NIHRDataInsights/HRCSData huggingface dataset:
Title: A novel approach to improve the repair of injured peripheral nerves
Funder: Medical Research Council

Abstract: Peripheral nerves, unlike their CNS counterparts, are capable of extensive regeneration following an injury. Despite this intrinsic capacity to regenerate, the repair of damaged peripheral nerves remains a major clinical problem. This is due to two main reasons: failure to regenerate when the degree of damage is too severe and aberrant regeneration that can result in pain. We have recently characterised the complex multicellular response by which peripheral nerves regenerate and found a major role for Schwann cells, the main glial cell of the PNS, in this process. In important findings, with implications for future therapeutic approaches, we found that the collective migration of Schwann cells as cords along a polarised newly-formed vasculature was the mechanism by which regrowing neurons could cross the injury site. In unpublished but patented findings, we have now identified the Schwann cell chemotactic factor that is secreted by macrophages within the wound site. The aim of this proposal is to determine the therapeutic potential of using this factor to improve the repair of serious nerve injuries and to address its potential as a target for the treatment of neuropathic pain. To address these aims we will do the following: 1. Using artificial conduits that mimic the environment of a regenerating nerve, we will test the potential of this factor to improve the efficiency of nerve regeneration following a serious injury. 2. Using a combination of 3D imaging approaches, genetic knock-out mouse studies and inhibitor experiments, we will determine the role of this Schwann cell chemotactic factor in the normal regeneration process. 3. Building on the recent advances in macrophage biology, we will use mouse models and molecular approaches to characterise the macrophages responsible for initiating the regenerative response.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The flexible and interactive neural, computational and neurobiological mechanisms underpinning semantic cognition and its disorders.
Funder: Medical Research Council

Abstract: Semantic cognition allows us to retrieve the meanings of words, objects, people, etc., and to use this rich store of knowledge flexibly to produce time- and context-appropriate behaviour. Given the central role of semantic cognition in communication (the core goal of which is to pass meaning from one person to another) and everyday life (e.g., object use), it is not surprising that patients with semantic impairments suffer from considerable disability in both their professional and everyday lives. Semantic impairments are a common deficit across many different diseases of the neocortex. These include patients with neurodegenerative disease (e.g., frontotemporal dementia, Alzheimer's disease) or following an acute episode (e.g., cerebral vascular accident, herpes simplex encephalitis, head injury, neurosurgery). It is paramount, therefore, to understand the neural basis of normal and impaired semantic cognition, and then to use this knowledge to improve treatment and clinical management. The long-term aim of our continuing research programme, therefore, is to understand the flexible and interactive nature of semantic cognition, at the behavioural, neural, computational and neurobiological levels. Using our innovative combinations of cognitive and clinical neuroscience investigations, we will tackle this target through three interlinked research themes: (a) Exploring the nature and components of the network for semantic cognition; (b) Investigating the flexible interaction and compensatory processes within the semantic network; and (c) to beging to extend the neurocognitive account of semantic cognition to neurobiological mechanisms. These three themes will be integrated through implementation of the first neurocomputational model of semantic representation and control, in which the model architecture will assimilate neuroanatomical and neurobiological information and the model will be required to generate normal semantic function and dysfunctions after damage.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: Novel therapeutic strategies to target RAN translation of pathological C9ORF72 repeat transcripts and associated neurodegeneration
Funder: Medical Research Council

Abstract: Hexanucleotide repeat expansions in the C9ORF72 gene are the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum of fatal adult-onset neurodegenerative diseases. FTD involves neuronal loss in the frontal and temporal lobes of the cerebral cortex, leading to cognitive and personality alterations. ALS is characterised by selective degeneration of upper and lower motor neurons, progressive paralysis and death usually within 3-5 years from symptom onset. The pathophysiology is complex, potentially involving haploinsufficiency, sequestration of RNA-binding proteins and production of dipeptide-repeat proteins (DPRs) by repeat-associated non-AUG (RAN) translation. Recent evidences, including my own research, point DPRs as a primary driver of pathogenesis in cell and animal models of C9ORF72-ALS/FTD. The mechanisms driving RAN translation of C9ORF72-related DPRs are unknown. We recently uncovered two RAN-associated translation factors using transfected human embryonic kidney reporter cell models. We will now test whether partial and single depletion of these RAN translation factors inhibits DPR production in neurons derived from C9ORF72-ALS/FTD patients and in a Drosophila model of disease, and respectively prevent neuronal death and neurodegeneration-associated motor deficits. We will also investigate the C9ORF72 repeat RNA-binding activities of the RAN translation factors using RNA immunoprecipitation experiments in cell models and in vitro biochemical assays with recombinant proteins. The potential co-localisation of the RAN translation factors with C9ORF72 repeat transcripts will also be assessed in vivo by dual immunofluorescence and fluorescence in situ hybridisation studies in human C9ORF72-ALS/FTD brains. Finally, transcriptomics and polysome profiling assays in human cells depleted of these factors will allow investigation of genome-wide effects on the expression and translation of cellular transcripts.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND: Systems Analysis of Key Nodes in Neurodegenerative Diseases
Funder: Medical Research Council

Abstract: Our working hypothesis is that common checkpoints controlling protein homeostasis go awry in neurological diseases. We aim to understand whether these checkpoints fail for the same or different reasons in each of these diseases. Towards this aim we will tackle the following research questions: (i) Which differences in mRNA levels, metabolism, and translation, vesicle content or associated trafficking proteins characterise these diseases? (ii) How does neurotransmitter exposure or cell stress influence in each of the NDs alter stress granule function, vesicle content or trafficking protein expression or function? (iii) Are those differences related to genetic vs spontaneous disease onset? and (iv) Can the above data highlight key regulatory nodes that are altered across the diseases? To answer these questions we have developed the following Aims: Aim 1: Generate different cell types from mutations that cause AD, ALS, BD, and PD. Aim 2: Gain a comprehensive understanding of which sets of genes are translationally controlled in response to NDs. Aim 3: Develop a rigorous model of the intracellular processes that affect chemical transmission in these NDs. Aim 4: Identify how cell metabolism and cell phenotypes vary across the NDs and how these change depending on the neuroprotective agents provided. Aim 5: Validation of identified key nodes via pharmacological or genetic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND - Intraneuronal transport-related pathways across neurodegenerative diseases
Funder: Medical Research Council

Abstract: The spread of the lesions is a common feature of Alzheimer disease, Parkinson's disease, and Huntington disease, but strikingly starts and progresses in different brain sub-regions for each pathology. According to recent observations distinct aggregate conformers could be responsible for different clinical subtypes. Here, we aim at revealing the specific mechanisms by which distinct fibrillary protein polymorphs of Abeta1-42, Tau, alpha-synuclein and HTTExon 1, are taken up and transported by neurons. We will use different types of mouse neurons maintained in primary culture to establish a structure-function relationship for distinct pathogenic protein assemblies and their conformers by analyzing their binding, uptake and cellular trafficking after extracellular application. More specifically, we will quantify the binding of the fibrillary proteins polymorphs to the neuronal plasma membrane, identify their membrane protein partners, assess the role of endocytosis, identify their cargoes within the cells and quantify their intracellular transport and export/release in the extracellular medium, after anterograde or retrograde transport, to identify common and divergent protein networks and characteristics that account for distinct diseases. By doing so we will address: 1. How distinct pathogenic fibrillary protein polymorphs bind to neuronal cells and to which membrane components; 2. How exogenous pathogenic fibrillary proteins are taken up and transported; 3. How pathogenic fibrillary proteins traffic within cells by identifying; 4. The relationship between the traffic of pathogenic fibrillary proteins and neuronal activity; 5. The protein networks that account for distinct diseases; 6. How genetic risk factors affect the interactomes and transport mechanisms of distinct pathogenic fibrillary proteins polymorphs; 7. The identification of common pathways involved as novel therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Modelling brain ageing using neuroimaging to improve brain health in older adults
Funder: Medical Research Council

Abstract: Older age is associated with cognitive decline, decreased well-being and increased risk of neurodegenerative disease and dementia. Fostering healthier 'brain ageing' would benefit for society by reducing these risks. However, the factors that specifically affect the brain are uncertain and brain ageing does not affect people uniformly. Hence, I have developed a neuroimaging-based biomarker of brain ageing, that quantifies individual deviation from healthy brain ageing; brain-predicted age difference (brain-PAD). I have shown that brain-PAD relates to cognitive performance, the presence of neurological disease and predicts future cognitive decline and dementia. Brain-PAD also relates to physiological ageing and predicts mortality risk in older adults, showing its utility as surrogate measure of future neurological and general health. Here, I will use brain-PAD to identify the genetic and environmental factors that influence brain ageing. This will provide mechanistic insights into causes of poor brain health and inform clinical efforts to promote healthier brains as people age. I will achieve this by measuring brain-PAD in the UK Biobank. This unprecedentedly large study currently includes high-resolution, multi-modality neuroimaging data from over 19,000 adults aged >40. Using the detailed demographic, behavioural, physiological, medical and genetic information collected from this cohort, I will: 1) Identify personal (age, sex), lifestyle and environmental (e.g., diet, smoking) factors that correlate with brain-PAD. 2) Determine genetic factors relating to brain-PAD, resulting in a polygenic risk score for brain ageing. 3) Explore gene-environment interactions in relation to brain-PAD, moving towards personalised risk assessments for poorer brain health during ageing. 4) Design a machine-learning software tool for estimating brain-predicted age at a regional level or in different components of brain structure and function.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: JPND Biological Resource Analysis to Identify New MEchanisms and phenotypes in Neurodegenerative Diseases (BRAIN-MEND)
Funder: Medical Research Council

Abstract: Current classification of neurodegenerative diseases (ND) is based on clinical phenotypes and does not account for underlying disease heterogeneity or overlapping disease mechanisms, hindering therapy development. Reclassification of NDs is therefore urgently needed. From a therapeutic perspective, reclassification should be based on causal and druggable factors. BRAIN-MEND will reclassify existing phenotypes using pathway and network analyses within and across complex NDs including Alzheimer Disease, Parkinson Disease, ALS, FTD, Corticobasal Degeneration, MSA, and PSP. We will use three innovative approaches, pioneered or adopted by the consortium: WP1 will apply the latest methods to identify causal genetic factors acting on molecular pathways; WP2 will apply cutting edge methods to identify epigenetic factors associated with molecular pathways of ND; and WP3 will identify drug targets from network analyses using results from WP1 and WP2 without requiring prior knowledge of mechanism. WP4 will use analysis of medical literature and patient records to identify novel or under-recognized clusters of related clinical features. These complementary approaches allow for iterative cross-validation of elucidated factors by WP1-4. BRAIN-MEND will reclassify ND phenotypes based on biologically meaningful categories corresponding to subgroups (heterogeneity) and common pathways (pleiotropy) to enhance disease understanding and facilitate drug development across the entire complex ND landscape. WP5 will manage the project and disseminate results. Patients and caregivers will be intimately involved throughout the project. Our consortium is highly qualified to perform the work proposed, as evidenced by a mean PI h-index of 61, major impact in research in neurodegeneration and neuropsychiatry, direct expertise with and access to a large and rich dataset spanning all complex NDs, track record in cross disorder analyses, and the related tools, biobanks and cell models needed.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND: Altered mRNA translation as a pathogenic mechanism across neurodegenerative diseases
Funder: Medical Research Council

Abstract: Alterations in mRNA translation have been implicated in both neurodegenerative disorders, including Alzheimer's, prion, Parkinson's and Charcot-Marie-Tooth diseases, and neurodevelopmental diseases such as autism spectrum disorders. Currently, no curative treatments are available for these diseases, and the underlying molecular mechanisms are poorly understood, thus precluding rational drug design. In this proposal, we aim to gain novel insights into the molecular pathogenesis of these diseases and to identify common and disparate mechanisms underlying the translation defects across diseases. The complexity of cellular and molecular mechanisms demands state-of-the-art methods. One such approach that we will use in our study is based on non-canonical amino acid tagging that will allow us to cell-type-specifically characterize translation in vivo and to identify genome-wide proteomic changes selectively in the affected neuronal populations in mouse models of the respective diseases. The functional relevance of identified molecular alterations for mRNA translation defects and disease phenotypes will be evaluated using cell, mouse and Drosophila models of disease. By combining the complementary technical and thematic expertises of the consortium partners, we expect to gain unprecedented insights into the molecular mechanisms of these dreadful diseases and their associated translation defects, including insights into the cell type specific nature and late adult age of onset of neurodegenerative disorders. This may lay the foundation for rational drug design for these incurable diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND LOss of neurotrophic factors in neurodegenerative DEmentias: Back to the crossroads of proteins (LODE)
Funder: Medical Research Council

Abstract: The recognition that non-monogenic as well monogenic forms of dementia result substantially in the same disease, suggests that fundamental, simple mechanisms may underlie the apparent complexity of observed human neurodegenerative disorders. This project explores a key common pathological mechanism across AD, FTD, LBD. During conditions characterized by progressive loss of neurons, exosomes could become the key player of neuronal communication and the crossroads of proteins: accordingly, survival of neurons could be easily affected by factors modulating exosomes release and/or composition. Our working hypothesis is that loss of trophic factors is one of the main determinants affecting exosome release, thus influencing the fate of disease-related proteins across dementias. We envisage to address this issue by testing the link between i) neurotrophic factors and exosome generation (cellular and animal studies; neurobiological and neuropathological studies on patients); ii) exosome generation and neurodegeneration (cellular and animal studies; neurobiological, neuropathological and genetic studies on patients). To achieve these goals, we have organized a multidisciplinary team with a proven expertise in studying i) AD, FTD, LBD; ii) cellular and animal models; iii) human brain (neuropathology) and circulating disease markers; iv) proteins aggregation (abeta, tau, alpha-synuclein) v) exosome isolation/characterization; vi) genetic disease determinants; vii) nanoparticle delivery systems. LODE will achieve a great gain of knowledge regarding mechanisms of neurodegeneration but may also unmask novel disease markers and provide new targets for putative therapeutic intervention. Gender will be taken into account both in collecting and analysing data.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: JPND The locus coeruleus: at the crossroad of dementia syndromes
Funder: Medical Research Council

Abstract: Noradrenergic projection neurons from the locus coeruleus (LC) mediate attention, memory, and arousal and their loss occurs early in neurodegenerative conditions, such as Alzheimer's disease (AD), Down syndrome (DS) and even more in Parkinson's disease (PD). Consequently, LC neuronal loss affects the function of target areas such as the hippocampus and the cerebral cortex. Evidence from our consortium and others, suggests that AD, DS and PD may share key mechanisms of LC degeneration, affecting early onset and/or progression of neurodegenerative process. Our consortium has been successful in identifying new biomarkers of AD in DS, some of which have already been validated in sporadic AD and are also common to PD. Specifically, alterations in the endo-lysosomal system (within which amyloid-beta processing occurs) and changes in noradrenaline and its main metabolite (3-methoxy-4-hydroxyphenylglycol, MHPG) due to LC degeneration were found to be early markers of dementia in DS and also in other dementias. The goal of this project is now to uncover the common mechanisms and pathways related to dementia associated with LC degeneration among these three neurodegenerative diseases (AD, DS and PD). By using state-of-the-art technologies we will (i) characterize noradrenergic neurodegeneration and endo-lysosomal alterations in the LC of post-mortem brain material, iPSC-derived neurons/cerebral organoids from AD, DS and PD patients, and mouse models (WP1/2); (ii) characterize the noradrenergic system functionality in patients with and without dementia using biomarkers and PET studies (WP1); (iii) analyze the involvement of specific chromosome 21 genes (such as DYRK1A and APP) in AD, DS and PD pathways and their role as common risk or protective mechanisms for dementia (WP3); and (iv) identify common genes and pathways using transcriptomic studies (RNAseq) in the LC and validate new targets in post-mortem material from AD, DS and PD patients (WP4).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Genomic regulation of vertebrate development
Funder: Medical Research Council

Abstract: PROJECT AIM: This project will identify the genomic regions that play a crucial role during early vertebrate development and which of these are potential pharmaceutical targets for neurological disorders. BACKGROUND: Epigenetic and gene expression changes during development play crucial roles in determining cell fate. Insults during this time can cause abnormalities in these mechanisms and lead to diseases later in life, such as schizophrenia or ADHD. Determining the genomic regions that undergo changes during early development is essential to understand the molecular mechanisms involved in development and developmental disorders. To this date, no study has identified the genome-wide epigenetic and gene expression changes that occur in different cell types across several stages of early development. APPROACH: I will characterize the regulatory changes in specific cell populations during early development and identify potential targets for pharmaceutical therapies for neurodevelopmental disorders. Firstly, I will isolate purified cell populations from different tissue structures of the zebrafish embryo at different stages of development. These will be isolated using dissection and aspiration and/or cell sorting technologies. I will then characterise dynamic changes in histone modifications, DNA modifications, open chromatin and gene expression in each of these cell populations, using different genome-wide sequencing methods. To analyse these data I will use statistical methods and bioinformatics analyses. Finally, the epigenomic and transcriptomic changes involved in development identified during my fellowship will be compared to the existing genomics and transcriptomic datasets at Eli Lilly (in collaboration with the Lieber Institute for Brain Development and the Psychiatric Genomics Consortium) to help identify potential pharmaceutical targets for neuropsychiatric disorders with developmental origins.


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