NIHRDataInsights/HRCSData huggingface dataset:
Title: Bridging the gap: biophysical models of human frontotemporal lobar degeneration
Funder: Wellcome Trust

Abstract: To treat and prevent dementia in patients, it is essential to understand how microscopic changes in the human brain cause complex cognitive and behavioural disorders. My program addresses this critical gap in translational research, to facilitate clinical application of basic science discoveries. I have three goals, set in the context of frontotemproal dementia and progressive supranuclear palsy. First, I will develop quantitative biophysical models of human brain function that capture key cellular and pharmacological pathologies in vivo, with regional, laminar and synaptic specificity. These models of degenerating neuronal circuits are informed by individual measures of synaptic density (PET imaging with a SV2a ligand), GABA and glutamate (ultrahigh-field MR spectroscopy). They are optimised in vivo by inversion to magnetoencephalography, and tested post-mortem against neuropathology. This synergy of multi-modal imaging, together with BaYESian model comparison of Dynamic Casual Models, means one can drill down to the best mechanistic model of the human cognitive disorder. Second, I will show how harmful effects of dementia like apathy can be explained in terms of changes in synaptic density and loss of precision in hierarchical brain networks. Third, I will I demonstrate the readiness of my approach for experimental medicine, through longitudinal designs and pharmacological interventions.

Lay abstract: New treatments for dementia are urgently required, but they are held up by the knowledge gap about how damage to brain cells and brain networks leads to changes in thinking and behaviour in humans. Laboratory studies of animals give great detail, but cannot fully replicate the dementia affecting patients. My program bridges this gap. I build advanced computer models of the human brain based on knowledge of the brain's "wiring" and measurement of disease severity in individual patients with PET scanning. I use a type of brain scanner called magnetoencephalography to improve the computer models so that they match the reality of brain function. These "best" models are used to predict the problems caused by dementia, like apathy. I test this approach to the limit, using ultrahigh powered MRI and drug-treatments. This award focuses on frontotemporal dementia and progressive supranuclear palsy and develops methods to accelerate new dementia therapies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Using zebrafish to study myelination and neural circuit function.
Funder: Wellcome Trust

Abstract: There is now compelling evidence that dynamic regulation of myelination represents a form of functional plasticity in the central nervous system. For example, learning and sensory experience can alter myelin in humans and animal models, and neuronal activity can regulate specific aspects of myelination. Because myelin is the principal regulator of conduction speed, and thus the timing of information arrival at pre-synaptic terminals, its regulation is well-placed to fine-tune synaptic communication and circuit function. However, we don’t know how myelin is formed or remodeled along axons within neural circuits in vivo, nor how dynamic regulation of myelination affects conduction, synaptic communication, or the activity of neurons underpinning circuit function. Here, using zebrafish, I propose to combine live-imaging and electrophysiology to determine how the formation and remodeling of myelin affects conduction within well-defined circuits. By combining optogenetics, functional imaging and gene-targetting, we will identify the mechanisms by which neuronal activity dynamically regulates myelination. Finally, to assess how (dys)regulation of myelination affects circuit function, we will assess synaptic communication by electrophysiology, and the activity of neuronal populations by large-scale functional imaging. This work will provide insights into a poorly understood, but fundamental, aspect of nervous system function, relevant to health and disease.

Lay abstract: About half the volume of our brain is white matter, which contains the electrical cables (axons) that transmit information. In recent years, it has emerged that learning and sensory experiences can alter our white matter, suggesting that such alteration may play an active role in modulating brain function. The "white" in white matter is given by structures called myelin sheaths, which surround our axons. Myelin controls the speed of information transmission along axons. Therefore, it is thought that alterations to myelin could, in principle, fine-tune the speed of information transmission along axons, and thus brain function. Here we will use zebrafish to definitively test this idea: we can directly see myelin in the zebrafish brain and test how its alteration affects many aspects of brain function over time. This work will help us better understand some key aspects of our brain function, relevant to both healthy and diseased brains.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Lineage reprogramming of glia into subtype-specific cortical neurons
Funder: Wellcome Trust

Abstract: This proposal aims at delineating a development-inspired molecular logic for reprogramming brain-resident non-neuronal cells such as macroglia and brain pericytes into cortical interneurons. Using single-cell RNA-sequencing we will examine the gene expression programmes induced in macroglia and pericytes at distinct time points along the reprogramming trajectory following expression of transcription factors, epigenetic regulators, and microRNAs known to regulate interneuron specification during cortical development. Induced gene expression programmes will be compared to those of endogenous interneurons. Factor combinations that allow for conversion into neurons that closely resemble endogenous interneurons will be used for lineage reprogramming of glia in vivo. To study the in vivo reprogramming potential of human cells we will derive macroglia and pericytes from genome-edited human induced pluripotent stem cells, and after transplantation of these cells into the mouse cerebral cortex, we will induce lineage reprogramming at distinct stages of maturation. In vivo induced interneurons will be characterized for their functional properties and connectivity by electrophysiology and rabies virus tracing. We expect to obtain insights into the molecular logic underlying interneuron programmes, and to identify bottlenecks to lineage reprogramming dictated by the cells of origin, their developmental stage or local environment, as well as species differences in reprogramming competence.

Lay abstract: The cerebral cortex is the seat of higher cognitive functions but is often severely affected by disease or trauma. This proposal aims at assessing the potential for a novel strategy of cell-based therapy, namely cell fate conversion of brain cells other than nerve cells into induced neurons. The underlying idea is that the brain harbors many so-called glial cells which have been shown by us and others to be amenable to a cell fate conversion into induced neurons in vitro. This can be achieved by forced expression of proteins that regulate cell fate decisions during development. Recent work also suggests that this might be principally possible in vivo and the present proposal wants to rigorously scrutinize this possibility. Here we aim specifically at converting glial cells into local inhibitory neurons (interneurons) of the cerebral cortex as these cells are often afflicted in neurological and neuropsychiatric disorders. Induced neurons will be closely compared to endogeous neurons found in the brain. While many of the ground-breaking experiments will be conducted with mouse cells, we will expand the scope of our study by testing the possibility of converting human glia into induced neurons as a prerequisite for future translation into cell-based therapies.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Decoding the temporal structure of cortical interneuron lineages in mouse and human
Funder: Wellcome Trust

Abstract: The goal of this proposal is to identify the cellular and molecular mechanisms underlying the generation of interneuron diversity in the cerebral cortex. To this end, we will use an unprecedented combination of tools to link time and place of neurogenesis with interneuron identity in mice and humans. We will first use lineage tracing approaches based on genetic intersectional methods to determine whether a temporal sequence of neurogenesis exists for specific interneuron progenitor cells. We will also use live imaging to identify progenitor cell dynamics underlying this process. We will subsequently employ single cell transcriptomics and epigenomics in combination with lineage tracing approaches to characterise the molecular sequences regulating progenitor cell specification and the emergence of specific interneuron identities. Finally, we will study the organisation and dynamics of interneuron progenitor cells in humans, along with their specific transcriptional profiles, to uncover similarities and differences in the generation of interneuron diversity between mouse and human. In the long term, our results would allow us to explore how variation in the proportion of different types of cortical interneuron impact behaviour.

Lay abstract: Understanding how a small pool of progenitor cells generates the vast diversity of cell types that populate the nervous system remains a fundamental question in neuroscience. This is highly challenging in the cerebral cortex —a region of our brain critical for decision-making, language and cognition—, because it contains over a hundred different types of neuron segregated into layers and functionally distinct areas. This proposal aims to identify the mechanisms controlling the generation of different types of cortical neuron during embryonic development using the mouse as a model organism. In addition, we will investigate this process in human embryos obtained from legally terminated pregnancies, which will allow us to identify distinctive features in the development of our brain. Elucidating how different classes of neurons emerge during development is critical for understanding brain function in health and disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Epilepsy and neurodegeneration : disease mechanisms and early detection
Funder: Wellcome Trust

Abstract: Cognitive decline represents a significant and debilitating co-morbidity for patients with epilepsy which is poorly understood with an urgent clinical need for diagnostic, preventative and treatment strategies. Large epilepsy MRI datasets confirm progressive cortical atrophy and white matter abnormalities ; age-accelerated Tau protein accumulation has been reported in surgical resections, correlating with cognitive decline. We propose a comprehensive evaluation of mixed neurodegenerative processes integrating cross-sectional and longitudinal MRI, DWI, DCE-MRI and Tau-PETimaging with quantitative neuropathology measurements of cortical, white mater atrophy and vascular pathology and pTau in resected surgical specimens in the context of cognitive impairment and genetic risk. We aim to characterise tau forms in surgical and post-mortem cohorts compared to Alzheimer's disease and other tauopathies. In prospective surgical cohorts, Tau-PET will be correlated with CSF markers, tissue levels using autoradiography and extent of cortical atrophy with high resolution in-vivo 7T and ex-vivo 9.4T MRI. In addition, cellular drivers for tau accumulation, as MTOR and seizure activity, will be explored through human slice culture experiments with gene-expression analysis and the kinetics of tau incorporation through SILK studies and mass spectroscopy of tissues. These studies will elucidate pathomechanims of cognitive impairment, identify early disease-stage biomarkers enabling prediction and preventative strategies.

Lay abstract: Epilepsy is most common in people aged >65 years, can lead to cognitive impairment similar to early stages of Alzheimer's Disease (AD), with memory impairment and ongoing decline often a more significant clinical burden in epilepsy patients than seizures themselves. In a well-characterised adult epilepsy surgical series we will investigate whether we can find changes in brain specimens of people with epilepsy who had surgery in the past, or are about to undergo surgery, that are also known to occur in neurodegenerative conditions or "tauopathies", like AD or chronic-traumatic-encephalopathy. We will compare pathological changes with results from repeat neuroimaging and cognitive studies in the same individual up to 20 years following surgery, or with imaging before and after surgery. In tissue cultures we will explore unique cellular drivers for these pathological processes, which could be potential therapeutic targets not only for people with epilepsy, but also with other neurological conditions.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Preventable axon degeneration in human disease
Funder: Wellcome Trust

Abstract: Programmed axon degeneration (or Wallerian degeneration; WD) is a preventable and druggable mechanism of axon loss. WD is well-characterised in animals and highly conserved. Blocking WD alleviates axon loss and symptoms in multiple disease models, suggesting a common, downstream mechanism. Human data are essential to confirm the role of WD in specific human diseases, ensuring drugs under development are tested in highly-relevant disorders and patients. We reported mutations in rare human axonopathies that aberrantly activate WD, and lifelong rescue of a related mouse model. Our programme determines the wider involvement of WD in rare and common human disorders, specifically peripheral neuropathies and ALS, where axon degeneration is important. We use online resources (100,000 Genomes, Project MinE, UK Biobank, etc.) and targeted sequencing of well-phenotyped cohorts and test roles of gene variants in causation, risk and severity. We determine their functional impact using complementary human iPSC and mouse modelling and develop specific biomarkers of WD for clinical samples. This project will provide insight into pathogenic mechanisms and a firm platform for developing and testing therapeutics. Our team, a world leader in Wallerian degeneration and leading neurogeneticists in rare and common neuropathies and human iPSC modelling, is uniquely placed to deliver this.

Lay abstract: Nerve cells have long, thin structures (axons), that project around our brain and spinal cord, and to skin, muscles and other organs. Axons make connections that control our bodies. They are lost early in many disorders causing pain, paralysis, spasticity, tremor, memory deficits or blindness. We identified, and characterised along with other scientists, a preventable axon degeneration mechanism common to many diseases. Here, we will use the extensive knowledge gained animal studies to test for human diseases involving this degeneration mechanism. This is important to known which diseases may respond to drugs that block it. We will use human genome sequences, stem cell- and neuron cultures to study rare, inherited disorders, motor neuron disease, and peripheral neuropathies caused by diabetes or cancer chemotherapy. This study, together with ongoing drug development, could result in major improvements for some rare disease patients, and may lead to widely-applicable therapies in neurodegenerative disorders.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Taking the long view: Identification of plasma protein biomarkers for dementia risk
Funder: Wellcome Trust

Abstract: The overarching goal of this collaborative project is to make a step change in knowledge of dementia biomarkers by focusing on plasma proteome. We hypothesize that plasma is biologically informative due to the presence of protein signals: imprints of subclinical dementia progression that can be identified via repeated proteomic profiling decades before clinical symptoms, providing novel candidate targets for preventative treatments. We will use the largest plasma proteome platform currently available, with three aims, to (1) prospectively examine 4,993 plasma proteins in relation to subsequent accelerated cognitive decline and clinical dementia across multiple cohort studies; (2) determine whether the protein hits identified in aim 1 have a causal association with dementia, whether modifiable and druggable, using analysis stratified by time between protein measurement and dementia onset and Mendelian Randomization framework in relation to novel genome-wide, and druggable-genome arrays; and (3) examine whether proteins predicting dementia risk are imprints of risk factors for dementia. The expected new outcomes include protein targets for drug development; improved identification of potentially modifiable lifestyle risks; dementia trials surrogate outcomes; improved diagnostic markers, plus data resource for future in-depth research on the multisystem aetiology of dementias and proteomics of a range of major diseases beyond dementia

Lay abstract: Alzheimer’s disease (the commonest dementia cause) is thought to be caused by two proteins/peptides in the brain, called amyloid and tau. Numerous drugs trials, targeting and sometimes reducing these biomarkers have failed to prevent disease or reduce deterioration. Studies looking for blood proteins have recruited people, aged over 65, followed-up for under 10 years. Therefore, biomarkers identified may be cause of or consequence of dementia. Our collaborative team (experts in cohorts, causal inference, biomarkers, dementia, drug development) takes a different approach. We have blood stored from 1-25 years before dementia onset; from UK, US and norwegian cohorts, in people followed to old age. We will analyse thousands of blood proteins from these midlife samples for new proteins associated with risk or protection from dementia, then check findings in independent cohorts. We will examine whether the associations represent cause-and-effect relationships. Our results will identify new targets for preventing or delaying dementia.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Feasibility of silk nerve conduits for spinal repair application
Funder: Innovate UK

Abstract: Spinal cord injury (SCI) is an overwhelming health condition that causes permanent disabilities and even death. Left untreated the spinal cord is not able to heal itself There are currently no implantable devices for spinal cord nerve injury. Rehabilitation is expensive and has limited success with respect to regaining mobility and improving patient quality of life. Our first (IP protected) product is a peripheral nerve repair bridge with a standardised design that will be available off-the-shelf in a range of lengths. Stents 3 cm in length will be compared to autografts (2-3 cm as standard) with the option for longer lengths (<5 cm). The bridge is an all silk biocompatible tubular silk conduit surrounding silk fibres of bespoke dimensions. These luminal fibres have proven nerve-regenerating properties with the sleeve tube designed to protect the growing nerves and encourage vascularisation. Given that peripheral nerve fibres are the same everywhere in the body we provide a new approach to treating patients for injuries caused by trauma or invasive surgery that would currently face absence of treatment options or suffer the morbidity of autograft repairs.


Research activity codes: 5.3 MEDICAL DEVICES;5.4 SURGERY
Health categories: NEUROLOGICAL
Title: Vagus nerve stimulator and recorder for epilepsy treatment
Funder: Innovate UK

Abstract: The global Vagus Nerve Stimulation (VNS) market was $505.2 million USD in 2018, it is expected to have a compound annual growth rate of 11.4% till 2026, reaching $1,195 million. VNS is part of the larger neurostimulation market, which incorporates many different stimulation techniques to combat a range of different conditions. The first VNS for refractory epilepsy, where the patient is not suitable for resective surgery, was FDA-approved in 1997. In early devices, stimulation was started by moving a magnet over the implant which then delivered a fixed dose. The aim of the stimulation was to reduce the frequency, severity or length of seizures. The standard VNS device has been the subject of many clinical trials which have successfully demonstrated its safety. However, individual response to VNS is variable. Mertens et al. [2019, [https://doi.org/10.2217/bem-2019-0004][0]] defined a responder rate as the proportion of patients with =50% seizure frequency reduction. This rate was found to be 20-40% one year after implantation, and 63% after approximately five years. More recent devices have tried to improve efficacy by introducing an autostimulation feature (LivaNova, AspireSR(r) and SenTiva(r), FDA approved in 2015 and 2017). The autostimulation works alongside the magnetic switch, providing extra stimulation if the heart rate increases beyond a specified threshold. Clinical trials have shown a responder rate of 30-59%, greater than or equal to the standard stimulator. Additionally, of 63 patients who upgraded their existing VNS stimulator to the AspireSR, 71% experienced an additional >50% reduction in seizures. The SenTiva(tm) device includes autostimulation and also wirelessly connects to the clinician for remote control of device stimulation. electronRx aims to build the next generation of intelligent VNS devices that can detect seizures with a higher accuracy than is currently possible. This requires identifying the biomarkers of interest and developing smart algorithms that use this data to predict seizures, thereby allowing the treatment regime to be patient-specific for optimal alleviation of symptoms. The long term goal is to integrate the technologies in eletronRx’s neuromodulation platform and bring to market a universal Vagus Nerve neuro-modulator that adapts the applied therapeutic intervention based on physiological inputs. The device would potentially be used in the treatment of several conditions related to Vagal Nerve function in addition to epilepsy.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: NEUROLOGICAL
Title: Modelling O-GlcNAc transferase Intellectual Disability in Drosophila
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: O-Linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential enzyme which is


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Refinement: The impact of peri-operative analgesia on neuropharmacological outcomes in rodent models of chronic pain
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Chronic pain remains an area of considerable unmet clinical need, affecting approximately 20%


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL