NIHRDataInsights/HRCSData huggingface dataset:
Title: DJ-1 and neurodegeneration: its roles in mitochondria and in protein misfolding
Funder: Medical Research Council

Abstract: Parkinson's disease (PD), the second most common neurodegenerative disorder, presents with loss of dopaminergic neurons and the accumulation of misfolded alpha-synuclein (aSyn) in Lewy bodies. The study of genes associated with familial PD - such as PARK7 which encodes for DJ-1 - is elucidating the mechanisms underlying this disease. DJ-1 has several roles in the cell: oxidative stress sensor, protein chaperone, and a regulator of mitochondrial function. Here we seek to clarify how DJ-1 contributes to mitochondrial function and protein misfolding, and how these roles contribute to pathogenesis in PD. In initial work we have found that mutations in DJ-1 modulate its relocalization to mitochondria in mammalian cells with paraquat treatment. We thus seek to further characterize this effect with a range of disease-causing and functional mutants, additional oxidants, and in the context of aSyn expression. We also plan to investigate how DJ-1 mutations affect function and morphology of mitochondria. Finally we plan to extend this approach by studying how DJ-1 mutants modulate the structure and function of mitochondria in fruit flies. We will also explore the relationship between DJ-1 and the Tau protein, which is involved in the pathogenesis of Alzheimer's disease (AD), is a major component of neurofibrillary tangles, and has been recently genetically linked to PD. DJ-1 modulates misfolding/toxicity of several aggregation-prone proteins and co-localizes with Tau inclusions in AD and other brain disorders. Interactions between DJ-1 and Tau have not been studied, and their relationship in the context of PD has not been explored. Thus we propose to study the interaction between DJ-1 and Tau in living mammalian cells using bimolecular fluorescence complementation, and to what extent, if any, this alters Tau toxicity or formation of fibers. We will extend this work to a fruit fly model of Tauopathies, to ascertain whether DJ-1 modulates disease-relevant phenotypes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Roles of protein SUMOylation in AMPA receptor trafficking, synaptic dysfunction and cognitive impairment in dementia
Funder: Medical Research Council

Abstract: Understanding the fundamental causes of dementia is one of the most important challenges in neuroscience. Synaptic dysfunction, with a persistent and pathological enhancement of LTD, is the earliest and most reliable indicator of dementia pathogenesis. LTD is mediated by dynamic changes in synaptic AMPARs and we have shown that activity-dependent AMPAR trafficking requires protein SUMOylation. More recently we have obtained preliminary data revealing that SUMOylation is a key regulator of both NMDAR-LTD and mGluR-LTD. The purpose of this application is to test the hypothesis that dysregulation of synaptic protein SUMOylation is a causative factor in the defective AMPAR trafficking and synaptic plasticity that leads to dendritic spine regression, synaptic collapse, neuronal death and network failure in dementia. We shall determine 1) how levels of protein SUMOylation are altered in human AD brain and animal models of dementia; 2) how SUMOylation regulates AMPAR trafficking in NMDAR-LTD and mGluR-LTD, and how this is affected in disease models of dementia 3) if manipulation of protein SUMOylation can be protective against synaptic dysfunction, synaptic loss and cognitive deficits in dementia. We will use biochemical and histological analyses of post mortem human tissue in combination with functional and intervention studies in transgenic mouse models of dementia. The study will exploit a multidisciplinary array of techniques ranging from molecular biology, biochemistry and immunocytochemistry through electrophysiology and live cell imaging to animal behaviour. The applicants have complementary expertise and proven track records in all of these approaches. Our ultimate aim is to identify one or more SUMO-substrate proteins that could provide tractable therapeutic targets to reduce or prevent synaptic dysfunction associated with dementia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Imaging the spatial organization of brain connections
Funder: Medical Research Council

Abstract: This proposal aims to develop new approaches for defining and measuring functional organization in the human brain. The current paradigm in macro-connectomics is the idea that we can summarise brain connectivity using a network of "nodes" and "edges" - distinct brain units and the connections between them. However, the concept of "nodes" as segregated brain units remains elusive; and the simplistic view of the brain as a discrete set of units with edges representing their interactions overlooks complexities that have important functional consequences. Brain connections often follow a spatial organisation. Tracer studies in non-human primates have shown that large-scale connections can be organised into local patterns such as topographies, gradients or sub-clusters. Crucially, different spatial patterns of connections can overlap within the same regions. These anatomical facts have important functional implications. The coexistence of spatial patterns of connections within a single cytoarchitectonic area suggests that neuronal activity may also follow spatial patterns dictated by superimposed connectivities. Overlapping connection patterns may interact in complex ways to enable more elaborate functions. Spatial patterns of large-scale connectivity are currently ignored within the macro-connectomics research community. My proposal aims to fill a conceptual and methodological gap, and develop new approaches for defining and measuring the spatial organisation of human brain connections. These methodological developments will be carried out along two fronts: (i) development of novel methods for diffusion modelling and tractography; (ii) development of a mathematical framework for the characterisation of spatial connection patterns using in-vivo connectivity data. These novel methods will be useful to all researchers in the neuroimaging community, and will constitute a major advance in the way brain networks are currently modelled and interpreted.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: NEUROLOGICAL
Title: Gene therapy for refractory epilepsy
Funder: Medical Research Council

Abstract: Our proposal builds upon our recent breakthroughs in preventing epileptogenesis and treating established epilepsy with gene therapy using lentiviral overexpression of the potassium channel Kv1.1 and the optogenetic inhibitor halorhodopsin. We will determine which gene therapy tools are most effective for suppressing seizures and which are best tolerated. This involves testing a carefully selected series of different channels (Kv1.1, Kir2.1, Kv7.2/3; synthetic receptors, and improved opsins), promoters (inducible and cell specific), and vectors for delivery (non-integrating, and AAV). We will investigate how well the evolution of focal seizures in our models maps onto human disease and how they are disrupted by gene therapy. We will also push to expand the therapeutic potential by testing our best candidates in additional models of focal epilepsy (visual cortex induced by tetanus toxin, ferric chloride and cobalt), limbic epilepsy, and generalised epilepsy. Much of our work is aimed at identifying the optimal strategy that can lead to clinical trials in patients with refractory epilepsy, but we will seek separate funding to perform toxicology studies and meet the regulatory requirements in preparation for such trials. This is a revision of a highly ranked proposal entitled 'Viral manipulation of brain excitability for treatment of epilepsy' (September 2012), which received very positive evaluations but was criticised by two reviewers for focusing mainly on focal neocortical epilepsy with less attention to temporal lobe epilepsy. Focal neocortical epilepsy actually represents a greater unmet need than TLE, which can in many cases be treated by surgery. We recently audited our epilepsy practice and confirmed that 56% of patients referred for consideration of surgery had neocortical epilepsy. We have included pilot data acquired since the first submission and made further alterations and clarifications to address other points in the Case for Support.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Improving function in Huntington's disease through neurofeedback: using real-time fMRI to enhance cortical plasticity in early stages of the disease
Funder: Medical Research Council

Abstract: Huntington's disease (HD) is a genetic, neurodegenerative condition that leads to extensive brain atrophy, starting from the striatum and gradually spreading throughout the brain. Clinically it is characterized by progressive motor impairment, e.g. chorea, cognitive decline and neuropsychiatric symptoms. There is currently no known cure for HD and treatments prescribed for symptom management have significant side-effects. This project will deliver "proof of concept" testing of a novel, non-invasive intervention: neurofeedback training using real-time functional MRI (rt-fMRI), which will induce neuroplasticity and could help patients better manage the disease symptoms. Patients will be scanned using fMRI and will be trained to regulate the activity of specific brain regions through receiving in-scanner real-time feedback about the activity of these regions. We hypothesise that training patients to regulate the activation of brain regions whose activity has been disrupted by the disease (e.g. premotor cortex and striatum), will lead to improvements in behaviour and slowed disease progression. Such rt-fMRI has already been used for the treatment of other clinical conditions (e.g. Parkinson's disease, chronic pain, depression) with positive results on behaviour and symptom management without any side-effects. The proposed study will be the first "proof of concept" for HD and will provide preliminary evidence on the feasibility and efficacy of the intervention in early stage HD. If the results are positive, then these data will support further development with a large scale, randomized controlled trial in both early stage and premanifest HD. HD is an excellent model of neurodegenerative diseases as there is a precise genetic test, which allows prospective study of disease progression particularly in the premanifest phase. Our results may therefore have broad applicability and be extrapolated to other more common neurodegenerative diseases such as Alzheimer's disease.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: Peptide conjugated oligonucleotides for splice switching therapy of Spinal Muscular Atrophy
Funder: Medical Research Council

Abstract: SPINAL MUSCULAR ATROPHY (SMA) is a leading genetic cause of infant mortality due to progressive lower motor neuron death leading to muscle weakness. SMA is caused by loss of the SMN1 gene. Patients carry the very closely related gene SMN2 which is only partially functional due to its alternative splice exclusion of exon 7. There is a clear correlation between the variable copy number of SMN2 and the disease course, with milder patients having 3 or more SMN2 gene copies. SPLICE SWITCHING OLIGONUCLEOTIDES (SSOs) are single-stranded, steric block oligonucleotides which, when directed toward splice sites of pre-mRNA, block the binding of the splice enhancing or silencing proteins. SSOs which modify SMN2 splicing to facilitate exon 7 inclusion and generate functional SMN protein are being tested in early Phase I/II clinical trials. Current SSOs do not penetrate the blood brain barrier (BBB) and are therefore administered through invasive intrathecal injection. This is necessary for adequate spinal cord drug delivery but is not practical as a long term therapy and also fails to treat systemic features of the disease, especially important in the most severe cases. We have developed advanced SSOs comprising a peptide-conjugated SSO platform permitting effective systemic SSO delivery to peripheral tissues (e.g. skeletal muscle) and brain penetration which we will now take through rigorous preclinical development. Utilizing the PMO SSO chemistry, we will optimise PMO length and sequence for modifying SMN2 splicing and test three lead peptides for highest level of delivery to peripheral tissues and spinal cord. The most effective peptide-PMO compounds will be extensively studied to determine pharmacokinetics and an optimal treatment dose in order to generate a multi-dose, long-term treatment regimen that will be studied for efficacy and safety in SMA model mice. This lead compound will subsequently be taken forward for clinical development to be evaluated in SMA patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: MICA: Detecting ictogenicity and epileptogenesis
Funder: Medical Research Council

Abstract: Rationale: To validate the positron emission tomography (PET) tracer [18F]GE-179, which binds to the open NMDA receptor (NMDA-R), as a diagnostic tool to detect epileptogenic foci to guide invasive EEGs and refine surgery, and to identify those who will develop epilepsy after 1st late unprovoked seizure following either traumatic brain injury (TBI) or cerebro-vascular accident (CVA). Methods: (i) To detect brain tissue capable of generating seizures (ictogenicity), 30 patients with refractory focal epilepsy will be scanned prior to surgical resections. Of those, about 60-70% (~18-21) patients are expected to be seizure-free 1 year after surgery. (ii) To detect on-going ictogenicity, patients with focal epilepsies will be re-scanned either 1 year following surgery, if seizure-free, or at time of seizure-relapse. . (iii) To detect the development of epilepsy (epileptogenesis), we will study a further 50 subjects at-risk of developing epilepsy after 1st late (>7 days) unprovoked seizure following either TBI or CVA. Of those, about 30-40% (~15-20) patients are expected to have a 2nd seizure within 2 years. Twenty healthy controls will be studied for comparison, of those ten will be scanned twice for determining test-retest variability. We expect a 10% failure rate in chemistry production and 10% scan failure for subject-related reasons. Based on previous studies and pilot data, our group sizes are sufficient to detect a large effect size (0.8) with approximately 80% power. Hypotheses: [18F]GE-179 will show increased uptake in individual patients (i) with refractory epilepsy at the epileptogenic focus in those who benefit from surgery, (ii) localised increases outside the area to be surgically resected in those who relapse following surgery on stable or reduced medications, and (iii) who will develop epilepsy after their 1st unprovoked seizure following TBI or CVA.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Development of functional somatosensory circuits in the human infant brain
Funder: Medical Research Council

Abstract: I intend to establish a London based research program to study the mechanisms underlying the formation of early somatosensory cortical networks and the role of spontaneous and evoked neuronal activity in the developing human infant brain. The work will be cross-disciplinary involving neurophysiology, imaging, statistical analysis and neonatology at UCL, King's College London and their hospitals. I plan to record non-invasive electrophysiological activity (EEG) and the structural and functional brain correlates (MRI and fMRI) in premature and term infants of 28-42 weeks corrected gestational age in the neonatal units at UCLH and St Thomas' Hospital. I will: (i) compare the development of the EEG signal at rest with the structural and functional MRI within the same infants to establish the involvement of developing brain structures in generating the endogenous neuronal activity responsible for the initial formation of the somatosensory cortical circuits; (ii) compare the scalp topography and related cortical functional activation of different activity patterns to establish how early spontaneous and somatosensory-evoked activity shape and refine local and global cortical networks; (iii) explore the emerging organization of the somatosensory cortical maps using fMRI and sensory evoked potentials ; (iv) study the effect of early postnatal intensive care experience upon the development of cortical somatosensory function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Prediction mechanisms of the brain: a computational taxonomy
Funder: Medical Research Council

Abstract: The proposed research aims to develop a computational characterization of the roles of different brain systems in the formation and tuning of predictive models of the environment. The central theme of the research is to investigate the notion that the involvement of certain brain structures in a diverse range of cognitive processes can be understood in terms of formally equivalent computational functions provided in a range of superficially different cognitive contexts. I will focus on three computational challenges that the brain faces when forming predictive internal models of the environment, and which arguably cut across multiple behavioural and cognitive contexts: How to focus on the relevant dimensions of content and ignore irrelevant variation (computation 1: marginalization)? How to focus processing resources within a dimension to reflect the structure of the perceptual world, or task demands (computation 2: reparameterization)? How to balance the need for stability in predictive models with the need to incorporate new information about a changing environment (computation 3: stability/malleability of representations)? For each identified challenge, I will develop models of the core computational processes at both an algorithmic level to predict behaviour, and a biophysical level to predict brain activity. An important part of the biophysical modelling will be to incorporate physiological characteristics specific to the brain systems underlying each computation, to explain why these particular brain structures are suited for the computations they perform. To test the models, I will use a combination of imaging paradigms (using fMRI and MEG) that are carefully designed to test hypotheses about the neural code underlying brain activity (e.g. MVPA and cross-stimulus suppression techniques). I will also test specific hypotheses about the roles of neuromodulators by combining brain imaging with pharmacological manipulations in healthy volunteers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Targeting the innate immune system in Huntington's disease
Funder: Medical Research Council

Abstract: Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene, leading to an expanded poly-glutamine tract in the HTT protein. Considerable evidence suggests that HD is associated with increased systemic inflammation that may contribute to progression of the disease. We have shown previously that myeloid cells from HD patients are hyper-responsive to stimulation and that this is due to the intrinsic expression of the mutant HTT protein in these cells. Our hypothesis is that mHTT primes myeloid cell hyper-reactivity to immune stimulation and that the resultant low-level systemic inflammation contributes to HD progression. We aim to determine the mechanisms by which mHTT affects myeloid cells isolated from the blood of HD patients as compared to those from non-HD individuals, by means of full-transcriptome sequencing and methods to monitor transcription factor activation and binding. We also aim to establish the extent to which components of the peripheral innate immune system contribute to HD and to determine whether systemic inflammation can be targeted to modify disease progression. We will specifically target cells and pathways by genetic and/or pharmacological means in ways that might ameliorate aspects of disease, allowing us to dissect the contribution of specific cell populations, signalling pathways and molecules to HD progression. We hope this will form the basis of further work seeking therapeutic intervention that targets in peripheral innate immune system and systemic inflammation in HD. Understanding the contribution that systemic inflammation makes to pathogenesis is essential in determining whether targeting it might be a viable therapeutic strategy in HD. A complete mechanistic understanding of these events may identify targets that lead to the development of novel therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A Stem Cell Model to Study Human Cortical Interneuron Function
Funder: Medical Research Council

Abstract: Dysfunction of the cortical GABAergic interneurons has been identified as the core pathophysiology of epilepsy and neuropsychiatric disorders. Moreover, abnormal cortical development has been suggested as a major contributor to the development of these illnesses. However, due to our limited knowledge of human cortical development and a lack of defined aetiology and causal mechanisms of the pathogenesis, there is currently no effective treatment for these conditions. Pluripotent stem cells (PSCs) are capable of generating all types of somatic cells in the laboratory culture dish and therefore offer a valuable tool to understand human cortical development. Moreover, the generation of induced pluripotent stem cells (iPSCs) from patient somatic cells carrying defined genetic variants offer iPSCs a unique path to investigate the underlying disease mechanisms. It is hoped that knowledge obtained from these studies would lead to the development of new, rational treatments for a variety of neurological diseases. Substantial funding has been made available worldwide to create banks of iPSCs from healthy people and those with genetic diseases. In order realize the great promise of iPSCs in medicine, the next critical step will be the development of strategies that drive iPSCs towards somatic cell types targeted by a given disorder from hPSCs. Therefore, the main aim of this proposal is to develop strategies that command hPSC differentiation towards cortical interneuron subtypes. This work will prove the principle that hPSCs can generate defined disease relevant units of neuronal network amenable to controlled activity perturbation, which serve as the foundation for exploiting patient-derived induced pluripotent stem cells in understanding aberrant human cortical development and neurobiology associated with neurological and psychiatric diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL