NIHRDataInsights/HRCSData huggingface dataset:
Title: Basal ganglia signalling mechanisms and aging
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We have recently shown that loss of TrkB signalling in striatopallidal ENK+ neurons lead to age-dependent spontaneous hyperlocomotion, associated with reduced striatopallidal activation, demonstrating that BDNF-TrkB signaling in striatal ENK+ MSNs contributes to the inhibitory control of locomotor behavior exerted by the indirect pathway. Hence, we have established a unique mouse model that provides a rare example of age-dependent locomotor defect. To address the mechanisms underlying TrkB signalling contribution to normal and altered locomotor activity control during aging we will perform time course transcriptome analysis (by RNAseq) of young and aged striatopallidal neurons, in the presence or absence of TrkB signalling. This analysis will be performed on a mouse line carrying both the fluorescent reporter allele (tdTomato) and specific Trkb deletion in striatopallidal neurons (TrkbPenK-KO;Ai9/+), and a respective control line (BAC-Penk-Cretg/+; Ai9/+ and), to allow isolation of a pure population of striatopallidal neurons, and subsequent data validation analysis by the Biomark Fludigm Dynamic Array system for quantitative real-time PCR analysis. These experiments will then be followed by the in vivo functional validation of identified GOIs. For this analysis we will use a lentiviral shRNA transduction approach. For genes/pathways that are down-regulated in aged/mutant mice we will test if knockdown wholly or partially generates a phenocopy of the hyperlocomotor phenotype. Conversely, for genes/pathways where up-regulation correlates with hyperlocomotion knockdown will be performed on aged mutant mice displaying the phenotype, and these will then be analysed for (wholly or partial) correction of the phenotype. In vivo knockdown efficiency will be validated by FACS of EGFP+/tdTomato+ cells followed by real-time PCR analysis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of the descending dopaminergic projection in spinal development and regeneration
Funder: Biotechnology and Biological Sciences Research Council

Abstract: In contrast to zebrafish, the human spinal cord is unable to generate new motor neurons with devastating consequences in neurodegenerative diseases or after spinal cord injury. We have recently discovered that dopamine is a long range signal that acts on spinal progenitor cells to increase motor neuron generation during development and after a spinal lesion in zebrafish (Reimer et al, Dev Cell, 2013, 25, 478). This action of dopamine is evolutionarily conserved, as in human stem cell cultures, dopamine signalling enhances motor neuron differentiation. Hence, it is important to determine which progenitor cell types and which subcellular signalling pathways dopamine acts on during developmental and regenerative neurogenesis. Moreover, with its requirement for early function, the zebrafish motor system is uniquely placed to allow us to address the functional consequences of altered dopamine signalling. We will use anatomical, electrophysiological and high-speed video assays to determine how dopamine affects spinal neurogenesis and motor function during critical phases of development and regeneration. Finally, we will perform expression profiling of highly purified progenitor domains to discover new pivotal genes for spinal neuron (re-)generation. This project aims to elucidate fundamental vertebrate mechanisms and genes involved in functional spinal cord development and regeneration. Therefore, our research will inform future therapeutic approaches to motor neuron degeneration and spinal injury. Moreover, knowledge of critical dopamine-dependent developmental phases for motor neuron generation may be relevant in the context of psychoactive drugs taken during pregnancy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: NeuroChip: A microfluidic sensor for electrophysiological recording of a nematode neural network
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Pharmaceutical and agrochemical industries have an increasing need for cost effective experimental platforms for compound screening. We have invented a device to screen compounds for effects on the nervous system using the microscopic nematode worm C. elegans. We liken it to a worm 'EEG'. It exploits the cost effectiveness of using an invertebrate model whilst providing an exquisite level of detail and resolution on drug action. The device is a microfluidic chamber, 'NeuroChip'. It traps the worm, records the activity of a neural circuit in its head and applies compounds through a system of microvalves. This has particular relevance for the Crop Protection and Animal Health industries as the nervous system is a proven target for the majority of compounds that are currently deployed as nematicides and antiparasitics. Moreover, it provides the potential to deliver a neurotoxicological and biological activity profile for compounds that are of interest to the pharmaceutical industry.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Function and regeneration of dopaminergic neurons in the brain of zebrafish
Funder: Biotechnology and Biological Sciences Research Council

Abstract: In contrast to mammals, adult zebrafish regenerate neurons and axons in the CNS. The dopaminergic (DA) system is evolutionarily conserved, with neuronal somata situated mostly in the forebrain and axons reaching through the CNS. Thus the DA system in zebrafish offers an excellent opportunity to study replacement of a specific, highly connected cell type in the adult CNS in a genetically accessible model vertebrate. Moreover, the zebrafish is being developed as a model for neurodegeneration of DA neurons. However, surprisingly little is known about regeneration of this cell type in fish. We aim to determine the regenerative capacity of DA neurons in the CNS of zebrafish after selective ablation of these cells by genetic and pharmacological means. We will analyse changes in gene expression, functional recovery and signals that promote regeneration of DA neurons. In this context, we will explore the role of dopamine itself, which has been described as a negative regulator of DA neuron regeneration in salamanders (Berg et al., 2011, Cell Stem Cell, 8, 426-33), but has been found by us to augment neuronal regeneration from spinal progenitor cells in zebrafish (Reimer et al., 2013, Dev Cell 25, 478-91). Our preliminary results indicate that toxin-induced ablation of specific populations of DA neurons leads to microglia activation, a loss of the entire DA projection to the spinal cord and to robust deficits in shoaling behaviour, but not in basic swimming capacity. Within weeks, numbers of DA neurons are restored. Elucidating the mechanisms and signals of dopaminergic cell regeneration in the CNS of adult zebrafish will help us to understand the inability of the mammalian brain to regenerate this type of neurons.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: 14TSB_NAT Neurotox: A novel integrated BBB-brain model for comprehensive Dr.ug permeability and toxicity testing
Funder: Innovate UK

Abstract: The blood-brain barrier (BBB) is a highly organised microvasculature system composed of different cell types including brain endothelial cells, pericytes and astrocytes. Disruption of the BBB results in various brain diseases including stroke and Alzheimer's disease. Understanding of BBB integrity and maintenance is, therefore, essential to developing measures for preventing its disruption and also for effective Dr.ug delivery to the brain. Currently, most studies on BBB integrity and damage are performed on in vivo models and the current in vitro models do not reflect the cellular interactions that occur in in vivo, as different BBB cell types are cultured and studied in different types of media. The present project aims to develop a three dimensional (3D) in vitro BBB construct within the Kirkstall Quasi-Vivo culture system, which allows multiple cell types to be cultured in inter-connected chambers. Real time tracking of solutes across the BBB will be undertaken using a novel combination of laser and electrochemical bio-sensor based interrogation. Once developed, this in vitro model will be more accessible than an in vivo animal model for investigation of Dr.ug transport across the BBB.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: NEUROLOGICAL
Title: To define molecular aspects of strain identity and strain mutation
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Scrapie has been endemic in the UK sheep flock for over 200 years and multiple strains exist in the field. They can be cloned and passaged in suitable hosts in the laboratory, but characterising the differences between these strains and the way in which they are encoded is a major challenge. Likewise, it is exceptionally challenging to determine how novel TSE isolates emerge – are they always present at low levels but get selected for by changes in human practices? Do pre-existing strains of TSE disease mutate to result in modified strains that propagate in new niches such as particular Prnp genotypes? It is also possible that novel strains of TSE disease have always been present but that increased surveillance is only now beginning to pick up these novel cases. We have been working at the forefront of this challenge for many years and are well positioned to continue to define the interactions between TSE strains, their selection and altered pathogenesis in animals. Through extensive in vivo studies of large and small animals we have shown that some TSE agents can be readily modified/mutated on passage through new hosts whilst others appear more stable in a variety of hosts. Targeting of pathology is determined by both strain characteristics and host genetics but the detailed mechanisms causing this are not yet established. In this theme, we aim to determine how the characteristics of TSE strains are encoded, how they are manifest and how they can interconvert in suitable hosts leading to novel isolates displaying different peripheral pathogenesis in animals and with potentially novel host ranges.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Determining transmission characteristics of endemic and emerging TSEs
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Although cases of classical TSE disease in ruminants appear to be in decline, while TSEs remain in the environment and new emerging isolates are being identified there are still major concerns for food security. The transmission potential of novel isolates to other ruminants and to humans is still unknown. As with any disease, the risk of intra- and inter-species transmission is a composite of many factors, including the infectivity levels in tissues and/or bodily fluids of the infected host, the routes by which that infection can pass to the new host and the way that the new host responds to the incoming infection. Host-specific variables control some of these aspects, whilst pathogen-specific variables affect others. The major aim of work in this theme is to acquire a thorough understanding of the cellular and molecular factors influencing TSE transmission that are dictated by both the new host and the TSE agent. This work intersects with the aims of ISP3 focusing on the innate immune system, which we anticipate will identify common candidate genes underlying genetic resistance to disease as well as similar pathways that are modulated by pathogens. In line with our intention to produce work with impact, this research aims to identify candidates for future transgenic approaches, for the development of diagnostic tests, to target therapeutic intervention and to aid our understanding of the risk of transmission of novel TSE agents through the food chain. The work therefore fits entirely within the BBSRC strategic priority of food security.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Motor axon stabilisation in zebrafish and models of motor neuron disease
Funder: Motor Neurone Disease Association

Abstract: In motor neuron diseases (MNDs), motor neurons degenerate, starting at the end of their, processes where they make contact with muscle cells. Therefore, it is important to learn how these, contacts are established and can be stabilised. The embryonic zebrafish has emerged as a faithful model of different kinds of MNDs with overlapping symptoms For example, formation of, nerve/muscle contacts can be directly observed in transparent embryos and defects caused by, introducing disease genes can be rescued by introducing other genes and drugs. This may predict, similar rescue of motor neurons in mouse models and patients. We propose a PhD project in which, the action of one of these rescue genes that we discovered – chondrolectin - is studied in detail, using time-lapse microscopy and biochemical analysis. Moreover, hundreds of drug-like molecules, will be screened in zebrafish MND models for their ability to rescue motor neurons. This projects, aims to contribute to our understanding of fundamental processes in motor neuron/muscle, interactions to identify potential gene targets for future therapies in MND. At the same time we aim, to find drug-like compounds in the zebrafish system, which can be further tested in mouse models, and may ultimately lead to human therapy.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Autophagic dysfunction in cellular models of inherited MND/FTLD
Funder: Motor Neurone Disease Association

Abstract: Groundbreaking studies of rare families with inherited forms of motor neuron disease (MND) have led to the identification of specific errors in the instructions that the body uses to build and maintain healthy cells and tissues. Over time, these errors lead to the weakness and muscle wasting seen in individuals with MND. Recently, two more errors have been discovered that cause MND. The aim of this research proposal is to determine how these new errors cause MND. Our team has found preliminary evidence that these new MND-linked errors affect the innate ability that cells and tissues have to destroy and dispose of their damaged constituents. We think that some of the problems associated with MND are caused by a defect in how cells in the brain and spinal cord deal with this waste material. We suspect that waste-accumulation in the brain and spinal cord causes some cells to die prematurely eventually leading to MND. Our team will determine how the two recently described errors in MND impair this naturally occurring process. We can model this phenomenon directly by depriving cells of certain nutrients or with chemicals that cause cell stress. In the future we hope that our understanding of these processes will lead to the development of drugs that could improve the way brain and spinal cord deal with their damaged components possibly alleviating some of the symptoms of MND.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The Eyewriter Project
Funder: Motor Neurone Disease Association

Abstract: This grant provides a small amount of funding to support a student undertaking a research project during the summer vacation, which will be continued as his final year research project. The aim is to develop a free downloadable application for tablets, laptops and phones that will allow MND patients to use these devices using only their eye movements, possibly assisted by movements of their head. Various 'eye-tracking' devices are already available, and are useful for some people with MND, as the eye muscles are rarely affected. However, they tend to be expensive. The academics who are co-supervising the student have a mixture of clinical medicine and engineering background. They hope that use of the cameras now present on smartphones and tablets, along with 'open source' eye-tracking software, can be combined with a specifically designed interface to enable many more people to make use of smartphones and tablets as communication tools.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: Neurodegeneration triggered by dysfunction of FUS protein - studies of the mechanism using in vivo models
Funder: Motor Neurone Disease Association

Abstract: Changes in the structure and/or function of a protein called FUS are believed to trigger a chain of molecular events that cause the damage of motor neurons and the development of ALS or related motor neuron diseases. It is still not clear how this happens. It is known that an important function of FUS protein is to regulate the routing of genetic information from its main store, DNA, to the places where it could be used for building encoded proteins. The role of a “messenger” belongs to specific molecules of RNA and FUS protein possesses specific signals that allowsits binding to these RNA for regulating their transport, modification and when required, temporal storage. One idea is that in the disease nervous system FUS protein becomes unable to perform this important role or performs it erroneously. Another important consequence of FUS protein modifications is that it becomes sticky and therefore, forms large aggregates within neurons that damage these cells. Results of our previous studies let us to suggest that these two changes in FUS status, deficiency in RNA binding and increased propensity to aggregate, are linked together in triggering pathological processes in neurons. To prove this hypothesis in a model organism we created mice that produce human FUS protein without a part of the signal responsible for binding to RNA. As predicted, FUS protein aggregated in mouse neurons and these animals developed pathology that resembled ALS. The aim of the proposed project is to study in details mechanism of disease development in this model, and to create and study another model, mice producing human FUS without another, functionally different part of the signal for RNA binding. These studies shall improve our understanding of the mechanism leading to motor neuron damage in MND and reveal new potential targets for therapeutic drugs. We will also use these new models to assess how efficient are certain recently created neuroprotective chemicals in slowing down or even halting the development of motor neuron pathology and improving animal health. In particular we will test several so called gamma-carbolines, chemicals that have recently attracted close attention as potential drugs for combating pathological protein aggregation typical for neurodegenerative diseases, including MND.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identification of prognostic factors and development of prognostic models in parkinsons disease using long-term data from a large incidence-based cohort
Funder: Chief Scientist Office (Scotland)

Abstract: Background Many aspects of prognosis in Parkinson‟s disease (PD) are unclear, including to what degree mortality is increased and which factors influence prognosis. There are no prognostic models available in PD. Improved understanding of prognosis and in particular the development of prognostic models has important benefits, including guiding clinical decision-making, improving clinical trial design and enabling case-mix corrected comparisons between different cohorts. The optimal way to obtain prognostic data is long-term follow-up of community-based incident cohorts. Aims 1. To perform systematic reviews of mortality and disability in PD; 2. To identify factors that influence prognosis; and 3. To develop prognostic models in PD. Methods I will perform comprehensive systematic reviews of mortality and disability in PD and meta-analyses where possible. We have recruited a representative community-based incident cohort of 213 patients with PD and 266 matched controls, who currently have up to nine years follow-up and whom we will continue to follow-up lifelong. We collect data on multiple outcomes including mortality, impairment, motor and non-motor complications, disability and quality of life. Collaboration with colleagues from other centres who have followed up similar incident cohorts will increase our available dataset. I will identify which baseline and evolving factors influence specific outcomes (including survival, impairment, disability and quality of life) using multivariate regression analyses or Cox proportional hazards modelling and, where appropriate, with judicious selection of variables, develop prognostic models e.g. for mortality and disability. I will perform internal validation and, if possible, external validation in another cohort.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: NEUROLOGICAL
Title: Does the use of home based restorative rehabilitation technology enhance the clinical effect of botulinum toxin treatment for children with cerebral palsy who have arm movement difficulties?
Funder: Department of Health (England)

Abstract: Cerebral palsy(CP) affects 1 in 400 children. Weakness and spasticity have a significant effect on arm movement. Botulinum toxin(BT-A) treatment reduces muscle spasticity but does not address underlying weakness. In our preliminary NEAT study, children with CP using our home-based exercise device demonstrated improved arm function. This pilot will refine and develop this system and evaulate whether its use with BT-A treatment results in improved functional outcome greater than that achieved with either treatment alone, through a pilot randomised controlled trial of BT-A treatment with routine NHS therapy compared with BT-A treatment, use of home-based exercise device and routine treatment.


Research activity codes: 6.7 PHYSICAL;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Exploring practice in NHS inpatient dementia wards: developing an integrated assessment document and decision-making tool
Funder: Department of Health (England)

Abstract: This study will explore the development of an integrated assessment document and decision-making tool for use in NHS inpatient dementia wards. To date, there has been a paucity of research conducted in inpatient dementia environments. This is concerning as it is recognised that people with dementia admitted to these wards have complex needs and are admitted at a time of crisis. Nurse-led research in such environments is virtually non-existent. The project will use a mixed methods approach to address the study aim. The study will form the development phase of the MRC framework for complex interventions.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL
Title: Cognitive Orientation to Occupational Performance Intervention with Paediatric Dystonic Movement Disorders
Funder: Department of Health (England)

Abstract: Brain disorder in children such as dystonia that affect movement can cause significant problems with self-care and independence later in life. Current medical treatments are limited while surgical treatments, although useful, are invasive and expensive. This study will test a specially adapted form of occupational therapy, delivered to children with family involvement in their own homes. The treatment will be compared to standard care to see if it is feasible, acceptable to children and families and likely to be effective. At the end of the pilot study, results will help to develop a full-scale randomized controlled trial.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL