NIHRDataInsights/HRCSData huggingface dataset:
Title: Changing network interactions in models of medically refractory epilepsy
Funder: Medical Research Council

Abstract: Drug-resistant epilepsy is a major clinical problem, affecting approximately a million people across Europe today. We propose to address this issue by examining a notable feature of a widely used in vitro model of pathological epileptiform discharges, induced by washing Mg ions out of the bathing medium. Previous work has shown that this model displays a striking transition from early pharmaco-sensitive, to late pharmaco-resistant patterns of activity. This model therefore represents a highly tractable system for understanding the cellular basis of one example of drug-resistant epileptiform discharges. We will test a key hypothesis that this transition arises from dysregulation of neuronal chloride. Initial experiments will examine changes in neuronal function and synaptic connectivity associated with the evolution of epileptiform activity in this model. We will use a combined patch-clamp / optogenetic approach, recording from brain slices prepared from young adult mice, in which various optogenetic proteins are expressed under cell-specific promoters. We will focus on the three most abundant cell types: pyramidal cells and interneurons expressing parvalbumin or somatostatin), exploring how cellular excitability and synaptic function changes as the epileptiform activity evolves. The epileptic network transitions occur relatively abruptly, so a particular focus will be to relate these to the kinetics of change of the various cellular changes. These temporal associations will then be further tested, using several experimental manipulations, which either speed up or delay the network transitions. Finally, we will use a novel optogenetic strategy that we have recently developed, called Cl-out (Alfonsa et al, 2016), which allows a light-activated rapide extrusion of chloride from neurons. We will test whether this optogenetic chloride extrusion can reverse the late stage pharmaco-resistant state, thereby reintroducing sensitivity to diazepam.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identification of novel bioactive mediators of tissue scarring, inflammation and extracellular matrix remodeling after spinal cord injury
Funder: Medical Research Council

Abstract: Spinal cord injury (SCI) can result in severe and lifelong disability, with profound social, health and economic consequences. With an estimated 4 million people worldwide living with SCI, healthcare costs among the highest of any medical condition, and no regenerative or disease-modifying therapies available to SCI patients, it remains a severe unmet need. There is an urgent need for innovative approaches to understand the molecular and cellular processes that underlie the chronic tissue pathology that is intractable to repair. Chronic dysregulated inflammation, tissue scarring and maladaptive changes in the extracellular matrix are central pathological processes responsible for the failure of tissue repair and functional recovery following traumatic SCI. Yet these processes are still poorly understood. In this translational project we will utilise multidisciplinary and complementary expertise to study how distinct inflammatory mechanisms affect extracellular matrix synthesis and fibrotic tissue remodelling after SCI. Our collaborative network (SCI-NET) will combine basic science and clinical approaches together with innovative proteomics technology to: a) characterize how intrinsic pattern-recognition inflammatory mechanisms affect matrix synthesis and proteolytic remodelling after SCI, b) identify novel cellular and extracellular bioactive proteins in SCI tissue and c) identify novel bioactive mediators with diagnostic and therapeutic potential for human SCI. The SCI-NET Consortium will examine the role of inflammatory activation on tissue remodelling and scarring in clinically relevant rat (Bradbury group) and mouse (David group) models of SCI, while the presence of endogenous alarmins will be assessed for the first time in human SCI plasma and cerebrospinal fluid (Schwab group). Advanced proteomics analysis (Schlapbach group) will characterize changes in the extracellular proteome related to alarmin signalling in rodent SCI tissues and human samples.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Laminar fMRI and resting state fMRI in the somatosensory system - effect of peripheral nerve injury on cortical circuits
Funder: Medical Research Council

Abstract: The goal of this project is to understand function and information flow in cortical laminar circuits, by using laminar resting-state fMRI (rs-fMRI) and fMRI to study the sensorimotor circuits in the human cortex at 7T. We aim to apply this technology to investigate plastic changes in cortical circuits after peripheral nerve injury. Despite regeneration and reinnervation, full functional recovery is impaired by cortical plasticity occurring during the long period of axonal regeneration. A better understanding of the changes in these circuits after nerve injury may help improve prognostics and guide future improvements in rehabilitation strategies. Because ultra-high-resolution fMRI and rs-fMRI can visualize the cortical layers, it offers the possibility of measuring input-output connectivity of cortical circuits, and the direction of information flow between brain areas. We will implement and optimize the technology and evaluate its potential for investigating processing in sensorimotor cortical circuits in healthy volunteers. Subsequently we will employ laminar fMRI and rs-fMRI to investigate plastic reorganization of cortical circuits resulting from interruption of sensory input after peripheral nerve injury. We will investigate changes in laminar functional activity and connectivity acutely after injury, and following subsequent regeneration and re-innervation after peripheral nerve regeneration. This project will improve our ability to interpret fMRI and rs-fMRI signals and provide an important tool for obtaining mechanistic insight into normal brain function and plastic reorganization in response to injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Determination of optimal medication to support efficacy of hESC-derived transplants for Parkinson's disease and assessment of side effect risk.
Funder: Medical Research Council

Abstract: Stem cell based approaches are poised to take over from foetal cell therapy as experimental approaches to the treatment of Parkinson's disease. Robust differentiation protocols have been identified and 2 hESC cell lines (H9 and RC17) are being produced to GMP grade materials for clinical trial. However, preclinical experiments have not, as yet, addressed the risk of reproducing the graft-induced dyskinesia identified in foetal cell transplantation trials, or evaluated the possible influence of ongoing medication on the survival and function of transplanted cells. Two approaches will be used to determine the safety profile and effect of medication on grafts of these hESC-derived dopaminergic cells. The design of this study is based on a review of patients in the TransEUro foetal cell transplantation, who are on average taking a combination of 3 antiparkinsons medications, as well as antidepressant and sleeping medication, prior to and following transplantation. 6-OHDA lesioned rats will receive transplants in two parallel experiments. The first experiment will examine the likelihood of commonly used anti-parkinson's and other neuroactive medication (L-DOPA, dopamine D2 agonist, MAO-B inhibitor, SSRI antidepressant and GABAA allosteric modulator anxiolytic sedative) having significant acute effects on the early phase (20 weeks post-transplantation) of graft survival and function in immunosuppressed 6-OHDA lesioned rats. Experiment 2 will explore the longer term consequences of L-DOPA exposure on functional efficacy and side effect risk using neonatally tolerised 6-OHDA lesioned rats (to avoid the use of immunosuppression) treated with saline or L-DOPA prior to and following transplantation and will be monitored for 1 year. Outcomes will directly influence the design of clinical trials with these cells, but will also be presented to GForcePD which has representatives from all groups working on clinical stem cell therapy for Parkinson's disease globally.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Developing slow wave activity saturation as a marker of depth of anaesthesia
Funder: Medical Research Council

Abstract: Anaesthetists currently have no robust way of detecting when a patient under general anaesthesia stops perceiving the outside world. Knowledge of the precise point when an individual's brain becomes unresponsive allows delivery of the optimum anaesthetic dose, thus reducing the risks associated with over- and under-anaesthesia particularly in vulnerable and at-risk patients. We propose a depth of anaesthesia monitor using a potential individualised biomarker for loss of perceptual awareness called slow wave activity saturation (SWAS). Our previous experiments, using electroencephalography (EEG) and functional magnetic resonance imaging (FMRI), indicate that the brain's electrical activity at slow wave frequencies (0.5-1.5Hz) saturates with increasing propofol anaesthetic dose. Our FMRI data show that at SWAS, thalamocortical isolation from sensory stimuli occurs and an alternative brain network persists. We believe this network, and the SWAS endpoint, represents the key transition when an individual's brain becomes disconnected from the external world and sensory events. Subsequently, we have shown that SWAS occurs during surgical anaesthesia for different hypnotic agents and in the presence of anaesthetic co-induction agents, such as opioids and muscle relaxants. We have recently developed a real time Bayesian prediction model (SWAS-BPM) that will allow titration of surgical anaesthesia to the SWAS endpoint, thus achieving perception loss within that individual. After optimisation of the SWAS-BPM for real-time titration, we will apply the prototype SWAS-BPM system in a feasibility study of 200 patients. We will confirm clinical effectiveness of SWAS based: on 1) no evidence of conscious cognitive state, 2) improved cardiovascular stability and 3) improved post-operative recovery compared with standard clinical monitoring. This study will enable a larger late-stage clinical trial of a SWAS-based depth of anaesthesia monitor with a commercial partner.


Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL
Title: A phase 1 trial of a retinoic acid receptor beta agonist for the treatment of spinal cord injury
Funder: Medical Research Council

Abstract: There are no effective treatments for spinal cord injuries (SCIs). We have developed a novel orally available retinoic acid receptor beta (RARb) agonist, KCL-286, that induces axonal regeneration in an adult rat model of brachial plexus avulsion (BPA). In BPAs the motor and sensory roots are severed from the spinal cord and the latter never regenerate, leaving these patients with a permanently impaired limb. KCL-286 modulates inhibitory components of the injury induced glial scar and intrinsic neuronal programs, promoting axonal regeneration in the central nervous system (CNS) and permitting sensory recovery. The proposed project is to carry out a first in man (FIM) study, with adaptive design to investigate the safety and pharmacokinetics (PK) of single and multiple oral doses of KCL-286. Target engagement will also be assessed as a surrogate measurement of KCL-286 activity. We have identified a putative pharmacodynamic (PD) marker: plasma tissue-type plasminogen activator (t-PA) which is known to be directly regulated by RARb activation. A regeneration marker has also been identified, S100B in plasma, that in preliminary studies, directly correlates with KCL-286 induced axonal regeneration measured at the end of treament in our animal model. If successful, the Phase 1 trial is intended to be followed by a small exploratory Phase 2a study in male patients who experience BPA, to assess efficacy. Funds for this proof of concept (POC) study are not sought in this current application but a team of surgeons specialised in this injury has been set up in preparation for the possible forthcoming trial. BPA qualifies for orphan drug designation (ODD) for which we intend to apply. Additionally, KCL-286 will potentially have a considerably wider applicability to other CNS injuries, such as stroke, contusions and traumatic brain injuries (TBI), which could lead to valuable healthcare benefits.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Defining and predicting variability in early Parkinson's disease using quantitative MRI
Funder: Medical Research Council

Abstract: Aims: This work will recruit individuals with established PD, possible prodromal PD and healthy controls into a longitudinal MRI study to answer these principal questions: 1. Can in vivo quantitative disease staging be achieved in PD using quantitative MRI (qMRI)? 2. What neuroanatomical features explain the clinical variability observed in PD? 3. Can future outcomes be predicted from a single baseline time-point? 4. Can qMRI detect PD during the pre-clinical phase of the illness? Through these, a quick, non-invasive way to quantify patterns damage in PD will be developed. Methodology: This work will recruit three cohorts: - Healthy controls - Idiopathic PD - Rapid Eye Movement Behavioral Disturbance Both clinical groups will undergo assessment and MRI scanning at baseline and two further annual assessments with repeat scanning at the final time-point. At baseline, the controls will be matched to the PD cohort, and a proportion of this group will undergo the same follow-up as the clinical cohorts. Detailed clinical assessment will be performed in all groups at each time-point. Scientific opportunities: This work is specifically powered to detect changes within brainstem structures involved at the earliest stages of PD, using imaging methods developed to allow subcortical nuclei affected by PD to be mapped in vivo. This allows a priori hypotheses based on post-mortem data, linking clinical variability to anatomical differences in PD, to be tested and developed further to predict future outcomes of disease. These approaches will also provide an accurate way to discriminate PD from normal ageing, that can then be applied to the RBD cohort to detect pre-clinical PD. Combined, this work has the potential to provide a quick, non-invasive means to diagnose pre-clinical PD, identify more homogenous PD subtypes, help tailor clinical decisions to individual patient trajectories and provide sensitive quantitative metrics for clinical trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The NET-PDD study: defining the roles of NEuroinflammation and Tau aggregation in Parkinson's Disease Dementia
Funder: Medical Research Council

Abstract: BACKGROUND Dementia affects half of Parkinson's disease patients within 10 years of diagnosis with a major impact on quality of life. Whilst cortical a-synuclein pathology has been linked to PD dementia (PDD), other factors are implicated. I hypothesize that PDD is driven by oligomeric forms of tau as well as a-synuclein, which provoke a neuroinflammatory response through activation of microglial Toll-like receptors (TLRs), in turn catalyzing the disease process. AIMS 1. to establish that neuroinflammation and tau aggregation are critical early events in PDD; 2. to demonstrate that oligomers of tau and a-synuclein are quantifiable in CSF and blood and are reliable biomarkers of PDD risk; 3. to show that these oligomers play a critical role in driving an inflammatory response in PD through activation of TLRs. METHODS I will compare 2 groups with newly-diagnosed PD, at 'high risk' (n=20) or 'low risk' (n=20) of dementia, and age-matched controls (n=40). Participants will undergo PET scans, lumbar puncture and blood sampling at baseline and 3 years, with interim clinical assessment. Specifically: 1. [11C]PK11195 and [18F]AV1451 PET will be used to measure microglial activation and tau deposition in the brain respectively; 2. CSF and serum samples will be analyzed for inflammatory cytokines, a-synuclein and tau using multiplex immunoassays; 3. novel methods will be used to quantify oligomers in CSF and blood including single molecule fluorescence spectroscopy and proximity ligation assays; 4. the inflammatory response of participant monocytes to tau and a-synuclein oligomers will be measured in vitro, with and without TLR inhibition. Candidate CSF and blood biomarkers will be validated in an independent cohort (200 PD, 100 controls). IMPORTANCE This will provide definitive evidence to support clinical trials of immunotherapeutic and anti tau-aggregation therapies to delay the onset of dementia in PD, and establish optimal biomarkers for these trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Glucocorticoid dynamics in health and disease
Funder: Medical Research Council

Abstract: This programme grant integrates cellular, tissue, whole animal and human volunteer investigations to investigate the biological mechanisms underlying the way the body has adapted to read the rhythmic output from the hypothalamic-pituitary-adrenal (HPA) axis. The underlying hypothesis we wish to test is that the dynamic oscillatory patterns of HPA activity provides patterns of glucocorticoid secretion that are critical for optimal brain function. We shall determine how different glucocorticoid receptor containing brain areas involved in cognitive and emotional responses respond differentially to altered patterns of CORT administration using genome-wide ChIP-Seq and RNA-Seq. We shall see how these region-specific changes relate to behavioural responses in the realms of motivation, effective bias and hippocampal memory. We shall go on to clinical studies looking at motivational and autonomic circuitry using fMRI and pupillometry. Ultimately our aim is to understand the role of CORT rhythmicity in brain pathways associated with apathy - and use this knowledge not only to treat patients on glucocorticoid replacement therapy but also to stratify patients with other conditions associated with apathy and HPA abnormalities such as depression, PTDS and chronic fatigue syndrome.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: In vivo pathway analysis to determine the mechanistic role of susceptibility genes for Parkinson's disease
Funder: Medical Research Council

Abstract: Genome wide association (GWA) studies have identified 24 risk loci for sporadic Parkinson's disease (PD). However, PD GWA loci often contain more than one gene. Furthermore, for most currently proposed PD GWA genes within the associated PD risk loci, the mechanisms linking them to PD are only tentative. The aim of this proposal is to undertake a biological validation of plausible PD GWA risk genes in zebrafish (Danio rerio), using a CRISPR/Cas-based, in vivo pathway analysis approach. Zebrafish offer unprecedented opportunities to rapidly study crucial aspects of PD GWA genes in a well characterised vertebrate model system. Zebrafish share greater sequence homology and are more likely to have functionally conserved mechanisms than other small model organisms. They also provide excellent opportunities to study the effect of GWA genes on a wide range of relevant mechanisms, including the 1. Dopaminergic neuronal activity in vivo, neurotransmitter homeostasis and loss of dopaminergic neurons; 2. Interaction between neuronal and non-neuronal cell death mechanisms (in particular neuroinflammation); 3. Interaction between PD GWA genes and ageing. We will combine neurophysiological, neurochemical, morphological and functional analyses with comparative RNA-seq based transcriptomic studies. Using the CRISPR/Cas strategy, we have already made stable mutant zebrafish lines for the PD GWA risk genes mccc1, gak, inpp5f, vps13c, gch1, sipa1l2, srebf1, acmsd, stx1b and tmem175 as well as additional stable mutant lines for the familial PD genes PINK1, LRRK2, Parkin and ATP13A2. The immediate availability of these lines will greatly accelerate the progress of this proposal. We will particularly focus on three pathobiological mechanisms, namely mitochondrial function/mitophagy, the autophagy/lysosome system and neuroinflammation. We will also undertake an in vivo gene-gene interaction screen to investigate PD GWA genes for their functional interaction with familial PD genes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Beyond the neuromuscular junction: dysfunction of spinal synaptic targets of motoneurons in Amyotrophic Lateral Sclerosis
Funder: Medical Research Council

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease that leads to impairment of motor control, paralysis, and death. While its causes are unknown, a number of different mutations accounts for approximately 20% of cases. This has enabled the development of mouse models that mimic the human disease. We propose to use two different animal models of ALS to study the specificity of spinal circuit dysfunction in ALS: the well-established SOD1G93A and the recently developed aggressive TauONhFUSP525L. While much past research has focused on molecular and electrophysiological changes occurring in motoneurons (Mns), there is evidence that synaptic contacts made by Mns within the spinal cord are also affected. These synapses are the basis for a negative feedback loop mediated by Renshaw cells that inhibit the same Mns they are excited from and a positive feedback loop mediated by contacts of Mns on each other. We will compare the strength of recurrent excitation and inhibition in Mns from wild type and ALS affected animals in order to quantify impairments in synaptic transmission, with each experiment being performed at different stages (beginning pre-symptomatically) of disease. First, we will establish the time course of the impairment of recurrent inhibition using EMG recordings. We will then use electrophysiological (patch clamp) recordings of Mns and Renshaw cells. We will perform quantal analysis of synaptic currents evoked by antidromic stimulation of motoneurons or during paired recordings of connected cells in order to measure features of individual synapses. Furthermore, we will use holographic two-photon stimulation to map the pattern and strength of connectivity between Mns and Renshaw cells, to verify whether ALS alters the architecture of recurrent circuitry. The identification of synaptic and circuit abnormalities in an ALS model could potentially identify a new therapeutic target for controlling the symptoms and slowing progression of disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL