NIHRDataInsights/HRCSData huggingface dataset:
Title: Reducing the burden of COPD by targeting skeletal muscle mass and function. Targets and endpoints for drug development
Funder: Medical Research Council

Abstract: The overall aim of this work package is to gain new information regarding the aetiology underlying loss of skeletal muscle function, since this has a clinically relevant impact on morbidity, mortality and healthcare utilisation in Chronic Obstructive Pulmonary Disease (COPD). Key components of the program include (a) quick wins by screening material from available cohorts to assist with development decisions for available products and the development of regulatory endpoints relevant to the non-pulmonary effects of the disease, (b) direct measurement of protein synthesis using labelled amino acids and (c) extension of existing cohorts both when stable and at times of changing muscle bulk (after rehabilitation and exacerbation). Novel clinical features of the cohort will be the assessment of quadriceps strength, bulk, field test of walking performance and the obtaining of paired muscle and blood samples. Signalling pathways to be evaluated by the consortium will include (i) Muscle cell phenotype (MHC gene expression and fibre-type, mitochondrial function, myogenic transcription factors, such as myf5, myoD, myogenin, SRF, MRTFA/B and MASTR, and mechano-sensitive regulators of transcription factor activity specifically FHL1 and FHL3 (ii) Anabolic and insulin signalling (Akt,mTOR, P70s6 kinase, 4EBP1, FOXO1, IRS-1, IRS-2 and phospho-IRS-2 and GLUT-1/GLUT-4 expression (iii) Myostatin signalling (myostatin and extracellular regulators of myostatin (follistatin, FLRG and GASP-1) by ELISA (iv)Protein degradation (MAFbx, cathepsin-L and PDK2 (mRNA by qPCR, total and phospho, protein by Western blotting), (v) metabolism; Muscle metabolites (ATP, PCr, glycogen, lactate by fluorescence), muscle pyruvate dehydrogenase complex activity pyruvate dehydrogenase kinase 2 and 4 mRNA and (vi) cellular markers of ageing. Importantly material will be made available to pharma who have offered to share the cost of these analyses as an ?in-kind contribution. Within the workpacakge a responsive management style will allow movement of funds so that the consortium as a whole can focus its funds to obtain maximum productivity and will have a steering committee co-chaired by academia and pharma. Externally the WP will interdigitate with WP 1,2 & 3 for maximum ?added-value? and more widely with the PRO-active and COPD Foundation initiatives with the aim of supporting regulatory approval for outcomes relevant to antisarcopenic drugs


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: MUSCULOSKELETAL;RESPIRATORY
Title: Longitudinal determination of the role of inactivity in skeletal muscle dysfunction in individuals with chronic obstructive pulmonary disease
Funder: Department of Health (England)

Abstract: Skeletal muscle wasting is a major cause of morbidity and mortality in respiratory disease, particularly in individuals with chronic obstructive pulmonary disease (COPD). Current evidence perpetuates an ambiguity as to the drivers of the skeletal muscle changes, with a presumption remaining that disuse is likely to be the primary driver. I propose the first longitudinal study to determine relative contributions of factors potentially causing skeletal muscle wasting in patients with COPD. Using a large prospective cohort study I will not only uncover development of muscle dysfunction and the associated clinical impact, but also characterise the relative contributors of drivers towards muscle weakness. Detailed measurements of exercise capacity, strength and activity combined with biological and molecular analyses will allow the determination of the precise mechanisms of skeletal muscle wasting. These findings will help guide appropriate and timely interventions, resulting in improved exercise tolerance, quality of life, and potentially reducing resource utilisation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;RESPIRATORY
Title: A randomised placebo-controlled trial investigating the effect of bilateral quadriceps neuromuscular electrical stimulation on exercise capacity in patients with severe COPD.
Funder: Department of Health (England)

Abstract: Fifty-two patients with severe COPD and debilitating breathlesness will be randomised to receive either active or placebo neuromuscular electrical stimulation (NMES) to the thigh muscles. Both programmes will consist of 30 minutes of daily stimulation for six weeks and the level of stimulation will be set to either elicit a muscular contraction (active) or provide sensory feedback only (sham). All will undergo assessments of exercise capacity, muscle function and size, physical activity level, quality of life and service utilisation at baseline, after the NMES programme, and after twelve weeks. A sub-group will reflect on their experiences during a qualitative interview.


Research activity codes: 6.7 PHYSICAL
Health categories: MUSCULOSKELETAL;RESPIRATORY
Title: ERICA: Evaluation of the Role of Inflammation in non pulmonary disease manifestations in Chronic Airways disease (COPD)
Funder: Innovate UK

Abstract: The project consists of three elements and seeks to determine the ability of fibrinogen to identify patients with COPD who have muscle and/or cardiovascular disease manifestations. The first part is focused on supporting Regulatory acceptance of clinical biomarkers representing the non-pulmonary disease subtype of COPD with the aim to ensure that assets in our Portfolio are not discarded due to an inappropriate clinical development plan. The second part includes a clinical trial with a novel Phase II anti-inflammatory in a selected subset of COPD patients with elevated blood fibrinogen to assess its effect on our chosen clinical biomarkers. The third part is an experimental medicine study with a Phase I novel drug candidate with an unprecedented mechanism of action which, together with the 2 other parts, may provide a path for a novel therapy for COPD patients at risk of cardiovascular-related events.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;RESPIRATORY;CARDIOVASCULAR
Title: Physiological systems integration in the optimisation of exercise tolerance
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The ability to sustain muscular exercise is a key determinant of cardiovascular health, quality of life, and mortality. Exercise tolerance depends on the effective integration of the pulmonary, circulatory and muscular systems to transport and utilise oxygen. The effective integration of these systems dynamics, however, is still poorly understood. It is known that O2 transport and utilisation (VO2) kinetics are fast in endurance trained subjects and slow in the healthy elderly. Slow VO2 kinetics place an increased reliance on energy contributions from anaerobic sources that contribute to fatigue, dyspnoea and pain and thereby limit exercise tolerance. The purpose of this project is to develop a computational model to explain integrated dynamics of the pulmonary, circulatory and muscular systems across the continuum of healthy human biology. To facilitate this we will study cardiopulmonary and neuromuscular dynamics in healthy young, elderly and endurance trained subjects. Specifically we will investigate the relationship between the parameters of the power-duration curve (determining exercise tolerance) and VO2 kinetics (determining aerobic energy provision) using breath-by-breath gas exchange and instantaneous measurements muscle fatigue during dynamic exercise. In addition, we will measure the heterogeneity of regional muscle oxygenation, metabolism and recruitment using simultaneous near-infrared spectroscopy, magnetic resonance spectroscopy and imaging during exercise to the limit of tolerance. These data will be used to generate a systems biology framework to better understand energy provision during exercise over a variety of conditions. The findings from these studies will underpin the development of new strategies (either pharmacological or exercise based) for ameliorating the mechanisms limiting exercise tolerance, and thereby contribute to the maintenance of health, quality of life, and longevity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;RESPIRATORY;CARDIOVASCULAR
Title: Molecular and physical mechanisms of collagen fibril organisation.
Funder: Wellcome Trust

Abstract: Collagen is the structural building block of most of our tissues where it occurs in the form of microscopic fibres in skin, tendon, bone and other tissues that are mechanically stressed. On a strength-for-weight basis, collagen fibrils are stronger than steel! Their enormous strength is multiplied by being organised into cables (in tendons), sheets (in cornea) and criss-cross patterns (in skin) just like wool can be woven into garments. These amazing patterns are made during embryonic life wh en the blueprint of our tissues is being established, but how they are made is poorly understood. In our laboratory we have discovered a structure that protrudes from the cell (like a finger) and contains newly-forming collagen fibrils. We call these fingers fibripositors . We think that fibripositors are important in making the fibrils and pulling them straight. The assembly of collagen fibres goes awry in several human diseases, including surgical adhesions. This is when collagen fibrils gl ue internal organs together after surgery. We are asking for money from the Wellcome Trust for us to do research to understand how cell use fibripositors to make tendon and adhesions, and to find ways of stopping surgical adhesions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL;SKIN
Title: Over two years to investigate sleep and memory in children with focal epilepsy
Funder: Action Medical Research

Abstract: Background Epilepsy in early childhood is associated with a high rate of learning and behaviour problems, particularly when epileptic seizures continue. The exact cause of these problems remains unclear. Abnormal electrical activity seen in children with epilepsy on brain wave testing (epileptic discharges) has been shown to interrupt the learning process. Further, some types of epilepsy with increased epileptic discharges in sleep are associated with impairment of learning. Evidence suggests that sleep may help to make memories more permanent but we know little about this process, especially in children with epilepsy. Research project This study will evaluate the effect of epileptic discharges on the learning process in children with different types of epilepsy. It also aims to assess whether disruption of sleep patterns interferes with learning in these children and whether this is related to epileptic discharges. The results could change the way doctors think about the treatment of childhood epilepsy. Seizures and brain wave abnormalities at night may require closer attention, and the effect of treatment on sleep may also become an important consideration.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Over eighteen months to study augmented reality stories for upper limb rehabilitation of preschool children with hemiplegic cerebral palsy
Funder: Action Medical Research

Abstract: Background The most common form of cerebral palsy is hemiplegic cerebral palsy, affecting one in 1,300 live births. Movement on one side of the body, either the left or the right, is impaired, with hand and arm movements usually being the most severely affected. Children with hemiplegic cerebral palsy tend to develop strategies and techniques to manage tasks with one hand and therefore neglect the affected limb. Lack of use in childhood can lead to irreversible impairment later in life. However, if children are encouraged to use and develop the affected hand and arm regularly from an early age, their chance of being able to use both hands and lead fully independent adult lives are increased. The research project Whilst most parents are willing to carry out home-based rehabilitation programmes, it can be difficult to get young children to cooperate if they find the tasks boring and meaningless. The aim of this project is to develop an application or app for tablets or smart phones allowing therapists to create computer animated storybooks for pre-school children with cerebral palsy. Children will use their hands and arms to control the onscreen characters while a parent or carer reads the story. Customised computer software will recognise the movements of coloured markers on the child's fingers and use them to control the onscreen activities of characters, allowing the story to unfold under the child's direction. The storybook will be designed to deliver highly motivational therapy to be enjoyed by the whole family and, as children progress through the stories, the movements required to interact will form the basis of a progressively more complex home-based rehabilitation programme. By the end of the study it is hoped that the application will be developed for different types of smart phones, tablets or adapted for use on a laptop to make them readily available to families.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Over thirty months for understanding the genetic basis of childhood ataxias
Funder: Action Medical Research

Abstract: Background Ataxias are disorders of balance and coordination which can cause significant physical disability. They are caused by damage or degeneration of the nerve cells in the part of the brain known as the cerebellum or the pathways from peripheral nerves and spinal cord which lead to the cerebellum. Important causes of ataxia include genetic factors. When other family members are affected, a genetic cause is highly likely. However, even when there is a clear family history, most children do not get a definite genetic diagnosis. Without a clear genetic diagnosis it is not always clear whether the ataxia may get worse or not as different gene problems cause different types of ataxia. This team recently investigated whether the low genetic diagnosis rate was because genetic testing was not widely available or because the genes underlying the condition were unknown. They sequenced all known genes in a group of patients with an ataxia likely to be of genetic origin and found that over 80 per cent of cases were not caused by mutations in known genes. They also identified a new genetic condition causing childhood ataxia. The research project The researchers propose to further investigate this recently identified gene and to find other new genes associated with ataxia. One type of ataxia is ataxic cerebral palsy and the work may also allow the team to determine if this condition is caused by genetic factors. A specific genetic diagnosis avoids unnecessary investigations and provides children and their families with important information about their future outlook. If appropriate, treatment can be started immediately. It also enables genetic counselling in adult life when people with ataxia are thinking of starting a family. Genetic testing is very straightforward compared to other investigations and would be the method of choice when available. It is hoped that this work will result in genetic testing for ataxia becoming part of normal clinical practice and that gaining a better understanding of the genetic basis of ataxias will lead to the development of new treatments.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: An investigation to determine the efficacy and safety of lentivirus mediated FXN gene delivery for the correction of Friedreich ataxia’
Funder: Ataxia UK

Abstract: Lentivirus vectors (LV) provide stable and long-term gene expression in several cell types and are therefore highly suited to the treatment of genetic disease. We have previously shown that LV can be used to correct haemophilia B, a genetic disorder of the liver. More recently, we have also shown that novel envelope pseudotyped LV can efficiently reach other tissues, including the cerebellum, dorsal root ganglia, spinal cord, heart and pancreas. These are the primary tissues that show frataxin deficiency in Friedreich ataxia. Therefore, our aim is now to use LV to deliver the FXN gene to these tissues, to restore normal frataxin levels and to correct the disease phenotype. To show proof of principle that this can be achieved we will use HIV-1 based LV to deliver the FXN gene initially to cultured FRDA fibroblasts and neurons and then to FRDA transgenic mice. We will create LV carrying the FXN gene driven by the spleen focus forming virus and ubiquitously acting chromatin opening element promoters to achieve high-level and long-term FXN expression. In parallel we will examine LV safety by profiling vector effects on the mouse genome using a series of genotoxicity assays developed in our laboratory.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Molecular function of human senataxin protein, mutated in ataxia oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4), in the pathology of these conditions
Funder: Ataxia UK

Abstract: Ataxia oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4) are neurodegenerative inherited disorders characterised by degeneration in the brain and spinal cord, causing progressive muscle weakness and finally atrophy. The gene mutated in these highly disabling conditions encodes a senataxin (SETX) protein, a putative DNA/RNA helicase. This PhD project will investigate the function of human senataxin protein, uncovering the molecular mechanism underlying the pathology of AOA2 and ALS4. In particular, this project will characterise the transcriptional and RNA processing defects associated with the disorders and investigate the behaviour and function of the mutant forms of senataxin protein detected in people with the conditions. It will also examine the correlation between disruption of the senataxin function in human gene expression, and severity of the conditions. Furthermore, the novel senataxin-interacting partners will be indentified, and their function in human cells and role in AOA2 and ALS4 pathology will be established. Understanding the molecular basis of AOA2 and ALS4 has to be ranked as one of the current major challenges in development of therapies for the conditions. This project will advance our understanding of gene regulation in AOA2 and ALS4 and provide a solid foundation for the development of novel molecular therapies, improving the health and quality of patients’ lives.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Elucidating the reversibility of SCA5 as a basis for development of therapies
Funder: Ataxia UK

Abstract: Scientific summary In humans mutations in the gene encoding -III spectrin cause spinocerebellar ataxia type 5 (SCA5) and in mice loss of -III spectrin function results in aberrant dendritic development, progressive motor deficits and Purkinje cell dysfunction and degeneration. To elucidate whether any aspect of pathogenesis can be halted, alleviated or reversed in -III-/- mice, -III spectrin will be re-expressed, at different time points, both in vitro and in vivo. Purkinje cell morphology, cellular physiology and motor coordination will then be evaluated by morphometric analysis, electrophysiological recordings and performance on motor tasks, respectively. Given known links between calcium signalling and neurite growth, dysregulation of calcium homeostasis in other SCAs and signs of dark cell degeneration in -III-/- mice, another aim is to investigate the role of disrupted calcium signalling in -III-/- mice. Application of pharmacological inhibitors and overexpression of either calcium-activated kinases or small G-proteins involved in reorganization of the actin cytoskeleton will identify cellular pathways leading to aberrant dendritic morphology which may underpin Purkinje cell dysfunction both in -III-/- mice and other forms of ataxia. This work will highlight the extent to which progressive ataxia can be halted or reversed and provide experimental evidence pointing towards therapeutic strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of glia in the pathogenesis of the ataxic syndrome Dentatorubropallidoluysian Atrophy (DRPLA)
Funder: Ataxia UK

Abstract: Several dominant ataxias are polyglutamine (polyQ) disorders caused by the expansion of polyQ stretches in the affected proteins. We investigate DRPLA, caused by polyQ Atrophin-11. We have pioneered the study of Atrophin functions in Drosophila2 and used this organism to develop models for DRPLA. These studies have provided important clues into the specific features of this form of neurodegenerative ataxia, including a striking reduction in lifespan when polyQ Atrophins are expressed in the glia3-5. A sensible hypothesis is that affected glia will act non-autonomously on neurones as in other neurodegenerative pathologies. This is an emerging field that yields new and important therapeutic possibilities. We now wish to elucidate the mechanisms through which degenerating glia impairs organism functions, and identify genes involved cell-autonomously and nonautonomously in generating this aspect of the pathology. First, we will investigate the impact of glial polyQ Atrophin on motility, of great relevance to DRPLA. Second, to identify new regulators of gliopathology we will conduct unbiased genetic screens for mutations that modify the lifespan of DRPLA flies. We will then expand our analysis of behaviour and interactors to other fly models of polyQ ataxias. Our studies will be paramount in deciphering the complex glia-neurones interactions in ataxias and may be beneficial for several ataxias. They will open up new avenues for therapies aimed at targeting glianeurone interactions during progression of DRPLA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Digital Healthcare Platform for Early Dementia Diagnosis
Funder: Innovate UK

Abstract: Most of the 700,000 people in the UK with dementia have not received a formal diagnosis, so are denied access to benefitial treatments. The current NHS approach is slow (often more than 12 months) and often of low quality. This project will develop a novel digital healthcare system that will allow dementia diagnoses to be made quickly, cost effectively, and earlier in the diease course. It makes a novel combination of computer-based tests of memory and thinking and computerized analysis of MRI brain scans, which have been used in research for several years. It will provide support in diagnosis, making available the quality of information currently only available in highly specialist centres to doctors treating all patients, with the aim of reducing time to diagnosis to 3 months. We will build and test a prototype and demonstrate its value before developing a refined prototype that can be rolled-out nationally.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL