and drugs are withdrawn. We will investigate the side-effects associated with NSAID use including stomach ulcers and heart attacks, and which patients are at highest risk. A better understanding of NSAID use in the community will ensure patients receive the best treatment whilst minimising unwanted side effects.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;DISPUTED AETIOLOGY AND OTHER
Title: Assessment of Peripheral Muscle Mass in the Critically ill and its response to external muscle stimulation
Funder: Department of Health (England)

Abstract: Each year, 110,000 patients are admitted to Intensive Care Units (ICU) in England and Wales. Many face prolonged disability as a result. Over two thirds have moderate-extreme limitation in their usual activity a year later, and one-third are severely affected, being unable to continue “most activities,” or to live independently. Quite why is not known- but severe muscle wasting may play an important role. We hope to find out, measuring the degree of wasting in patients, and seeking potential causes. We shall also address the mechanism of wasting, which may reflect an altered balance of activity in muscle growth pathways and those that break muscle down. We’ll do this by collecting data, taking regular blood tests, scanning the leg muscles with an ultrasound machine, and analysing small muscle samples. In addition, we’ll accurately and objectively measure how impaired these patients become, using specialist questionnaires, special monitoring equipment, simple walking tests and occasional special (‘Cardio-Pulmonary’) exercise tests. We’ll try to see how badly activity is limited, and tease out whether muscle weakness plays a significant role in this. Finally, keeping muscles working (hard to do when unconscious/drowsy/bed-bound) may maintain muscle mass, so we’ll see whether maintaining muscle activity using painless electrical stimulation will help.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE
Title: Multi-layered abstractions for PDEs
Funder: Engineering and Physical Sciences Research Council

Abstract: Partial differential equations (PDEs) are the mathematical basis ofvast areas of science. From fluid problems such as flow past anaircraft or the circulation of the worlds oceans to structuralproblems in bridges or inside the bones of a body and even in t


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE
Title: A Large-Scale Predictive Musculoskeletal Model to Simulate Human Walking
Funder: Engineering and Physical Sciences Research Council

Abstract: Walking is our most fundamental and widespread mode of transportation and is recommended for a healthy lifestyle. We walk automatically without the need for conscious attention. However, this seemingly simple task requires very complex control between our


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE
Title: Understanding mammalian biomineralisation in health and disease via a molecular dissection of the mechanisms underpinning amelogenesis imperfecta.
Funder: Wellcome Trust

Abstract: Biomineralisation is the process by which the body controls mineral deposition within the skeletal tissues. Dental enamel is the most extreme example of biomineralisation, with almost 97% of the tissue occupied by mineral, providing its functional properties. Amelogenesis imperfecta (AI) is an inherited condition affecting dental enamel. AI enamel is often thin, soft and fragile, pitted and discoloured, causing patients embarrassment and discomfort. We know that some forms of AI are due to mut ations in genes which produce proteins that regulate enamel biomineralisation; however, we have yet to identify all of the genes leading to AI and we know almost nothing about why mutations in these genes lead to dramatic biomineralisation defects. We have brought together a team of geneticists, clinicians and biochemists who will combine studies of AI patients genes with mouse models of the human condition to elucidate AI disease mechanisms, identifying the genes and molecules responsible and the disease mechanisms underlying the clinical condition. We will use this information to improve understanding of biomineralisation events and to inform design of new therapies and treatments for skeletal disease as well as feeding back to our patients and their families to help them understand the basis of their condition.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE
Title: DeltaVision Core Microscope.
Funder: Wellcome Trust

Abstract: This application is for a specialised fluorescence microscope that will provide the temporal and spacial resolution to allow us to persue four crucial areas of our research. These involve: (a) detailed studies of how drugs activate cell surface receptors to stimulate signalling pathways inside cells; (b) establishing the role of specific mutations in a specialised protein (p62) in a common clinical disorder called Paget's disease of bone; (c) studying the role of a group of proteins that are e ssential for cell division and (d) establishing the effects of inflammatory signalling molecules on the movement of factors that regulate gene expression into the cell nucleus where than can stimulate the production of new cellular proteins.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE
Title: Blastema formation and skeletogenesis during arm regeneration of the brittle star Amphiura filiformis: cellular and molecular characterization.
Funder: Wellcome Trust

Abstract: The aim of this research project is to understand the initial stages of brittle star arm regeneration in terms of stem cell involvement, cell specification and the earliest activation of the skeletogenic gene regulatory network. The brittle star is a marine organism with a unique capability for regenerating whole arms post-amputation or after injury. To determine whether the regenerative blastema, a mass of proliferative cells giving rise to the entire structure, is composed of stem cells or dedifferentiating cells, molecular tools will be employed for their characterization. Stem cell markers and lineage tracing techniques will be used to identify the nature of the cells, their origins and migratory behaviour. The regenerating arm of the brittle star is contains several skeletal structures and the second aim of this project is to understand the cohort of signalling pathways involved in the early specification of the cell lineages which will develop into this adult tissue. This will be achieved by using molecular techniques and a candidate gene approach for studying the genes that have already been well-characterised in the closely-related sea urchin, , for which a complete gene regulatory network for the embryonic development of skeletogenic cells has been published.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE
Title: The role of the Golgi martix protein giantin in extracellular matrix secretion and ciliogenesis.
Funder: Wellcome Trust

Abstract: Recent data from in vitro and invivo systems suggest important roles for the transmembrane Golgi protein giantin in extracellular matrix secretion and ciliogenesis. We propose to us in vitro cell biology experiments together with the use of zebrafish as an animal model to define the molecular basis for giantin function in cartillage and bone formation. We propose to combine molecular and ultrastructural approaches to elucidate how giantin regulates extracellular matrix protein transport, notably during the early stages of development, and also participates in cilia formation. Targeted gene silencing and knockout in both cells and zebrafish will be used with cargo transport assays to define the role of giantin in trafficking to cilium and in matrix secretion. Scanning and transmission electron microscopy will correlate these findings with ultrastructure in vitro and in vivo. Zebrafish genetics also enables us to image cell populations (e.g. neural crest cells and cardiomyocytes) during embryonic development in a variety of transgenic lines since embryos are translucent. These experiments will define the role of giantin in these two key cellular processes and illuminate the interplay between them during embryonic development. Our ultimate goal is to extend these finding to the medically relevant area of chondrogenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE
Title: Pharmacological Mobilization of Progenitor Cells for Tissue Regeneration.
Funder: Wellcome Trust

Abstract: Professor Sara Rankins research aims to develop innovative regenerative medicines. By combining her knowledge of pharmacology and in-depth understanding of bone marrow biology she will use this award to dissect the molecular mechanisms regulating stem cell mobilization from the bone marrow. The stem cells that she is particularly interested in are mesenchymal stem cells that can turn into cartilage and bone and also exhibit some immunomodulatory properties. Her work may may lead to the developme nt of new therapies that can selectively release these mesenhchymal stem cells from the bone marrow, boosting their nunmbers in the blood and thereby increasing the pool of stem cells available to home to areas of tissue damage to promote repair. This type of therapy could accelerate the rate of tissue regeneration, for example, in the context of bone fractures or heart disease. Professor Rankin will perform a rigorous molecular and functional characterisation of the mesenhcymal stem cells that can be mobilized. In the future it is likely that this type of regenerative therapy would be used primarily to treat an ageing population, therefore another focus of this award will be to investigate the impact of ageing on these processes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Drosophila model for muscular pain
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Maladaptive homeostatic plasticity, as a consequence of non-cell autonomous insults, is one of the central aspects in chronic pain studies, where changes in excitability in the nociceptive system, such as sensory neurons, occur following a damaging insult elsewhere. Rbfox splicing factor family regulates genetic output of muscles and neurons by mediating alternative splicing and mRNA degradation. The ability of Rbfox family to respond to upstream activity changes and subsequently to regulate excitability and activity provide intriguing mechanisms for the adaptation of functional circuits to local environments resembling prerequisite characteristics for homeostatic plasticity. Preliminary data and literature suggest that Rbfox splicing may be involved in sensory neuron sensitization. The proposed study aims to establish Drosophila models to understand the role of Rbfox in sensorimotor circuit homeostasis, with particular focus on balance between the muscle and sensory neuron function. These Drosophila models, which allow monitoring Rbfox activity, will be tested for their potential to serve as a novel, so far unrepresented, sensor tool to study non-cell autonomous sensory neuron sensitization in chronic conditions affecting the skeletal muscle. The substantial functional consequences, like changes in mRNA splicing, translation and degradation as well as miRNA metabolism, upon altered Rbfox activity would provide complementary advantages to tools like calcium sensors. The power of the model will be demonstrated by subsequent analysis of genes already known to participate in mediation of chronic pain as well as known Rbfox targets, linked to sensory neuron sensitization. The relevance to inflammatory response and ability of the model to replace moderate severity limit protocols, such CFA-injection in the muscle of mice for studies of chronic inflammatory pain mechanisms, will be examined.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Multiscale topographical modulation of cells and bacteria for next generation orthopaedic implants.
Funder: Engineering and Physical Sciences Research Council

Abstract: The UK has an aging population and we need to plan ahead to deal with this. Many of us will outlive the useful lives of parts of our skeleton through e.g. arthritis. Currently, e.g. hip replacements have a good survival rate between 10-15 years but then many patients require revision surgery. This is costly to the NHS and hence taxpayer, time consuming to the surgeon (it is far more complex than primary surgery) and is performed on elderly and frail patients where e.g. use of general anesthetic is a concern. The surgeons have two major concerns regards current orthopaedic implants. Firstly, the materials used are inert. This means that the body has a low response to the materials. This is an advantage as there is no immune response (inflammation) and a disadvantage as there is no bone response. If selective bioactivity could be produced (i.e. no immune response but increased bone response) then the implant could be locked in place by growing bone and implants for life developed. This lack of bone response means that the implants are not well held and can move about during walking. This is termed micromotion. This leads to failure with time as the extent of micromotion increases. Secondly, they worry about infection control. Even after sterilisation bacteria may be present on the implant materials in low numbers or can be introduced during surgery. If the infection can take hold it has major impact on the implant lifetime and this can result in younger patients having revision surgery and that has much higher failure rates. We have developed very small, nanoscale patterns that can be used to tune bone growth and prevent bacterial adhesion. We will thus optimise these patterns to achieve bacterial control and bone formation at appropriate points of the implant. A major advantage is that we can process these patterns in titanium, a material commonly used for orthopaedic implants due to its high strength (i.e. it can withstand the weight of the human body as we walk). Such an approach is a step towards making implants for life and planning ahead for the aging population.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL;INFECTION