NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of the nervous system
Funder: The Francis Crick Institute

Abstract: The main focus of our work is to understand the cellular and molecular mechanisms that govern the development, organisation and maintenance of the nervous system of animals. Our goal is to understand how diverse subtypes of neurons and glia are generated in the embryo and how they establish specific connections to form functional neural circuits. We are also interested in understanding how the assembly and functional organisation of the nervous system is influenced by non-neural tissues (such as the immune system) and environmental factors (such as the microbiota). To achieve these goals we focus on two distinct types of neural circuits: those that are intrinsic to the gut wall and regulate gastrointestinal activity (enteric nervous system) and those that provide inhibition in the cerebral cortex (inhibitory cortical interneurons). The enteric nervous system is an exceedingly complex neural network with many types of neurons and glial cells but no obvious topographic organisation. Neurons with different molecular profiles and physiological properties are scattered throughout the network of enteric ganglia and connect in an unpredictable manner. Despite their seemingly chaotic organisation, intestinal neural circuits control highly stereotypic activities of the gastrointestinal tract (such as peristalsis) and mediate stereotypic responses of the gut wall to local and systemic signals. Using various experimental models we explore how meaningful functional output (gut physiology) emerges from an apparently disordered neural network (ENS) and how the dynamic microenvironment of the gut influences the activity of intestinal neuroglial networks. Cognitive activity and complex behaviour depend on the assembly of functional neural circuits in the cerebral cortex. Cortical interneurons constitute a highly diverse population of locally projecting neurons which provide essential inhibition to the excitatory neurons of the cerebral cortex. Deficits of this neuronal subpopulation are associated with common neurodevelopmental and behavioural disorders. Our goal is to identify and characterise the molecular genetic cascades that control the migration, fate restriction and differentiation of cortical interneuron progenitors. We also aim at understanding the molecular mechanisms that regulate the functional maturation of interneurons in concert with and in response to emerging neural activity. To address these questions we employ a wide spectrum of experimental approaches ranging from cell culture experiments to physiological and behavioural studies. Molecular, cellular and imaging approaches are employed in conjunction with genetic manipulations to understand how multiple developmental signals converge to control gene expression and neuronal and glial cell differentiation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Function and connectivity of the cerebral cortex
Funder: The Francis Crick Institute

Abstract: In order to understand how the brain works, we first need hypotheses about what it is exactly doing. Recently, there has been a shift away from considering the brain as a feed-forward processing device towards a predictive hierarchical generative framework. According to these theories, brains, and especially the cerebral cortex, constantly attempt to match bottom-up sensory input with top-down, internally generated predictions. We are interested in the functional and structural underpinnings of how internally generated and external, sensory information interact in cortex to guide behaviour. We specifically study the visual and vestibular systems and their interaction with the best-studied internal representation: that of space. To dissect and interrogate inherently complex cortical networks, we use a multi-scale approach and take advantage of recent technical developments in genetic tools in mice. With the use of cre-driver lines and virally mediated transsynaptic tracing we can map the synaptic partners of single cells and functionally defined neuronal populations to elucidate the underlying rules of such connectivity. Using genetically encoded biosensors and electrophysiological approaches both in vivo and in vitro we can directly assess the physiological relevance of single cell and network function. We also utilise optogenetic activation or silencing of neurons to test the causal relationship between single cell or network activity and function. We aim to provide detailed and quantitative description of single neuron and microcircuit function, not only to generate new knowledge, but also to build new models and hypotheses about the hows and whys of the brain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Regulation of boundary formation and neurogenesis
Funder: The Francis Crick Institute

Abstract: The complex organisation of the adult body arises by the generation of distinct tissues, many of which become subdivided into domains which each have a specific regional identity. For precisely organised patterns to be generated and maintained, it is important that each tissue, or region within it, is not intermingled with its neighbours. This is reflected by the formation of a sharp boundary between the adjacent cell populations that have distinct identity. In some tissues, sharp boundaries also act to localise specialised signaling cells which regulate the local pattern of cell differentiation. Sharp boundaries form despite the extensive intermingling of cells during growth and morphogenesis. The inhibition of such mixing across boundaries has a crucial role in stabilising many tissues during development, and also in the adult, and when disrupted can contribute to disease, such as the invasive behaviour of tumour cells. We study molecular mechanisms underlying boundary formation during hindbrain development, and how these boundaries organise neurogenesis. Our studies revealed that signaling between Eph receptors and ephrins expressed in complementary domains underlies the segregation of cells and formation of sharp boundaries. We are using two approaches to analyse the mechanisms by which Eph-ephrin signaling acts: (1) gene editing, generation of transgenic reporter lines and in vivo imaging in zebrafish; (2) cell culture assays of segregation and boundary formation, in combination with computer simulations based on quantitative analysis of cell behaviour. These studies reveal that Eph-ephrin signaling triggers cell repulsion that can drive cell segregation and border sharpening. The generation of the correct number of neurons and glia requires that the differentiation of neural progenitor cells is regulated in time and space. In the zebrafish hindbrain, neurogenesis becomes confined to neurogenic zones that flank hindbrain boundaries. Our studies show that this patterning is organised by chemorepulsive signaling from hindbrain boundaries which positions fgf20-expressing neurons at segment centres. The fgf20-expressing neurons in turn locally inhibit neurogenesis. We are studying the mechanisms by which fgf20 signaling regulates neurogenesis by identification and functional analyses of target genes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Biological clocks and sleep
Funder: The Francis Crick Institute

Abstract: Objectives: This research focuses on the molecular basis of 24 hour (“circadian”) biological clocks and their interface with sleep. Both of these processes are important for health and wellbeing, and disrupted significantly in the lives of many because of our modern way of living. Plan and methodology: Our work encompasses the use of a number of models to understand clocks and sleep. Since the molecular clockwork is present in single cells, we often use cell based assays to interrogate clock function. In tandem, we use transgenic mouse models that are either “clock mutants” (e.g. have no 24 hour rhythms) or reporter mice (e.g. bioluminescenct and fluorescenct proteins expressed in tissues in the mouse). The allow us to address mechanistic questions, including the role of redox proteins (e.g. peroxiredoxins) and redox state (e.g. using fluorescenct reporters), in a variety of experimental paradigms. We also use synthetic biology approaches to generate novel types of reporter proteins and utilise multi-omics approaches (ChIP-seq, RNA-seq, proteomics, metabolomics) to develop systems biology models of clock and sleep networks. In addition, we examine the neural connectivity of clock and sleep relevant brain regions by using specialised microscopy systems and fluorescent protein readouts of various activities in the brain (e.g. redox state, metabolite concentration). Translational issues: In order to probe the clockwork and sleep pathways, we develop novel chemical tools to do this. These target various pathways, including redox proteins, but also emerging targets as our research progresses. Some of these chemical probes may eventually form the basis of new therapeutic agents. Plans for medical exploitation: If novel chemical probes that can alter the clockwork (e.g. reset the clock) or sleep (e.g. induce sleep) look promising, we will aim to exploit these by further developing them using in-house Translational expertise within the Crick, but also by partnering with industry to maximise the chances of success. Such therapeutics could be useful for treating a variety of conditions including shift work disorder and many types of sleep disorder, including insomnia, which is highly prevalent.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Evolution of neural circuits
Funder: The Francis Crick Institute

Abstract: Sensory systems encode the world around us to produce context-dependent appropriate behaviours. However, we know little about the way new sensory evoked behaviours arise as neural circuits are re-shaped during evolution. Tackling this question requires a deep understanding of the circuits underlying specific behaviours and integration of this knowledge with tools from other fields, including evolutionary and developmental biology. Recent technological advancements on neural circuit interrogation and genome editing have put progress on this fundamental biological question within reach. The olfactory system of the larval stage of the fly Drosophila melanogaster and related species is an ideal model for investigating these questions because (i) D. melanogaster has pioneered both the fields of population genetics and neurogenetics and (ii) its olfactory system is one of the best-characterised neural circuits. In the lab, we address the question of how olfactory circuits evolve by studying different Drosophila species with divergent odour-guided behaviours. We employ a multidisciplinary approach, combining a variety of methodologies including field-work, bioinformatics, electrophysiology, imaging, behavioural analysis, electron microscopic circuit tracing and genetic manipulations. Specifically we address the following questions: 1- Which olfactory pathways are targeted during ecological specialisation? – Combining high-throughput behavioural assays, optogenetics and calcium imaging in the larva of different species we determine which olfactory pathways have switched valences or sensitivity. 2- How have central neural circuits diverged? – We address this question at unprecedented resolution through whole-brain calcium imaging and serial electron microscopy reconstruction. 3- What are the molecular and genetic bases of neural circuits rewiring during evolution? – Using transcriptomic profiling we identify differentially expressed genes in conserved and divergent circuits across species, and functionally probe selected candidates to establish causality 4- How do evolutionary forces shape olfactory circuits? – We investigate this question using field studies and population genetics. In addition, we use these tools and our knowledge in Drosophila to guide the study of the olfactory system in tsetse flies, carriers of sleeping sickness. By using a comparative approach, together with our collaborators in Africa, we hope to understand how these disease vectors find their hosts, which will eventually inform effective strategies to control them, thus stopping the spread of the disease they transmit. Together, our work aims at providing fundamental insights into how evolution sculpts nervous systems to give rise to novel behaviours, including those of species that promote the spread of diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Molecular mechanisms of CRPS pain.
Funder: Versus Arthritis

Abstract: Chronic pain affects up to 20% of the population in Europe at any given time, with different forms of musculoskeletal pain conditions representing at least half of cases. Despite the extraordinary number of subjects affected by chronic pain, it remains an area of significant unmet need since the current therapies are either associated with low efficacy or unacceptable side effects in major subsets of patients. An improved understanding of the aetiology of the underlying pathological conditions and of the cellular and molecular mechanisms responsible for pain is urgently required to improve the quality of life of patients and to facilitate identification of novel therapeutic opportunities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating the role of exercise and sleep in the management of chronic pain
Funder: Versus Arthritis

Abstract: This fellowship aims to develop a novel approach to the management of chronic pain, a debilitating condition that affects around 40% of the UK population. For the first time, it will formally investigate and quantify the interlinkages between chronic pain, exercise and sleep. Insights gained from this investigation will then be used to develop and pilot a new, combined package of therapy that simultaneously targets exercise and sleep behaviours in people living with chronic pain. My programme of research will:


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.7 PHYSICAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.7 PHYSICAL
Health categories: NEUROLOGICAL
Title: UK Japan Pain, Action and Movement Network
Funder: Versus Arthritis

Abstract: The proposed project creates a collaborative research network between UK and Japanese neuroscientists (from Cambridge, Oxford and UCL, and from Osaka University, ATR Laboratories, and the National Institute for Information and Communications Technology). The network develops new and existing collaborations to form a major body of technology-orientated neuroscience research, with a focus on understanding the relationship between movement and pain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Controlling Abnormal Network Dynamics with Optogenetics (CANDO)
Funder: Wellcome Trust

Abstract: Within the brain nerve cells connect together to generate rhythmic activity visible as brain waves on an EEG. In many neurological diseases this network is disrupted, producing abnormal patterns of activity. In epilepsy, abnormal activity can be localised to a small ‘focus’, but this can spread across the whole brain as a seizure. Epilepsy affects 600,000 people in the UK alone and uncontrolled seizures have a devastating effect on patients’ quality of life. Most cases respond to drugs, but if these are ineffective it may be necessary to surgically remove the ‘focus’. However, surgery is not suitable in all patients and can damage cognitive function. This project, led by Dr Andrew Jackson and Professor Anthony O’Neill from Newcastle University, proposes an alternative based on a small implant that continuously records the abnormal activity and provides precisely timed stimulation to prevent it ever developing into a seizure. This requires that some cells within the focus are genetically altered using a safe virus to become sensitive to light. The implant will monitor their activity and provide pulses of light from tiny LEDs to prevent the build of abnormal activity.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL
Title: Image-guided neurosurgical treatment of epilepsy
Funder: Wellcome Trust

Abstract: One third of individuals developing epilepsy are uncontrolled with medication. If epilepsy arises from one part of the brain, surgical removal of this area can be curative. This needs to be balanced by the risk of causing new deficits such as paralysis or impaired speech. Improved diagnostic methods, and surgical precision, will improve the benefit/risk ratio of epilepsy surgery, and increase treatment availability. At University College London, teams led by Professor John Duncan and Professor Sebastien Ourselin have developed software to visualise the whole range of 3D brain imaging, including normal architecture, abnormalities of structure and function, arteries, veins, critical brain areas and nerve pathways, and the skull. This increases the safety and precision of implantation of the electrodes necessary to pinpoint the brain tissue that needs to be removed to cure the epilepsy. This project aims to implement automated planning of electrode trajectories and robotic systems for placing the electrodes into the brain. It will also establish methods for automated 3D planning of neurosurgical resections, so that surgery is optimal and quicker. Consequently, curative neurosurgery will be available more quickly to more individuals. The surgical advances pioneered here will be applicable in future to other procedures, such as taking biopsies and tumour surgery.Note this is a HICF award but funded solely by the Trust as a Translation Fund project


Research activity codes: 5.4 SURGERY
Health categories: NEUROLOGICAL
Title: Capturing the neuronal ensembles underlying sleep and sedation.
Funder: Wellcome Trust

Abstract: Our major overarching question is: what mechanisms and neural circuitry make sleep inescapable when we are tired and deprived of sleep? In fact, the drive to "recovery sleep" after prolonged sleep deprivation seems so strong, that it is akin to taking a sedative drug. So, our second major question is: do sedative drugs cause loss of consciousness by activating the same mechanisms and circuitry responsible for this deep recovery sleep?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Bioengineered substrates for human pluripotent stem cell culture
Funder: Wellcome Trust

Abstract: Human pluripotent stem cells (PSCs) have enormous potential to treat various degenerative diseases and the first UK clinical trial “The London Project to Cure Blindness” involving these cells is now underway. This trial is focussing on age-related macular degeneration (ARMD) and involves transplanting PSC-derived retinal pigment epithelial (RPE) cells into the eye. There is now much optimism that similar PSC-based therapies could be used to treat other diseases, such as Parkinson’s Disease (PD). However, a current impedance to the translation of PSC-based therapeutics for such diseases is that it is difficult and very costly to produce sufficient numbers of cells under the necessary GMP and xeno-free culture conditions. Treating ARMD is not so problematic because only 50 thousand PSC-derived RPE cells need to be transplanted into the eye. However, to treat a patient with PD, 10 million PSC-derived dopaminergic neurons would be needed. Therefore, there is a pressing need for improved culture conditions to facilitate the scale-up of PSCs for clinical use. To address this need, we have developed a molecularly engineered protein-based PSC culture substrate that can be easily and cheaply produced. The proteins that constitute the building-blocks of this engineered substrate are of human origin and are produced in high yield via recombinant overexpression in bacteria. Thus, there is high scale-up potential. Our current data show that this substrate can support the self-renewal of human PSCs. We now need to develop a more thorough data package before moving on to scale-up activities. Goals: (i) assess whether the substrate can support the self-renewal of several different PSC lines in xeno-free medium; (ii) assess whether PSCs maintain a normal phenotype and can be differentiated to specific lineages; (iii) investigate if PSCs maintain a normal karyotype; (iv) investigate if the substrate is immunogenic The potential healthcare impact of our PSC culture substrate is that it will enable the affordable scale-up of PSCs under GMP and xeno-free conditions so that therapeutic cell types such as PSC-derived dopaminergic neurons can be generated in sufficient quantities for clinical applications.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Printable Graphene Metal Organic Frameworks (GMOF) Composite Sensor platform
Funder: Welsh Government Office for Science

Abstract: This project has several highly novel aspects: The core novelty is an electrocatalytic electrochemical (ECE) sensor platform that uses an interdigitated array consisting of an integrated graphene–MOF composite as a working electrode. MOFs are crystalline highly porous materials whose structures are defined by metal ions or clusters which act as lattice nodes linked to rigid multimodal organic spacers – in this case graphene. The beauty of MOFs complexes is that they contain functional group sites e.g. COOH groups that can be used to bind different bioreceptor molecules. This will be the world’s first printed “ECE-sensor strip”. This sensor platform has diverse applications that will be demonstrated in proof of concept health, food and environmental sensors: Health: A Traumatic Brain Injury (TBI) biosensor that detects µ-RNA biomarkers, related to TBI, is a novel application of this work. Currently no peripheral diagnostics exist for TBI and there remains an urgent need for early and sensitive detection of brain injury following head trauma. TBI sensors would represent a major clinical breakthrough, capable of distinguishing between severe and mild TBI. Food and Environment: MOFs can selectively and efficiently trap carbon dioxide in the food packaging. MOFs can adsorb nitric, nitrous acids which can damage environment.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL