NIHRDataInsights/HRCSData huggingface dataset:
Title: A neurodevelopmental origin of dystonia
Funder: Medical Research Council

Abstract: Here I propose a series of approaches to study the mechanistic basis of a prevalent yet poorly understood movement disorder: dystonia. Dystonia is characterised by involuntary muscle contractions, leading to twisted, contorted postures. It is the third most common movement disorder, affecting over 90,000 patients in the UK alone. Furthermore, dystonia is often co-morbid with a wide array of neurological syndromes, including Parkinsonism, ataxia, dyskinesia, tremor, autism, epilepsy, and intellectual disability. However, the molecular basis of dystonia has remained mysterious. In particular, whether mutations linked to inherited dystonia impact the development of movement-controlling neural circuits has yet to be resolved. To define the molecular basis of dystonia, my lab has generated a Drosophila model of an inherited dystonia linked to a mutation in the hSlo1 BK channel. This model exhibits organismal and circuit-level phenotypes similar to those observed in dystonia patients. Using genetic techniques unique to Drosophila, I unambiguously show that mutant BK channels act in cholinergic neurons and during a critical neurodevelopmental window to perturb movement; and alter the developmental of premotor circuits. I aim to uncover molecular mechanisms underlying these effects, and to confirm the broader relevance of these findings by generating an array of additional Drosophila models of dystonia. I further propose to take advantage of the unique opportunities presented by Drosophila models by performing a screen for novel drugs to treat dystonic movements. My proposal will enhance our fundamental knowledge relating not only to dystonia but also a range of disorders that frequently occur in concert with it. Thus, my proposal will have a broad, translationally significant impact and will significantly enhance my career development by allowing me to realise my aim of becoming an international leader in the field of neurological disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Regulation of axonal transport by neurotrophic factors in health and disease
Funder: Medical Research Council

Abstract: Charcot-Marie-Tooth disease type 2D (CMT2D) is a debilitating and presently incurable peripheral nerve disorder caused by dominantly-inherited, gain-of-function mutations in the housekeeping gene GARS, which encodes glycyl-tRNA synthetase (GlyRS). The mechanisms linking motor and sensory degeneration to GlyRS dysfunction remain unresolved; however, I identified that pathological mutations in GARS permit the mutant protein to aberrantly bind to the extracellular domains of mainly neuron-specific neurotrophin receptors. The activity of these important receptors is integral to the survival, development, and differentiation of motor and sensory neurons in all mammalian organisms. Perturbations in neurotrophin signalling account for pervasive in vivo defects in CMT2D axonal transport of signalling endosomes, which are reversed by administration of specific neurotrophic factors (NTFs). I have thus uncovered an unappreciated role for NTFs in regulating the dynamics of this essential neuronal process, and discovered a neuropathic pathway amenable to therapeutic intervention. I now propose to interrogate NTFs integral to transport in vivo in healthy and diseased peripheral axons. Detailed expression experiments of NTFs and their receptors will identify molecular determinants of differential CMT2D muscle vulnerability. These experiments will be coupled with mechanistic studies in primary peripheral neurons in vitro to elucidate how NTFs control transport and how mutant GlyRS disturbs this process. Virus-mediated gene therapies will be designed and tested in CMT2D mice to determine whether augmenting neurotrophic input in a muscle-specific fashion alleviates, in part or completely, neuropathic phenotypes. This combined approach provides a powerful, integrated platform to unravel the non-cell autonomous mechanisms governing axonal transport, with real possibility of producing a viable gene therapy for a currently untreatable neurological condition.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Dissecting the relative contributions of injured and intact primary afferents to neuronal plasticity and neuropathic pain
Funder: Medical Research Council

Abstract: Following peripheral nerve injury, aberrant primary afferent (PA) activity and altered spinal processing are key drivers of neuropathic pain. Ectopic activity occurs in PAs directly injured by the insult as well as in intact neighboring afferents; raising the question of how these two populations contribute to the different types of pain experienced. I will use genetic targeting of chemo- and optogenetic tools in rodent nerve injury models to address this central question. Adeno-associated viral (AAV) delivery of a modified glutamate-gated chloride channel (GluCl) to PAs allows for long-term silencing upon treatment with Ivermectin (channel agonist), making this approach ideal to study the effect of long-term neuronal activity to chronic pain. I will use Cre-ON and Cre-OFF GluCl AAV vectors in transgenic mice in which Cre is expressed de novo in injured afferents (ATF3-Cre and NPY-Cre). This approach will allow separate silencing of injured and intact PAs while pain behaviour is assessed. Condition place preference paradigms will be used to assess spontaneous pain and assays of reflex withdrawal will be measured (Von Fey and Cold Plantar) as secondary outcomes. PA activity is necessary for pain, however it also sensitizes spinal processing. We do not know whether changes occur in the central terminals of injured or intact PAs that facilitates pain transmission. Projection neurons (PNs) are directly innervated by nociceptors and relay nociceptive signals to the brain. I will record from PNs in ex vivo spinal slice preparations while injured/intact PA terminals are optogenetically activated and test whether synaptic transmission changes following nerve injury. Injured/intact PA synapse size and number on PNs will be contrasted in the same tissue by delivering a FLEX-switch reporter AAV to PAs of injured ATF3Cre mice. This work will gain important insights into the drivers of neuropathic pain and will define key neurons to target for effective therapeutic treatment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: How do microglia regulate myelin integrity and cognitive function in health and ageing?
Funder: Medical Research Council

Abstract: Cognitive decline with ageing is linked to loss of integrity of myelin, the insulation surrounding nerve fibres in the central nervous system (CNS) which is required for neuronal function. Mechanisms controlling myelin integrity in ageing are unknown, yet CNS macrophages termed microglia are known to regulate myelin integrity in youth, and are dysregulated in ageing. Thus, I propose that microglia dysregulation in ageing contributes to loss of myelin integrity and cognitive decline. Aim1 is to determine how aged microglia are dysregulated in association with loss of myelin integrity. We will determine how communication between microglia and cells that make myelin (termed oligodendrocytes) is altered in ageing via transcriptomics. In human brain, transcriptomic changes at the single-cell level on intact brain tissue will be correlated with myelin integrity and cognition in the same individual. In mouse brain, RNAseq will compare aged microglia and oligodendrocytes to young cells, narrowing down pathways related to myelin integrity by comparison to genetically altered mice in which microglia manipulation leads to premature loss of myelin integrity. Aim2 is to determine how aged microglia influence myelin integrity, by transplanting them into microglia-deficient mice or young wildtype mice, and assessing whether myelin integrity is disrupted. Aim3 is to determine whether rejuvenation of microglia improves myelin integrity and cognitive performance in ageing. First, we will use an approach known to rejuvenate microglia transcriptomes and improve cognition in aged mice: depletion of microglia followed by repopulation. Second, we will transgenically engage a pathway in microglia that is downregulated with ageing and involved in regulating myelin integrity and cognition: Wnt. We will supplement this with manipulation of pathways identified in Aim1, and assess whether myelin integrity and cognitive function are improved.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cell-Specific PRC1 Accessory Proteins and the Regulation of Mammalian Neurodevelopment
Funder: Medical Research Council

Abstract: The polycomb system is an important epigenetic regulator involved in directing differentiation, and cell identity. In the neural lineage, perturbations to this system are causal in both congenital and acquired brain pathologies, yet how polycomb proteins regulate transcriptional programmes during normal neurodevelopment remains poorly understood. I aim to elucidate how polycomb regulates neurodevelopment by determining how cell-type-specific protein factors alter the targeting and function of polycomb repressive complex 1 (PRC1). To address this I will combine state-of-the-art molecular approaches and advanced computational analysis to: 1). Determine the protein composition of PRC1 complexes in in vitro differentiated and ex vivo cultured neural progenitor cells (NPCs). 2) Apply auxin-induced degradation (AID) to reversibly deplete PRC1 components in mESCs and determine the impact of depletion on gene repression and the capacity to differentiate ESCs into NPCs. 3). Determine if neurodevelopment is disrupted, both in vitro and in vivo, in separation of function mutants (Ring1b I53A) in which the E3 ubiquitin ligase activity but not the structural function of RING1B is abolished. 4). Identify and validate NPC-specific PRC1 targeting factors using a combination of quantitative proteomic analysis of PRC bound chromatin and AID. 5). Determine the logic of PRC1 recruitment in NPCs by targeting prospective chromatin-recruitment factors with synthetic tools (TALs) in isolation or in combination with chromatin modifiers. Though these objectives I will determine not only the molecular basis of neuropathologies associated with PRC dysfunction but also provide insight into how cell-type-specific proteins adapt or target epigenetic systems to regulate gene expression.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: Harnessing knowledge of lifespan biological, health, environmental and psychosocial mechanisms of cognitive frailty for integrated interventions
Funder: Medical Research Council

Abstract: The Cognitive Frailty Interdisciplinary Network (CFIN) will promote multidisciplinary research tackling development of age-related cognitive frailty and associated reduced healthspan and quality of life. This is both a major societal challenge in our ageing populations and a research challenge to integrate findings from multiple fields into effective prevention and therapeutic interventions across the life course that are implementable in real contexts. The primary goal of this proposal is thus network building across disciplines (including biology, neuroscience, psychology, epidemiology, social science and citizen engagement) and groups (researchers, clinicians, learned societies, business, clinicians, support organisations, older adults and carers) to foster transformative collaborative research for the purpose of better understanding and alleviation of the burdens of cognitive frailty. Network creation will be achieved by forming an external advisory group (EAG) and convening meetings, building membership through existing networks of investigators and members, and by use of social media and judicious linking of a network website. The CFIN will be fully activated at a networking conference at 6 months. Specific outcomes in addition to the EAG and researcher network will be the production of a cross disciplinary evidence synthesis of biological mechanisms and exogenous factors as related to cognitive frailty, identifying gaps, to inform creation of interdisciplinary collaborations with specific goals. Specific small projects will be funded, forming the basis of further Network-based funding proposals to external funders. There will also be a consensus document produced using a two stage Delphi process bringing together membership expertise on the most evidentially supported multi-dimensional interventions for cognitive frailty. Both papers will be submitted for publication. A Mentorship programme and summer school for ECRs will also be supported.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: NEUROLOGICAL
Title: JPND GBA - personalised medicine for Parkinson disease: clinical and therapeutic stratification
Funder: Medical Research Council

Abstract: This grant will investigate the evolution of clinical features prior to and during the development of PD in those that carry GBA1 mutations, and the downstream molecular, biochemical and cellular consequences of the mutations in patient material, patient-derived cell and animal models. This will be translated into a personalised clinical and biochemical biomarker risk profile for GBA-PD. We will further test a small molecule GBA1 chaperone to slow or reverse the pathology of PD in cell and animal models as a means to develop personalised medical therapy for GBA1-PD. We will develop clinic and web-based recruitment of GBA1 mutant carriers (currently >700) to provide integrated and harmonised clinical and biochemical biomarker assessment tools across 4 European countries. We will investigate the molecular basis for the link between GBA1 mutations and PD pathology, specifically their relationship to the levels of alpha-synuclein (A-SYN) and its aggregation and spread. This will use patient-derived neuronal stem cells and 3-D mid-brain organoids of GBA1 mutations (L444P and N370S) with adeno-associated viral vector (AAV)-induced or endogenous overexpression of A-SYN or direct injection of A-SYN fibrils. We will also determine the mitochondrial and lysosomal functional consequences of GBA1 mutations, and their effects on glia and inflammatory activation. We will further investigate the ability of ambroxol, a GBA1 chaperone to reverse the abnormalities seen in our cell and organoid GBA1 models, to confirm this therapeutic approach as a rational intervention to slow or prevent PD development or progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND - Defining measures of proximity to symptom onset in the GENetic Frontotemporal dementia Initiative
Funder: Medical Research Council

Abstract: Frontotemporal dementia (FTD) is a highly heritable neurodegenerative disorder with the majority of that heritability accounted for by autosomal dominant mutations in three genes: progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72). The Genetic FTD Initiative (GENFI) is a European and Canadian multicentre natural history study of genetic FTD with detailed phenotyping of both presymptomatic and symptomatic mutation carriers. With trials imminent, it will be critically important to identify biomarkers of proximity to symptom onset, identifying on an individual basis those who are likely to progress to clinical FTD over the next 5 to 10 years. The aim of this study is therefore to characterize the prodromal period of genetic FTD, establishing cognitive, imaging and fluid biomarker measures that allow i) stratification of individual presymptomatic carriers into a stage proximal to symptom onset, and ii) measurement of subsequent disease progression during that proximal period. In particular, the work will extend the results found on a group basis in the prior GENFI studies to identify measures and patterns of change on an individual basis, thus paving the way for a precision medicine approach to FTD. It will make use of data from at least 950 participants already in the current GENFI studies with biomarker data acquired longitudinally (>2000 visits so far). It will focus on those likely to be in proximity to symptom onset, following 500 participants over time, with cognitive, neuroimaging, and fluid biomarker assessment as well as genomic, proteomic and transcriptomic profiling of participants. Integration of these approaches will allow stratification of genetic FTD, delineating an individualized disease profile that identifies those in proximity to symptom onset and their subsequent progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: JPND TRanslating Individual Alzheimer GEnetic risk into disease phenotypes
Funder: Medical Research Council

Abstract: We here propose to develop a method to link the individual genetic risk of developing AD to functional information about the underlying disease process and manifestations with focus on the microglia. We will genotype 200 participants from a memory-clinic based cohort of individuals with biomarker-proven AD at different clinical stages (prodromal, early, mid and late dementia stage). We will also include 180 participants from a longitudinal observation cohort of older adults at high genetic risk of developing AD. We will calculate Polygenic Risk Scores and profile the immune system of all individuals, and integrate those data with clinical data to obtain a complete map linking genetic profiles and disease manifestations across the entire spectrum of AD. From a selected subset of individuals across this map, we will generate induced pluripotent stem cells and differentiate them into microglia. We will then investigate microglia responses unbiasedly by single-cell RNA sequencing and functionally on synapse, amyloid and Tau effects, both in vivo in the context of a mature brain, after transplantation into mouse models for Abeta and/or Tau pathology, and in vitro in brain organoids. Both datasets will be benchmarked against ex-vivo human brain tissue. We will investigate how different PRS affect the response of microglia to amyloid plaques, neuronal tangles and their interaction with synapses. This work will establish how AD genetic risk translates into microglia behavior, and point to molecular and cellular pathways contributing to pathogenesis. By maximally exploiting clinical and research data and linking them to an individual risk score, this project will establish a roadmap towards precision medicine for AD. Our results will reveal novel therapeutic targets in AD and lay the foundations of a pre-clinical drug testing platform for AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: JPND: Oligomer-Focused Screening and Individualized Therapeutics to target Neurodegenerative Disorders (OligoFIT)
Funder: Medical Research Council

Abstract: Neurodegenerative disorders (NDs) are commonly associated with neuropathologically distinct amyloid plaques, neurofibrillary tangles, intracellular inclusions in the brain. The main perpetrators are believed to be small mobile aggregate forms called oligomers, such as a-synuclein (a-syn) in the case of PD, DLB and multiple system atrophy (MSA), so-called Lewy body disorders, that may act as potential biomarkers for those diseases. However, explaining the diversity of disease sub-classifications associated with each proteopathic protein is challenging. Recent findings have shown that oligomers possess a heterogeneity of forms, adopting different conformations, interacting with other proteopathic partners and are likely the result of a convergence of genetic susceptibilities, lifestyle/environmental factors and ageing. This postulates that disease progression is the result of several factors and as such possibly follows an individualized path for each patient. The existence of distinct strains of aggregates or combinations of aggregates may be indicative of disease subtype, stage and confer some prognostic value. Utilising a coordinated multifaceted approach, we will study oligomers (representing pathologically relevant species) and generate a panel of oligomer specific mAb binders (screening out monomer and fibril interactors). The project will further explore differences between physiological and experimental aggregate intermediates and test these in established and novel aggregation and seeding assays to determine behaviour and neurotoxicity. Innovative biosensors based on individual or multiple panels of interactors will be produced and tested with peripheral patient samples (e.g. cerebrospinal fluid and sera). Providing a unique opportunity to investigate differences in oligomers from different synucleinopathies as a strategy to inform the design of targeted immunotherapies, that can be personalized to match the individuals' unique biomarker signatures.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: JPND: Stratification of presymptomatic amyotrophic lateral sclerosis: the development of novel imaging biomarkers
Funder: Medical Research Council

Abstract: This consortium proposes to embark on a large, prospective, multicentre, longitudinal study of asymptomatic and symptomatic c9orf72 hexanucleotide carriers using a purpose-designed spinal and brain imaging protocol and comprehensive clinical, genetic, electrophysiological and neuropsychological profiling. Newly developed imaging techniques such as spinal cord NODDI, spinal fMRI, quantitative thoracic cord imaging will be implemented in addition to established spinal cord and brain imaging techniques. No accurate prognostic indicators currently exist in asymptomatic hexanucleotide mutation carriers to foretell if they will develop ALS or FTD and when symptoms are likely to manifest. Beyond the academic relevance of characterising presymptomatic propagation patterns, the study has a number of pragmatic deliverables such as the development of individualised prognostic indicators, sensitive imaging-based diagnostic protocols and novel monitoring tools which are indispensable for future biomarker-supported clinical trial designs. This proposal endeavours to capitalise on recent technological advances to develop precision imaging tools for academic applications, clinical trials, the clinical care of patients and suspected patients and the support asymptomatic relatives. The ultimate aspiration of this application is the optimisation of novel imaging protocols which will be transferable to other motor neuron diseases, dementia syndromes, and meaningfully contribute to the development of novel disease-modifying therapies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL