NIHRDataInsights/HRCSData huggingface dataset:
Title: Does FHL 1 enhanced myostatin activity mediate intensive care unit acquired paresis ?
Funder: Medical Research Council

Abstract: Our aim is to explore the hypothesis that FHL1 enhances myostatin signalling thereby contributing to ICU acquired paresis (ICUAP). FHL-1 and myostatin have been identified as important regulators of muscle mass and fibre type in many experimental models (including in COPD patients by Prof Polkey‘s group). Their activity is also known be dependent on muscle activity, denervation and, in the case of myostatin, corticosteroids - factors which are all thought to be important in the development of ICUAP. The objective of this research is to investigate the potential role of these proteins in the pathogenesis of ICUAP. Recent research has shown that both FHL1 and myostatin interact with SMAD proteins leading to the hypothesis that FHL1 will enhance the atrophic properties of myostatin. We have designed a series of studies to investigate this hypothesis and the effect of physical activity on these pathways in vitro and in vivo. Using cultured myotubes we aim to demonstrate the relationship between FHL1 and myostatin signalling via the SMAD proteins and determine the effect of activity on these pathways by stretching the cells. In an interventional trial of electrical muscle stimulation in ICU patients we will compare pre- and post-ICU quadriceps biopsies from trained and untrained legs. This will enable us to determine the effect of inactivity and ICU insults on these pathways and the effect of increased physical activity. We will also conduct a cross-sectional study of patients with and without ICUAP. ICUAP is a common problem affecting up to 30% of all critically ill patients and is known to be associated with poor outcomes and prolonged length of stay in ICU. A greater understanding of the pathogenesis of this disease and the identification of potential targets for treatment provide the opportunity to significantly improve human health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.7 PHYSICAL
Health categories: MUSCULOSKELETAL
Title: Defining the role of RANK in skeletal diseases associated with osteoclast dysfunction
Funder: Medical Research Council

Abstract: Receptor activator or NFkB (RANK) is critical for the formation, function and survival of bone-resorbing osteoclasts. A healthy skeleton is maintained by the balanced activities of osteoclasts and bone-forming osteoblasts. Mutations in RANK lead to the rare condition osteopetrosis and to early-onset Pagetic diseases. Polymorphisms in RANK are also associated with the common multi-factorial disease osteoporosis. In this project I will explore how mutations as found in the single-gene conditions caused by RANK affect receptor assembly, receptor turnover, ligand binding, and NFkB signalling in osteoclasts. In addition, I will screen a cohort of over 3000 women from the Aberdeen Prospective Osteoporosis Screening Study (APOSS) for known and novel polymorphisms in RANK. By analysing the functional consequences of such polymorphisms both individually and as haplotypes using the methodologies developed for the RANK mutations I will provide new knowledge on the role of RANK in maintaining bone mass and on its potential to act as an independent risk factor to help identify those at risk of osteoporosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Target validation and lead identification for the development of disease modifying drugs in osteoarthritis (OA)
Funder: Medical Research Council

Abstract: There is an urgent, growing, unmet need for OA disease modifying osteoarthritis drugs (DMOADs) as the incidence of OA is rising in an ageing and increasingly obese population. This project aims to deliver one or more novel LEAD COMPOUNDS as DMOADs. Osteoarthritis (OA) is the most common degenerative joint disease in the elderly, causing arthritis in over 70million people worldwide. Analgesics and joint replacement surgery are the only current treatment options. We have identified an OA specific enzyme which is expressed only in the OA joint following trauma or repetitive stress injury. The enzyme is an ideal target for an inhibitory drug as it initiates degradation in OA, but not normal, cartilage and is not expressed in the normal adult. It directly activates matrix metalloproteinases (MMPs), enzymes which are critical for cartilage destruction, via a receptor known to be elevated in OA and linked to pain. Effective enzyme inhibition will stop cartilage breakdown and reduce joint pain. Target validation will be confirmed in an established OA model using enzyme specific inhibitors (developed for cancer and provided by collaborators) and with a novel transgenic mouse. Novel lead compounds for OA will be generated using all known inhibitors and computational medicinal chemistry and selected by screening in OA models. This solution will slow OA progression and so mitigate health and social costs and improve quality of life for patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Regenerating Tendons with Biodegradable Fibrous Scaffolds
Funder: Medical Research Council

Abstract: Tendons, such as the Achilles and flexor, are affected by degenerative diseases, trauma and spontaneous rupture. There are approximately 400,000 total tendon procedures performed each year in Europe; and 550,000 cases of severed hand tendons reported annually in the USA. Currently, there are poor surgical procedures for injured tendons, and repair generally involves the formation of scar tissue, which is biochemically and biomechanically inferior to natural tendon tissue. This leaves the healed tendon prone to further injury. We propose an innovative tendon repair process involving biodegradable materials. We have developed 3D poly(?-caprolactone) scaffolds, which mimic the natural tendon tissue and have yielded positive results in tendon repair following a pilot animal study. This scaffold provides a novel device for use in regenerative tissue engineering of tendon and can be used in both augmention and reconstruction. The team has expertise in biology, engineering and clinical practice. With MRC funding, we intend to develop the scaffold through laboratory and pre-clinical studies leading to validation for clinical studies/commercialisation. This will require robust in-vitro and in-vivo data packages and the necessary commercialisation strategies and outputs. The surgical input into the project is an essential component of the study.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;5.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: Bioactive orthopaedic implants using nanopatterned 3D materials
Funder: Medical Research Council

Abstract: Current orthopaedic procedures have moved from cemented to cementless implants (held in place by osteointegration). When first implanted there is only 20% contact between the bone and the implant. As osteointegration occurs over a period of several weeks it is essential that the implant fits tightly and that micromotion is minimal post surgery. To increase the bone growth on the implant and increase the life time of the implant, the surface is now coated with hydroxyapetite giving an osteoconductive surface. However, the roughened and coated surfaces do not control the fate of the progenitor cells which will be present after the surgical procedure and importantly during the healing process. Primary cementless total hip arthroplasty results are still worse than cemented shown by national joint registry data (UK and Australian -2% revision at 3 years). However, cementing is technically demanding and therefore not reproducible without a long training curve and will remain intraoperatively more time consuming and therefore an expensive procedure. We know from cadaveric studies that even the best present day cementless prosthesis obtain only a 25% bony on/ingrowth and consequently less than ideal physiological loading. Also, even the best performing smooth taper, cemented stems are associated with abnormal physiological loading (Scottish arthroplasty project shows a ten years fracture rate of 1.7 % for primary THA). We have discovered a unique nanopattern which exactly provides this cue in vitro. A slightly irregular nanopattern of nanosized pits (100 nm diameter and an average of 300 nm centre-to-centre spacing) specifically differentiates skeletal stem cells into bone forming cells with the use of any hormones or growth factors but only driven by the surface topography. In this project we have devised an ambitious plan to translate our in vitro findings into a new generation of orthopaedic implants. To reach this goal, we will develop a number of new patterning methods which will enable us to pattern titanium implants with our unique nanopattern. In a series of ex vivo and in vivo experiments we will move from organotypic cultures to segmental mouse defects. In essence this will bring our technology from the Petri dish to a pre-clinical stage. This is an ambitions project and to the best of our knowledge this will be a world s first to develop osseoinductive metal implant surface for load bearing implants.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Somitic muscle growth: a new model for the role of force in morphogenesis
Funder: Medical Research Council

Abstract: The role of mechanical force in development is poorly understood. Forces drive morphogenesis, the emergence of biological form. Force also provides information to cells about their situation within a tissue. The aim of this proposal is to develop zebrafish skeletal muscle as a model for the study of force in biological systems, focusing on the role of force in morphogenesis. Specifically, we want to understand how muscle senses force and responds by changing the number and size of muscle fibres. Work from a small group of labs, including ours, has developed the zebrafish somite as an advanced model of early myogenesis, revealing mechanisms controlling diversification of muscle and associated stem cells. Our recent findings indicate that force regulates a later phase of somitic muscle growth and implicate muscle fibre end attachments as sites at which force is sensed. The evidence suggests that contractile activity and the force it generates control increase in both fibre number and volume. By describing the normal process of muscle growth at single cell resolution in live vertebrates, something not previously achieved, we are in a position to investigate exactly how the signals and forces that regulate muscle growth work. We will ask where force is sensed, what biochemical pathways are required to transduce force signals and which cells are the ultimate targets of such signals. Fibre end attachments are regions where muscle exerts force and simultaneously grows. Evidence leads us to hypothesise that fibre end attachments act as force sensors, feeding back information to the cell nucleus and to adjacent cells to regulate muscle growth. Understanding the role of force in muscle growth is an essential first step in developing optimised methods to prevent weakening in ageing-related muscle wasting, heart disease, cachexia and other diseases affecting muscle. It will also impact on sports science, meat production and regenerative medicine generally. The specific aims of this proposal are to study how muscle form arises from interactions of cells and forces by analysing: 1. The locations and mechanisms of somite growth in response to force. 2. Muscle fibre attachments and their role in force-sensing. 3. The origin, niche and regulation by force of muscle stem cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: The Role of Mitochondrial Biogenesis in Muscle Function recovery in Critical Illness
Funder: Medical Research Council

Abstract: Sepsis-induced myopathy and muscle wasting is increasingly recognised as a significant contributor to poor health outcomes from critical illness. A potential mechanism may be insufficient or delayed recovery of mitochondrial (bioenergetic) function. The host lab has shown that bioenergetic failure is associated with poor outcomes in both patients and animals with severe sepsis. They have also shown that early upregulation of markers of mitochondrial biogenesis (production of new mitochondrial protein) is associated with survival in critically ill humans. I propose to test the hypothesis that stimulation of mitochondrial biogenesis improves functional recovery of skeletal muscle on recovery from sepsis. I aim to characterise the recovery phase of a long-term rat model of faecal peritonitis with respect to restoration of bioenergetic capacity and associated improvements in skeletal muscle structure and function. In the same model, I will then either stimulate (with leptin and rosiglitazone) or inhibit (with chloramphenicol) mitochondrial biogenesis to demonstrate any influence on exercise capacity, histological recovery, and force generation using nerve stimulation. I will complement these lab studies with a patient study where critically ill patients being weaned from mechanical ventilation will be randomised to a graded exercise regimen (as exercise is known to stimulate biogenesis) or standard rehabilitation. Muscle biopsies will be taken on day 1 after intubation and subsequently on day 7 and, if indicated, Day 21. Markers of biogenesis will be measured and compared with functional and histological recovery. This study will hopefully demonstrate the importance of mitochondrial biogenesis on functional recovery after severe sepsis. If so, it may lead to a important new treatment paradigm that will facilitate and enhance outcomes in the critically ill patient.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.7 PHYSICAL
Health categories: MUSCULOSKELETAL
Title: A systems biology approach to studying skeletal muscle ageing
Funder: Medical Research Council

Abstract: Skeletal muscle is negatively affected by the ageing process whereas its functionality is a profound determinant of the quality of life and of metabolic health. Until the generation of the data presented in this application, there was a complete lack of large scale human molecular data to drive hypothesis-led experiments in the field of muscle ageing. The aim of the application is to utilise informatics analysis and statistical modelling to determine if bio-bank materials can permit hypothesis driven analysis (e.g. reverse genetics experiments in cells or animal physiological models). We present analysis of a novel bio-bank that has allowed us to produce the first robust and cross-validated classifier of age for human skeletal muscle using cross-sectional cohort design yielding a 13-gene signature that was 92% accurate in determining muscle age. Expansion of the bio-bank will allow us to determine how this gene expression signature varies with physical capacity and lean body mass in two longitudinal studies. We will establish if our ageing signature represents an underlying biological clock . We aim to understand the function of the 13-gene signature. Eleven genes are under-expressed in older compared with younger muscle, while two genes are over-expressed in older subjects. One gene is a validated age-related gene, triosephosphate isomerase 1 (TPI1) from the glycolysis pathway that is 50% lower in aged muscle and TPI1 appears to be a normal protection strategy, where increased expression reduces reactive oxygen species. The function of the remaining genes in skeletal muscle is unknown and we will manipulate the level of expression of each gene in isolation and together to determine if the genes function as a single transcriptional unit or whether they represent marker genes of several independent gene networks. Direct measurements of muscle function will complement these transcriptomic studies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: MUSCULOSKELETAL
Title: Yap: a novel regulator of satellite cell fate with regenerative medicine potential
Funder: Medical Research Council

Abstract: Satellite cells are somatic skeletal muscle stem cells. Recent experiments demonstrate that satellite cell grafts can be used to improve function in dystrophic muscles and ameliorate muscle ageing in rodents. Thus satellite cell based therapies are now a much more realistic strategy for the treatment of human disease and ageing than several years ago. Satellite cells could potentially also be targeted in situ for example to increase the decreased satellite cell numbers in sarcopenic muscle. Our preliminary data suggest that the Hippo pathway and its core member Yap are expressed in muscle cells including satellite cells. Our functional studies so far suggest that Yap can potentially be targeted to expand satellite cells or to manipulate asymmetric cell division. The aim of the proposed project is to study the function of Yap in satellite cells in vivo. To test whether Yap is required for satellite cell identity, activation and proliferation, we wish to breed a transgenic mouse with a switch that will allow us to knock out Yap selectively in satellite cells. We then wish to study whether postnatal growth, muscle regeneration after injury and muscle hypertrophy are affected as satellite cells play a key role in these processes. Next we plan to transplant transgenic satellite cells into mdx-nude recipient mice and then induce the overexpression of constitutively active hYAP1 S127A in the satellite cell grafts. This gold standard experiment of satellite cell biology will inform us whether Yap can be targeted to activate and/or expand satellite cells and whether Yap affects asymmetric cell division and thus the numbers of satellite cells that go on to differentiate or self-renew. We will also see how this affects the expression of dystrophin in the dystrophic recipients. Finally, we plan to use a method known as ChIP-Seq (i.e. chromatin immunoprecipitation followed by next generation sequencing) to identify binding sequence motifs to which Yap co-activated transcription factors bind in satellite cells and the genes that are directly regulated by Yap. This last experiment will give us insight into how Yap achieves its effects. This is not only important to understand the function of Yap in satellite cells but potentially also in other somatic stem cells, where Yap has already been identified as a key regulator. Taken together, these experiments will inform us about the function of Yap in satellite cells in vivo and about potential clinical applications.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Deadenylase enzymes as potential novel drug targets in osteoporosis, bone disease, and repair
Funder: Medical Research Council

Abstract: In this proof of concept project, we shall explore the development of small-molecule inhibitors of deadenylase enzymes as a novel therapeutic approach for bone-related diseases, such as osteoporosis. We hypothesise that small-molecule inhibitors of deadenylase enzymes involved in mRNA degradation lead to increased osteoblast activity, will enhance bone density in osteoporotic bone, and promote the healing of bone fractures. The basis for this hypothesis is the observation that the CNOT7 deadenylase is a repressor of osteoblast cell activity as exemplified by the observation that CNOT7-null mice have increased bone density. Similar effects on bone are observed in mice lacking the Tob protein, which interacts with the CNOT7 gene product as a positive regulator. The CNOT7 protein is a poly(A) ribonuclease involved in cytoplasmic mRNA degradation that acts as a repressor of bone morphogenic protein-mediated signalling in osteoblasts. We aim to identify small-molecule deadenylase inhibitors using an interdisciplinary approach that brings together expertise in the biochemistry and cell biology of gene regulation, the biology of osteoblast cells and bone tissue, and screening capabilities and medicinal chemistry at the University of Nottingham. We shall use complementary approaches to maximise the potential of identifying small-molecule inhibitors. In addition to virtual ligand screening based on high-resolution crystal structures that are available in the public domain, we will develop and deploy a fluorescent deadenylase assay screen of an extensive, chemically diverse library of small drug-like molecules using robotics. Hit compounds will be verified and their selectivity determined using secondary biochemical and cell-based screens with a range of deadenylase enzymes. Hit-to-lead conversion medicinal chemistry will be carried out and lead compounds will be profiled extensively in terms of target and cell potency, selectivity, specificity, and pharmacological action, including the use of human and rodent osteoblast cells. If successful, this strategy will identify lead compounds that can modulate bone formation in cell-based models in a manner that suggests potential therapeutic use, and that may represent candidates for future drug development. Furthermore, such compounds will have much wider use as chemical probes in molecular and cellular medicine.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Over 18 months to study sunlight exposure and vitamin D status of children of South Asian ethnicity living in the UK
Funder: Action Medical Research

Abstract: Background Vitamin D is essential for healthy bone growth in adolescence and is produced when skin is exposed to sunlight, with only small amounts obtained from food. Low vitamin D levels lead to weak bones and severely low levels can cause bone deformity. Vitamin D deficiency has been reported in 17 per cent of adolescents in the UK, and almost 50 per cent of South Asian adolescents. Sun protection campaigns which advise limiting exposure to protect against skin cancer tend to be geared towards white-skinned people. Pigmentation reduces sunlight penetration into skin, and there is urgent need for more appropriate information for darker-skinned children. The Project The researchers aim to measure vitamin D levels in school children of South Asian ethnicity and study how these levels are linked to the child's sunlight exposure. In each of the four seasons, sunlight exposure will be measured using special badges, and diaries will be used to record time spent outdoors, clothing worn and sunscreen usage. Vitamin D intake through food will also be assessed through diet diaries. Researchers hope that findings from this study will allow national recommendations on sun exposure to be devised for this specific group of the UK population who are at risk of poor bone health through vitamin D deficiency.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MUSCULOSKELETAL