NIHRDataInsights/HRCSData huggingface dataset:
Title: RNA processing proteins and neurodegeneration: exploring mechanisms and modelling disease
Funder: Medical Research Council

Abstract: Recent genetic and pathological discoveries have placed the RNA-processing proteins, TDP-43 and FUS, centre stage in the pathogenesis of ALS and FTLD-U. Here we present evidence that FUS and TDP-43 mislocalise and aggregate in FTLD-U patients with PGRN mutations. Aberrant processing of transcripts may cause neurodegenration due to a loss of function; however, these proteins also aggregate in affected neurons and may cause a toxic gain in function. The main aim of this proposal is to generate cellular and animal models to determine which mechanism is predominant (or whether both are necessary) and identify the events that initiate neurodegeneration. We will: _ Generate and characterise cellular models of PGRN, TDP-43 and FUS mediated neurodegeneration. _ Generate and characterise zebrafish and mouse models of PGRN, TDP-43 and FUS mediated neurodegeneration. _ Identify the physiological DNA and RNA binding targets of TDP-43 and FUS in cells and animal tissues. _ Define the transcriptional and proteomic signatures for loss and/or gain of function for PGRN, TDP-43 and FUS in cellular and animal models. _ Interrogate FTLD and ALS nervous tissues for loss and/or gain of function transcriptomic or proteomic signatures and compare these to other neurodegenerative disorders _ Identify the major sites of in vivo phosphorylation of TDP-43 and FUS, the kinases responsible and the functional consequences of these post translational modifications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mechanisms of neurotoxicity of amyloid aggregates
Funder: Medical Research Council

Abstract: Some of the most important but unresolved questions about the pathobiology of Alzheimers disease (AD) are: What are the neurotoxic species of Abeta? How do they injure neurons? How do they induce aggregation of intracellular proteins like tau, ?-synuclein, and TDP-43? Why are the normal mechanisms for removal of these intracellular aggregation-prone proteins overwhelmed in AD? Answers to such questions will provide both insight into the early stages of disease pathogenesis, and starting points for the discovery of novel diagnostics and therapeutics.|We hypothesize that the neurotoxicity of Abeta arises from heterogeneous mixtures of|soluble Abeta aggregates, which may have differing toxicities, but which activate complex, interlinked downstream pathways. To deconvolute this complexity we will apply an integrated suite of tools from physics, chemistry, engineering, systems biology and neurobiology to: 1) Investigate Abeta aggregation and its consequences in living cells and animals; 2) Identify its molecular targets; 3) Discover the downstream metabolic and signalling pathways activated by Abeta; 4) Identify the molecular mechanisms by which Abeta induces misprocessing of tau; and 5) Identify the regulators of autophagy (which is an important physiological mechanisms for removal of tau)|and determine why autophagy is down-regulated in AD).||


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A systematic investigation into the pathogenesis and course of Parkinson's syndrome
Funder: Medical Research Council

Abstract: In this ambitious proposal we have assembled a group of world-leading clinical and basic science researchers possessing complementary expertise to identify and tackle the causes of Parkinsons Disease (PD). The overall goal will be a fuller understanding of the molecular pathogenesis of PD as well as improved clinical assessment of the disease prodrome. The main goals of the project are:|1. To undertake comprehensive genetic analysis of a large number of well characterised PD patients to identify rare variants and novel genes that cause and predispose to disease.|2. To perform state of the art molecular and biochemical characterisation of existing and novel PD-causing gene products and their pathways to delineate the regulation and function of these proteins.|3. To clinically dissect the prodrome of PD using a large series of at risk patients.|The consortium brings together both established PD researchers and senior researchers from other disciplines whose expertise brings new skills to this programme.||This research should yield crucial new knowledge of the molecular pathways leading to neurodegeneration and shed insight into the causation of PD|


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Biomedical Catalyst – Digital Healthcare Platform for Early Dementia Diagnosis
Funder: Medical Research Council

Abstract: Most of the 700,000 people in the UK with dementia have not received a formal diagnosis, so are denied access to beneficial treatments. The current NHS approach is slow (often more than 12 months) and often of low quality. This project will develop a novel digital healthcare system that will allow dementia diagnoses to be made quickly, cost effectively, and earlier in the disease course. It makes a novel combination of computer-based tests of memory and thinking and computerized analysis of MRI brain scans, which have been used in research for several years. It will provide support in diagnosis, making available the quality of information currently only available in highly specialist centres to doctors treating all patients, with the aim of reducing time to diagnosis to 3 months. We will build and test a prototype and demonstrate its value before developing a refined prototype that can be rolled-out nationally.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: HTS - Maximising the value of MRC Brain Banks
Funder: Medical Research Council

Abstract: The aim of this study to maximise the value of the brain tissue samples available to the research community in the four MRC-funded brain banks by the systematic analysis and integration of data from genomic studies on cases currently available for research in the banks. . All MRC brain banks have ethics approval to function as tissue banks and to collect, store and release tissue samples and data from consented donors. Consent/authorisation for genetic research is recorded and will be used to identify cases for inclusion in this study. Governance mechanisms include local NHS governance, Human Tissue Authority licences and Healthcare Improvement Scotland accreditation, along with MRC policies on research governance. This study will involve the investigation of normal brains from a wide age range and brains from well-characterised disease cohorts in the MRC brain banks. We aim to genetically characterise 1500 representative brains with Alzheimer disease, dementia with Lewy bodies /Parkinson disease, vascular dementia, frontotemporal dementia/motor neurone disease, Creutzfeldt-Jakob disease and controls. The data generated will greatly enrich the clinical and neuropathological data currently associated with these samples. This work will therefore provide major added value to the exiting brain banks, opening up totally new opportunities for mechanistic and translational research in neurodegeneration and brain aging. This work links strategic priorities of MRC and the NHS: understanding dementia and the role of genetics in disease. The MRC brain banks in Edinburgh, Kings College, Newcastle and Oxford will all contribute tissue samples to this study to maximise throughput. Rapid progress will be ensured by the experience of the investigators, the substantial research infrastructure in all four centres, the existing availability of very large numbers of high quality frozen and fixed tissue samples in the MRC Brain Banks, and by outsourcing both nucleic acid extraction and sequencing, with in-house bioinformatics. All raw data generated will be stored in a secure database and made openly available to researchers using samples from the brain banks. In the short term, the data generated is likely to lead to the identification of new highly-penetrant neurodegenerative disease genes and novel disease phenotypes. In the longer term, the data will also will provide a unique resource to help the international research community define the role and clinicopathological spectrum of known genetic causes of neurodegeneration, enable the genetic recall of brain tissue by international research groups studying neurodegeneration and allow researchers to formulate novel hypotheses based on the data from this “deep genotyping” approach.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: LHA Programme 2: Life course determinants of cognitive capability and cognitive ageing and their functional consequences
Funder: Medical Research Council

Abstract: This programme brings a life course approach to bear on maintaining quality of later life through promoting cognitive capability and reducing risk of depression. The essence of this approach is to map life course determinants and consequences of cognition and affect; their associations with each other, and their associations with other aspects of health and function through common and sequential causes. Key recent accomplishments include: Clarifying the pathways through which cognitive development influences adult health: directly for health outcomes closely related to neural systems governing cognition (e.g. affective state, balance and coordination, and reproductive function); through social pathways, primarily education, for preventable chronic physical diseases. Conducting cross-cohort work demonstrating the impact of adolescent mental health, particularly conduct problems, on a wide range of life chances, from educational and socioeconomic attainment, to social roles such as family formation and citizenship, to health. Building on our long-term work showing that cognition, as well as affective state, is modifiable in midlife. In the case of cognition modifying factors range from the societal (e.g. education, occupation, neighbourhood) to the behavioural (smoking, exercise, alcohol, diet). In most parts of the world older people account for the fastest-growing proportion of the population, with huge corresponding increases in the absolute prevalence of dementia – a trend that is projected to continue well into the future. In addition the World Health Organization has identified depression as the leading cause of disease burden in middle and high income countries. The long-term priorities of this programme are therefore to reduce the risk of these outcomes using a life course approach across all levels of explanation: from societal opportunities and barriers, through behavioural choices, to underlying regulation from genes, endocrine systems, inflammatory mechanisms, and autonomic control. In regard to the next five years, work within this programme consists of three broad themes: Capturing mental ageing, involving defining lifetime cognitive trajectories; ascertaining cognitive impairment and dementia; conducting a neuroimaging sub-study; and ascertaining the lifetime prevalence trend of depression and its determinants Maintaining mental capability in early old age, involving the role of self-organisation and its consequences for self-management of health; and a focus on education and occupational attainment, and retirement, in relation to cognitive skills Integration of mental and physical ageing, including outcomes in relation to cognitive capability and mental health, cardio-respiratory function, metabolic disorders, musculoskeletal function, and mortality


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Organisation of the Neuronal Networks of the Basal Ganglia
Funder: Medical Research Council

Abstract: The basal ganglia are involved in a variety of motor and cognitive functions and their dysfunction is implicated in a variety of disorders, most notably, Parkinsons disease. The aim of the proposed work is to elucidate the principles of operation of the neuronal networks of the basal ganglia in health and disease. Our previous findings have elucidated the critical role of the cortex and the so-called ‘indirect pathway’ in the expression of basal ganglia function. However, the basal ganglia is richly endowed with afferents from sub-cortical structures, including the thalamus, dorsal raphe, tuberomammillary nucleus and the pedunculopontine nucleus, that probably preceded, in evolutionary terms, the cortical afferents and are critical in the expression of basal ganglia function. One of the aims of the current proposal is define, using combined anatomical and physiological approaches, the roles of specific sub-cortical afferents of the basal ganglia, how they interact with the cortical and dopaminergic afferents in the ‘selection’ of populations of striatal spiny neurons and how they are altered in models of Parkinsons disease. We will also define the properties of the sub-populations of striatal projection neurons that give rise to the so-called direct and indirect pathways using transgenic animals and elucidate the properties of sub-populations of dopamine neurons that show differential susceptibility to degeneration in Parkinsons disease. The outcomes of this study will be a new level of understanding of the organisation of the basal ganglia in which both cortical and sub-cortical afferents are integrated, insights into what goes wrong in disease, and clues to possible new therapeutic targets in disease. Specific aims Define the organisation of sub-cortical inputs to the basal ganglia and define their relationship to other afferents. Define the properties of identified striatal projection neurons that give rise to the direct and indirect pathways. Define the topographical relationship between the dual striatal input to GPe and the complex microcircuitry of the GPe. Define the properties of individual identified neurons of the pedunculopontine nucleus, define how their activity changes in models of Parkinsons disease and how any aberrant firing can be modified. Define the properties of sub-populations of dopamine neurons that show a differential susceptibility to degeneration in Parkinson’s disease. Assess the potential of olfactory stem cells as a source of dopamine neurons for transplantation therapies for Parkinsons disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Functions and molecular characterization of novel GABAB receptor interacting proteins
Funder: Medical Research Council

Abstract: Glutamate receptors mediate most of the fast excitatory neurotransmission in the central nervous system, whilst -amino butyric acid (GABA) receptors mediate inhibitory neurotransmission. Whilst both of these receptors utilize ion channels for fast signalling, they also have second messenger-coupled receptors that modulate neurotransmission on longer time scales. The ion channels opened by glutamate include the N-methyl-D aspartate (NMDA) receptor, which has an important role in learning and memory. The second messenger coupled receptors for glutamate (mGluRs) and GABA (GABAB receptor are also important therapeutic targets for a range of pathological conditions, including epilepsy, neuro-excitotoxicity, anxiety and depression. Understanding the structure and function of these receptors is, therefore, extremely important, especially as it has become apparent that they function in large molecular complexes, which can modulate their responses. This project aims to characterize the novel proteins, identified in previous studies, that contribute to these complexes for the GABAB receptor. Previous work in the laboratory identified an important role for the N-terminal domain of the NMDA-receptor in receptor assembly. To pursue this further we have established a collaboration with dr Radu Aricescu (Wellcome Trust Centre for Human Genetics, Oxford) who is MRC funded to examine the structures of the ionotropic glutamate receptor family. Preliminary results show that a soluble form of the domain obtained from the AMPA receptor subunit GluR2, can be crystallized, and does indeed oligomerize. This work continues and has been extended to look at interactions of other neuronal proteins. Recently we found evidence for the association of the GABAB receptor with members of the copine family of proteins, and with the chloride transporter KCC2. Collaborative studies with dr. Colin Akerman (Dept. Pharmacology, Oxford) has revealed that activation of the GABAB receptor causes a rapid and sustained decrease in the activity of KCC2. Currently experiments are being carried out to determine the mechanism behind this phenomenon and how it is regulated. The copines are a relatively little studied family of proteins but two members of the family are brain specific and one, copine 6, shows evidence of neuronal activity related changes in amount. The proteins are thought to move proteins to the plasma mambrane in response to changes in intracellular calcium./ Our current work is aimed at testing this hypothesis and characterizing the function of these proteins in the brain. This will involve the use of siRNA knockdown of the proteins in cultured neurones, the production of antibodies to them and the use of mutated and domain swapped versions of the proteins to perturb their function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Interactions within and between the basal ganglia and thalamocortical circuits in function and dysfunction
Funder: Medical Research Council

Abstract: This research programme will provide fundamental new insights into the mechanisms and functions of neuronal network activity in the basal ganglia. We place special emphasis on explaining how mutual interactions between these nuclei, as well as key inputs from the cerebral cortex and thalamus, orchestrate the activity patterns that are generated therein. In particular, experiments are designed to elucidate when, why and how specialised types of network activity, such as synchronised oscillations, are either advantageous or counter productive for the operation of these circuits in the intact brain. We will define the factors controlling the temporal and spatial boundaries of synchronised activity in these circuits that must be in place for normal information processing and behaviour to occur. As an important corollary of this, we will also dissect the cellular substrates and network mechanisms supporting the inappropriate synchronisation of activity that emerges in these circuits following the chronic loss of dopamine from the brain, as occurs in idiopathic Parkinsons disease and its animal models. We will use novel and advanced electrophysiological, anatomical and analytical techniques to achieve these aims: we will record neuronal activity from several sites in the basal ganglia, cortex, and thalamus simultaneously using high-density multi-electrode arrays. Time- and frequency-domain analyses of the extracellular data derived from such large-scale recordings will enable us to elucidate the potential circuit interactions underlying activity. Further mechanistic insights will be provided by selective pharmacological challenge, by intracellular recordings of single neurons and by optogenetic and pharmacogenetic circuit perturbations. In some experiments, single neurons will recorded extracellularly and then selectively labelled using a juxtacellular procedure, allowing the post-hoc identification of the structural and neurochemical substrates underlying activity. We will utilize two complementary in vivo preparations, anaesthetised rodents and behaving rodents (rats and mice). This multidisciplinary approach will enable us to reveal the importance and mechanisms of neuronal network activity at several functional levels. In elucidating the functional and dysfunctional roles played by synchronised oscillations and other activities in the basal ganglia and their partner thalamocortical networks, this programme will significantly progress our understanding of how these circuits work together to influence behaviour. Moreover, the advances made will place us in a much stronger position to provide a rational basis for the development of new therapeutic interventions that are able to more effectively counteract abnormal brain activities and provide improved symptomatic relief in disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The Marie Curie Dementia Research Programme: developing an intervention to improve end of life care in advanced dementia
Funder: Marie Curie

Abstract: Background: In the United Kingdom (UK) 600,000 people have dementia, increasing to 1.2 million by 2050; 1/3 of people aged over 65 will die with dementia. Detailed research on the symptom burden and needs of people with advanced dementia at the end of life, and their carers, is lacking in UK; access to good end of life care is poor. Aim: To develop and pilot a complex intervention to improve end of life care for people with advanced dementia. Objectives: 1. To understand in-depth the symptoms, health and social care needs of people with advanced dementia; current pathways of care at the end of life, and needs of informal carers at this time and in bereavement. 2. To develop a complex intervention to improve care including: explanations of its core components; how it may operate in different settings (transferability); cost effectiveness; what works for whom in what circumstances and why. 3. To pilot the intervention in one site, collecting data to inform a future definitive trial. Method: We shall work within a realistic evaluation framework to develop and pilot a feasible intervention, in three closely linked workstreams Workstream One (0-12 months) a cohort study of people with advanced dementia and their carers will provide data on clinical and social needs. This will indicate the potential interventions required and inform case studies and vignettes for use in an iterative cycle of workshops and interactive interviews with carers and professional stakeholders. We shall define the core components of the intervention, including an understanding of context and mechanisms, and potential outcomes. In Workstream Two (9-15 months) we shall refine our intervention, considering adaptation of existing care models. Our intervention, and the team needed, will be described in a manual. We shall consider training and support needs and the costs incurred. In Workstream Three (15-36 months) we shall pilot our intervention in one setting to understand the interactions required for it to work, how its components influence care pathways, patient and carer outcomes, and assess our training and support programme. We shall check for long term effects, potential for transferability, and describe the cost-effectiveness of its components. How results will be used An in-depth understanding of an intervention to improve care, what works for whom in what circumstances and why, will inform provision of good end of life care in advanced dementia., and also the design of a definitive trial.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.2 END OF LIFE CARE;7.3 MANAGEMENT AND DECISION MAKING;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: NEUROLOGICAL