NIHRDataInsights/HRCSData huggingface dataset:
Title: Simulation and Modelling Studies of Human Muscle-Specific Kinase
Funder: Wellcome Trust

Abstract: Muscle-Specific Kinase (MuSK) is a receptor tyrosine kinase (RTK) located in the mammalian neuromuscular junction, and is responsible for the aggregation of acetylcholine receptors (AChRs). Defects in MuSK, or autoantibodies against it, lead to myasthenia gravis. Portions of the MuSK receptor has been solved, but no one has previously looked at the fulllength receptor before. The major focus of this project is to build a complete model of the human MuSK receptor using previously published structures together with MD simulations. This will be used to understand the behaviour and dynamics of MuSK in a bilayer. Multi-scale MD simulations, as well as selected structure prediction software, will be used to examine: 1. The behaviour of the transmembrane region of MuSK in bilayers vs. micelles 2. The assembly of the full-length MuSK receptor 3. The effect of selected mutations in MuSK, and possibly the interaction of MuSK with other proteins in its signalling pathway


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Functional dissection of a pan-neuroblast transcriptional network in Drosophila.
Funder: Wellcome Trust

Abstract: The aim of the project is to identify key genome ]wide effectors of Deadpan, aHes family transcription factor that regulates neural stem cell behaviour in Drosophila. Leo Otsuki will use genome-wide chromatin profiling to identify targets of Deadpan throughout the genome, and transcriptome analysis to determine if these genes are activated or repressed.He will screen the target genes for neuroblast-specific phenotypes using targeted RNAi knock down. Phenotypes will be validated by comparison with classical genetic mutations and those genes with the most interesting phenotypes will be selected for an in depth characterisation of their molecular function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Role of mitochondrial protein O-GlcNAcylation in neurons.
Funder: Wellcome Trust

Abstract: Modification of proteins with O-linked N-Acetylglucosamine modification (O-GlcNAcylation) is a reversible post-translational modification that is driven by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAc hexosaminidase (OGA). The former exists in three splicing isoforms. One of those, mOGT, contains a mitochondrial localisation sequence, but the biological role of protein O-GlcNAcylation in mitochondria is not understood. More recently, mitochondrial dysfunction has been implicated in the pathogenesis of neurodegenerative disorders, in particular Parkinson's and Alzheimer's diseases. In my PhD project I aim to elucidate the role of O-GlcNAc in mitochondria, in particular its role in neuronal function and neurodegeneration. This proposed study will probe the links between energy metabolism in mitochondria, metabolic disorders and neuropathologies. Specifically, the main objectives of my PhD project are: 1. Study the function and localisation of the mitochondrial OGT isoform, 2. Determine the mitochondrial O-GlcNAc proteome, 3. Provide mechanistic biology of regulation of of mitochondrial protein function by O-GlcNAc,4. Probe the link between O-GlcNAc and the development of neurodegeneration.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Studies on alpha-synuclein degradation and its relevance to Lewy bosy disease
Funder: Wellcome Trust

Abstract: In the UK, every hour a new patient is diagnosed with Parkinsons disease (PD), a progressive movement disorder without cure and with treatment-induced complications. In brain cells there is accumulation of a small protein called alpha-synuclein and genetics and animal studies have shown that the content of this protein in brain is critical for the onset of PD. To design targeted therapies which prevent alpha-synuclein accumulation we need to understand what controls alpha-synuclein levels in cel ls. I have recently found specific enzymes that target alpha-synuclein for destruction and I propose to use cell models and brain tissue from PD and control cases to study the role of this degradation pathways in PD and whether it can be up-regulated to afford protection against toxicity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Clinical PhD Programme at the University of Edinburgh "Designing and manipulating neurons cultured on parylene-C/SiO2: how does the functionality of micro-engineered poly-neuronal networks change in response to
Funder: Wellcome Trust

Abstract: Enhanced understanding of neuronal networks is fundamental to comprehending how seemingly autonomous neurons and glia perform in unison to direct behaviour. Current understanding of this aspect of CNS function is in its infancy, profoundly limiting our ability to treat neurological diseases such as epilepsy and Alzheimer's disease. This project will involve development of a novel cell-patterning technology (using deposition and photolithographic patterning of parylene-C on SiO2) to guide adhesion of neuronal cell types along predetermined pathways. The system's fidelity will be iteratively enhanced by learning about the underlying parylene:neuron interaction. In parallel, techniques enabling stimulation and recording from patterned neurons will be developed and validated. Specifically, optical stimulation techniques will be enrolled as tools (optogenetic and photoconductive). Electrical activity within engineered networks will be assessed using patch-clamp techniques, voltage-sensitive dyes, and integrated carbon nanotube electrodes. As such, our aim is to construct and interrogate functional neuronal networks on silicon with the following key goals: (1) Optimize accurate and reliable patterning of neuronal cell types on parylene/SiO2 (2) Establish that pattered cells continue to behave in a viable and physiological manner (3) Validate optical techniques for stimulation and recording from patterned cells (4) Consolidate steps 1-to-3 to engineer and manipulate simple bi- and tri-neuronal reflexes (5) Iteratively enhance fidelity; testing more complex networks and subsequently integrating organotypic cultures and microfluidics


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Hyperpolarisation using SABRE as a new tool for imaging.
Funder: Wellcome Trust

Abstract: Although the crucial non-invasive technique of MRI is used in over 1.5million procedures per year in the NHS, nearly half of these require the use of an injected, heavy metal, contrast agent to provide diagnostic information about inflammation. Unfortunately, the use of these agents brings with it a risk of toxic side effects and the actual response is only an indirect measure of the disease state in a tissue. Whilst MRI has the potential to be able to directly probe a wide range of biologica lly important compounds it cannot be routinely exploited to detect the low-concentrations associated with most of these chemicals because of it very low sensitivity. In current clinical scanners, only 0.005% of the potential MRI signal can be harnessed. Thus there is considerable scope for improving the diagnostic usefulness of MRI and yet being able to carry out the procedures on smaller, less specialised, lower-cost machines. The key goal of this programme is to secure a new technology to b ring about, ultimately, a 200,000 fold improvement in the sensitivity of clinical scanners. To demonstrate the usefulness of such a radical change in sensitivity the method will be applied to the extremely common problem of neuroinflammatory disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Physiological and pathological regulation of calcium-channel and other ion-channel functions by alpha2delta-subunits and their interacting proteins.
Funder: Wellcome Trust

Abstract: Voltage-gated calcium ion (Ca2+) channels are essential for communication across synapses between brain cells. They do this by controlling the entry of Ca2+ which regulates presynaptic release of the neurotransmitters that provide the communicating signals. The regulation of Ca2+ channel levels and insertion into the plasma membrane at the correct location are key processes in the control of presynaptic function. The alpha2delta proteins are subunits of voltage-gated Ca2+ channels that modulat e the properties of the channels. These auxiliary subunits increase Ca2+ channel insertion into the plasma membrane thus enhancing their function, but the mechanism of this process is unknown. The alpha2delta proteins are also the therapeutic targets of gabapentin, an antiepileptic drug, which is also used in the alleviation of neuropathic pain resulting from nerve damage. We have made very important contributions to the understanding of the properties and mechanism of action of the alpha2delt a proteins, and my goal is now to develop a comprehensive picture of alpha2delta subunit function, in terms both of calcium channels, and of its interaction with other proteins mediating calcium channel-independent functions in neurons


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Integrated multimodal brain imaging for neuroscience research and clinical practice.
Funder: Wellcome Trust

Abstract: Scientists and doctors can take many different types of images of the brain in order to study different aspects of the brain and its function. Structural MRI gives detailed, still images of the structures in the brain and can distinguish grey matter (the parts that process information) from white matter (the wiring that carries information between gray matter areas). Functional MRI and MEG measure which grey matter areas are active during a specific physical or mental task. Diffusion and resting -state MRI tell us how these gray matter areas are connected, as well as the location of information pathways. Although these images are very complementary, they are currently analyzed separately. A major challenge is to bring all these pieces of information together. This would enable us to tell, for example, in an Alzheimer's patient, how loss of grey matter relates to changes in the white matter wiring and to memory loss, in order to understand how the disease affects the brain, and identi fy the disease as early as possible. We aim to combine different imaging data together, to use available brain scanning methods to their full potential, and therefore help with disease diagnosis and guide the search for effective treatments.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Dendritic integration in the ventromedial nucleus of the hypothalamus.
Funder: Wellcome Trust

Abstract: The brain processes and responds to information from the outside world using neurons - cells that are wired up in a network like a computer. Neurons receive input on so-called dendrites - long extensions resembling tree branches - which have properties that allow them to transform information before it reaches the output end of the neuron. Understanding how the brain processes information requires knowing how individual neurons and dendrites integrate input. In the primitive brain areas that con trol instinctive behaviours, neurons have a small number of dendrites, which simplifies the goal of fully understanding how each neuron processes information. In this project I aim to find out how the dendrites of primitive neurons integrate input. I will work on a mouse brain circuit involved in aggression, and begin by examining the integration properties of dendrites. I will then investigate how specific brain areas are connected to these dendrites and study how they processes information a rriving from each area. In the last stage I will use genetic methods to study the specific neurons that control aggression. The results of these experiments will provide insight specifically into how aggression neurons integrate input, and more generally into how primitive brain areas process information.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Infantile parkinsonism due to dopamine transporter deficiency: functional characterisation and therapeutic approaches .
Funder: Wellcome Trust

Abstract: Infantile Parkinsonism is a severe disorder which begins in infancy and progressively worsens during childhood. It has many features in common with adult Parkinson's disease, including abnormal movements, stiffness and unsteadiness. The condition is incurable and affected children usually die in their early teens. During my PhD, I identified the faulty gene that causes this condition. In this project, I plan to further understand how faults in this gene cause infantile parkinsonism, by modelli ng the disease in appropriate cells ( dopaminergic neurons ). As a doctor who specialises in looking after these patients, it is clear that all treatments are ineffective in improving movement difficulties and preventing death. A new treatment approach is needed and I plan to investigate gene therapy techniques for this condition. Already there has been considerable success using gene therapy for a number of medical conditions. In my experiments I will deliver a normal copy of the faulty gene to a mouse model with this disease. The mice will be monitored for improvement following gene transfer. Successful gene therapy in mice will allow us to proceed to patient clinical trials. The experimental techniques learnt during this fellowship will also be applicable to other incurable childhood brain disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The temporal dynamics of visual selection: convergence from lesion-symptom mapping and the intact functioning brain.
Funder: Wellcome Trust

Abstract: Visual attention refers to our ability to prioritize important information and disregard irrelevant information. Many studies have been devoted to localise the brain areas involved in generating attention, leading to the view that visual attention is the result of a network of brain areas. However, little is known about the communication between the brain areas in the network, and the time course of their brain activity. The goal of my research is to understand the timing of brain activity durin g tasks requiring visual attention, and to advance the knowledge about changes in temporal dynamics following brain lesions. I will begin my Fellowship by understanding the brain mechanisms underlying visual attention, taking advantage of the high spatial resolution of functional magnetic resonance imaging and the high temporal resolution of magnetoencephalography. Next, I will temporarily disrupt the neural activity in specific brain regions, to examine at which moments in time the activity in these regions is important for visual attention. Finally, I will investigate in stroke patients the effects of acquired brain lesions on the temporal dynamics of visual attention, and the value of these temporal dynamics in predicting behavioural recovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: MIND - Modelling and imaging using non-gaussian diffusion.
Funder: Wellcome Trust

Abstract: MRI provides non-invasive 'pictures' of the brain and since its introduction, the physicist has been stimulated with the challenge of proposing new 'cameras' returning more and more sophisticated contrasts. Amongst these efforts, the ability to quantify locally the diffusivity of water molecules has provided the amazing possibility of 'taking a picture within each pixel'. Each pixel of a diffusion-weighted image contains a snapshot of the water molecules path, frozen at a given instant. In the c onventional DT-MRI approach, which is now commonplace in hospital, the experimental design is tuned to focus on the diffusivity of water in the extra-cellular and extra-axonal space, that carries the fingerprint of the local structure. Other dynamics, e.g. those associated to water molecules trapped inside the axons, do not contribute to the current picture. My proposal aims to explore all those dynamics neglected in the DT-MRI approach, in order to create new diffusion-based approaches to take 'pictures' with a range of different focuses. In addition, I will link the output of these methods to the brain tissue microstructure and propose an optimised protocol ready for clinical use. My final goal will be to make new information available for neuroscientists and clinicians alike.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Pre-synaptic neurological channelopathies.
Funder: Wellcome Trust

Abstract: Electrically charged ions such as sodium, calcium and potassium flow through specialised channels through the membranes of neurons, and the precise way they are gated is fundamental to normal brain activity and nerve excitability. This project will focus on a group of epilepsies and movement disorders termed channelopathies, so called as they are caused by inherited abnormalities in the way these ion channels operate. The disturbance of brain excitability in channelopathies remains unclear, but it appears that signalling through synapses, which are communication points between neurons, plays a central role because most of the mutated channels occur in these structures. So far research into the synaptic mechanisms has been hampered by limitations in the methods to study how electrical impulses are generated in synapses. I will be using a novel technique called scanning ion conductance microscopy (SICM) which will give unprecedented information about how synapses work at the most ele mental level. Understanding the dysregulation of synaptic signalling in channelopathies may point towards new avenues for therapy. In the wider spectrum, neurological channelopathies may identify the signalling pathways and circuits involved in common diseases like epilepsy and migraine that accounts for a large burden to the public and health resources.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the temporal and spatial dynamics of somatic transposition events in fruitflies and mice.
Funder: Wellcome Trust

Abstract: Ever since the remarkable experiments of early neuro-anatomists such as Santiago Ramon y Cajal we have appreciated the unmatched diversity in shape and structure of neurons within an organism1. In addition, current efforts to study the brain structures of large cohorts of humans reveal a similar degree of diversity between the brains of individuals2. Transposons, mobile genetic elements, have been shown to actively "jump" within the neural genomes, makingthem diverse mosaics3-6. Somatic transposition events might be the source thatintroduces individuality and diversity into a pool of otherwise genetically identical cells7. The goal of this project is to further our understanding of somatic transposition in neurons of fruitflies and mice, and to unravel novel molecular principles that underlie behavioural diversity. I propose to first develop a novel method to detect somatic insertion site variants (SISV) between two different tissue samples (see appendix 1), second, to establish tools to study the temporal and spatial dynamics of SISVs in fruitflies and mice, and third to relate SISV patterns with distinct patterns in behaviour. The results will help identify key SISVs that might be responsible for the anatomical and behavioural diversity in insects and vertebrates.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL
Title: Development, plasticity, energy supply and pathology of myelinated axons
Funder: Wellcome Trust

Abstract: The white matter of the CNS allows rapid transmission of information at low energetic cost. Despite its importance for brain function, the development, plasticity, energetics and pathology of the white matter are poorly understood. We will investigate, in vitro in brain slices and in vivo in zebrafish: (1) how electrical activity in oligodendrocyte precursors regulates myelination; (2) mechanisms underlying the tuning of conduction speed of myelinated axons; (3) mechanisms localising mitochondria in oligodendrocyte lineage cells; (4) how microglia survey the white matter in health and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Single neuron connectomics and functional mapping in visual cortex
Funder: Wellcome Trust

Abstract: Understanding how cortical connectivity organizes cortical computations is a long-standing challenge in neuroscience. I propose to investigate the relationbetween circuit connectivity and circuit function in the primary visual cortex(V1). To this end, I will deploy a novel monosynaptic retrograde tracing strategy based on rabies virus to identify and functionally characterize the network of neurons that connect to a given postsynaptic V1 neuron. This network constitutes the neuron's "presynaptic connectome": it determines the neuron's functional responses and coding strategy. To measure and manipulate neuronal activity with single cell resolution, I will combine this approach with two-photon imaging of genetically encoded calcium indicators, with optogenetics, and with single-cell patch clamp recordings. My first aim is to establish how cortical connectivity governs sensory representation by population of neurons. To what extent do synaptic connections in V1 determine which neurons will fire together in response to sensory input? Recurrent connectivity in V1 microcircuits may constrain population responses to stereotyped patterns of activation (sensory representations) coding for specific features in the visual scene. My second aim is to elucidate how receptive field properties of V1 neurons originate from the interplay between neuronal microcircuits, and within them, from synaptic interactions among different cell classes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Probing the inhibitory neurosteroid binding site on the GABAA receptor
Funder: Wellcome Trust

Abstract: Neurosteroids are naturally occurring potent modulators of type A GABA receptors in the brain. Although there are many neurosteroid metabolites, these can be characterised into two distinct classes - those that potentiate GABAA receptor function and those that inhibit. Previously we deduced where potentiating neurosteroids bind on the GABAA receptor, but the inhibitory neurosteroids remain unaffected if this site is disrupted. This concurs with the belief that such inhibitory neurosteroids bind to another discrete site onthe GABAA receptor. Its discovery will allow the function of the inhibitory neurosteroids to be explored in the brain. We will select a GABA receptor thatlacks sensitivity to inhibitory neurosteroids and use this structure in combination with GABAA receptor subunits to make chimeric and eventually pointmutated receptors to identify the inhibitory neurosteroid binding site. Once the site is found, we will disrupt its function and then observe the consequences for inhibitory synaptic and tonic inhibition. Overall, this studywill use structural, electrophysiological, imaging, pharmacological and molecular approaches with GABA receptors. This study will bring much need clarity to the role and importance of inhibitory neurosteroids in the brain.


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