NIHRDataInsights/HRCSData huggingface dataset:
Title: Translational development of a 3D bioactive nerve conduit for peripheral nerve repair, through application of topographical cues and stem cell support
Funder: Medical Research Council

Abstract: Background: Peripheral nerve injury is common, affecting children or young adults, and can be associated with devastating individual, socioeconomic and healthcare costs (e.g.£50,000 cost for median nerve injury). Despite rapid advances in microsurgical reconstruction techniques outcomes following repair remain poor and commercially available nerve conduits fail to surpass the current gold standard of sensory nerve autograft. As we continue to uncover the delicate neurobiology of nerve healing new areas for improving function following injury arise. The rigid 2 and 3-dimensional directional control of axonal growth upon polycaprolactone (clinically licensed, biodegradable) by microscale topographical cues has been demonstrated within our group, University of Glasgow. Evidence of the beneficial impact of differentiated adipose derived stem cells and pharmacological neuroprotection upon neuronal growth has been confirmed by collaborating laboratories. This project will combine these results to form a 3-D bioengineered, micropatterned nerve conduit that addresses the neurobiology of nerve repair, over a three year PhD programme. Aim To develop a novel nerve conduit that negates the need for sensory nerve sacrifice and improves the rate and directionality of regenerating nerve fibres across the site of surgical repair. Method Optimal conduit specifications will be confirmed in vitro (year 1) before testing in-vivo (year 2-3), as is necessary prior to clinical translation. DRG explant models will be cultured on topographically enhanced 3-D PCL conduits (engineered in house). Optimal stem cell co-culture parameters will be determined and selected to construct the nerve conduit for use in in-vivo studies. Rigorous outcome measures will be used to assess rat sciatic nerve repair using the 3-D nerve conduit to the current gold standard (autologous nerve graft). Furthermore the novel application micro-CT will provide detailed 3-D evaluation of axonal outgrowth.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Exploring astrocytic orphan G-protein coupled receptors as potential targets for neuroprotective therapies
Funder: Medical Research Council

Abstract: The current project aims to explore a new avenue for treatment of neurodegenerative disorders, such as Parkinson's or Alzheimer's disease, and possibly others where destruction of catecholaminergic neurons is prominent. In contrast to most previous research which targeted neurones directly, we propose to explore the potential of a neuroprotective pathway mediated by astrocytes. Astrocytes express two closely related orphan G-protein-coupled receptors GPR37 and GPF37L1 at extraordinarily high levels. It has very recently been found that the natural ligand for these receptors is prosaposin, a peptide with essential neuroprotective properties. Previous research has implicated GPR37 and GPR37L1 in control of viability of catecholaminergic neurones. Although GPR37 and GPR37L1 and highly expressed in astrocytes, we know essentially nothing of their actions in these cells or the downstream consequences for neurones. We propose an exploratory project which will inform us about prosaposin-induced GPR37/GPR37L1 mediated effects on astrocytes and test the idea that this pathway improves survival and transmitter release by dopaminergic and noradrenergic neurones in vitro. The project involves profiling of GPR37 and GPR37L1 in astrocytes from different parts of the rodent brain; evaluation of the effects of prosaposin on cultured astrocytes and of the roles of GPR37 and GPR37L1 in its actions; development of knock-down vectors for these receptors; and tests in vitro for the role of this pathway in neuroprotection using a synthetic analogue of prosaposin, prosaptide. These studies will provide a theoretical base for drug development and further exploitation of the prosaposin-GPR37/GPR37L1 pathway. Given that G-protein-coupled receptors constitute approximately 40% of current drug targets, we may well be facing the opportunity to develop a new class of drugs which would operate via GPR37/GPR37L1-mediated neuroprotective functions of astrocytes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Manipulating mitochondrial dynamics as a potential therapeutic strategy for Parkinson's disease
Funder: Medical Research Council

Abstract: Mitochondria are dynamic organelles that can be controlled by fission (drp1 and hFis1) and fusion (OPA1 and Mfn1/2) proteins. Imbalances in fission/fusion can result in synaptic dysfunction and neurodegeneration. This research will use two novel animal models of Parkinson's disease to evaluate the therapeutic effects of promoting mitochondrial fusion. The virally-transduced alpha-synuclein rats represent a human relevant genetic model with neurodegeneration. Because regular wild type mice do not display striatal damage, the novel Oct3-knockout mice will be used to model paraquat neurotoxicity. We hypothesize that blocking drp1 or promoting OPA1 function will attenuate neurodegeneration and synaptic deficits in these animal models. To test these hypotheses in vivo, we will use rigorous state-of-the art techniques such as: 1) in vivo microdialysis in freely moving mice followed by HPLC to quantify evoked striatal dopamine release; 2) Electrophysiology performed in acute slices to further investigate synaptic activities in these animals; 3) The Seahorse XF24 extracellular flux analyzer to measure striatal synaptosomal mitochondrial respiration; 4) Laser capture microdissection followed by single cell RT-PCR to quantify mitochondrial DNA mutations in nigral dopaminergic neurons; 5) rAAV-mediated gene transfer to inhibit drp1 function or promote mitochondrial fusion. To complement our genetic approach, we will systemically inject a drp1 inhibitor. 6) Animal locomotor activities (using the highly sensitive force-plate actometer) and neuropathology (stereological cell counting, striatal DA terminal density and total striatal DA content as well as protein aggregation) will be assessed.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: MICA. Assessing tau levels after traumatic brain injury (TBI) using [18F]T807 positron emission tomography (PET)
Funder: Medical Research Council

Abstract: The long-term effects of traumatic brain injury (TBI) are often devastating and under-recognised. This has resulted in a 'silent epidemic' of disability, with enormous social and economic costs. In a unique patient cohort from Glasgow, the cumulative mortality rate 13 years after all types of head injury was more than 40%. Patients who survive, often develop catastrophic social problems A major factor driving disability is the development of neurodegeneration. A key pathological marker of this is the accumulation of abnormal tau protein. TBI patients are at risk of both Alzheimer's disease (AD) and chronic traumatic encephalopathy, with neurofibrillary tangles containing hyperphosphorylated tau present in both diseases. There is a pressing clinical need for in vivo tau neuroimaging as this would allow patients to be stratified using a key marker of the early stages of neurodegeneration after TBI. In collaboration with Imanova and AVID, we will investigate the utility of [18F]T807 as a tool to investigate tau pathology following TBI. We will test the hypothesis that patients with long-term disabilities after TBI have high levels of abnormal tau as measured by [18F]T807 PET. Patients will be recruited from the Glasgow cohort who have continuously followed-up since head injuries in 1995/6. The trajectory of clinical outcome has been tracked, allowing an accurate assessment of its relationship to tau pathology. Advanced MRI techniques will also be used to assess structural and functional measures of neurodegeneration, and these will correlated with the level of tau pathology. If successful this work will: (a) provide a sensitive and specific marker of tau pathology after TBI, which will allow us to stratify patients for risk of accelerated cognitive decline and dementia; and (b) provide support for the use of [18F]T807 PET as a diagnostic tool for the identification of neurodegeneration after TBI.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: MICA: Development of a software application for detection and monitoring of attentional deficits in delirium
Funder: Medical Research Council

Abstract: Delirium affects at least 1 in 8 acute hospital patients. It has multiple severe consequences, but is grossly under-detected. A fundamental cause of the low rates of detection is the lack of well-validated tests for the core cognitive diagnostic feature of delirium: inattention. Currently available assessments of inattention have several drawbacks including inadequate discrimination between delirium and dementia, specific training required to administer, and lack of objectivity. We previously developed a new neuropsychological test for the objective measurement of inattention in delirium. This was implemented on a purpose-built computerised device (Delbox). We have now developed a prototype software application (DelApp) for smartphones based on the same test. The DelApp has many advantages over existing tests, including objectivity, automated scoring and ease-of-use. Studies in 30 hospital patients showed highly comparable performance between the Delbox and DelApp. Further proof-of-principle single-rater studies using the DelApp in more than 200 hospital patients have provided additional evidence of good performance of the DelApp. The primary objectives of the programme of work are: (1) To further develop the DelApp, including optimisation of test parameters, user interface and data acquisition and display. (2) To conduct Phase 1/Phase 2 case-control studies in older patients (aged >64) in general wards (delirium, dementia, control groups) and in adult-age patients (aged >17) in intensive care units (delirium, control groups) to assess feasibility, reliability, diagnostic accuracy, and to inform optimal cut-points. (3) To conduct a Phase 3 study in unselected patients in general wards and intensive care units. The main aim is to determine the diagnostic test accuracy and other test characteristics of the DelApp in detecting delirium in representative patient groups and clinical settings.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL
Title: WNT signaling: biomarker and target evaluation in Alzheimer's disease
Funder: Medical Research Council

Abstract: The invariant failure of Biopharmaceutical pipelines to modify Alzheimer's disease (AD) progression indicates the need for new creative solutions beyond currently active areas of genetics, amyloid-ß, and Tau pathology. Very recent work from our groups and others indicate that novel elements of the canonical and noncanonical WNT signaling pathways could be targeted to modify and monitor AD progression. In this project we will use multidisciplinary approaches, including brain oriented drug screening, a novel proprietary mouse model of AD, new genetic and pharmacological tools for modulation of WNT/GSK3 and WNT/JNK pathways, human blood samples from our and the IMI/EMIF platform to identify novel biomarkers of AD progression and a pilot study on metabolomics, to explore the impact on AD of novel WNT elements including but not limited to clusterin, DKK1 and Nrf2. Our results in this pathfinder phase with the identification of new candidate targets and drugs for clinical studies will pave the way to therapeutic innovations in the long-term programme. Indeed, several Biopharma companies have initiated drug development programs aimed at targeting certain components of the WNT signaling pathway, including ligands and other small molecule regulators of Axin1 and GSK-3, and Nrf2 that will be interested in our findings.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Risk and Modifying factors in Fronto Temporal Dementia
Funder: Medical Research Council

Abstract: Fronto Temporal Dementia (FTD) is a devastating pre-senile dementia characterized by the progressive deterioration of the frontal lobe and changes in social and personal behaviour and blunting of emotions. Up to 40% of cases have a positive family history and this has been the key to the remarkable progress in our understanding of the molecular basis of FTD. Seven genes have been identified of which MAPT, GRN and C9Orf72 explain >50% of familial cases, but how these different genes lead to a very similar clinical phenotype is unknown. There is no cure for FTD and success of therapy will depend on whether a single therapy can be applied to all patients or if specific approaches are needed for the distinct genetic, clinical and pathological subgroups. Therefore it is essential to identify all major genetic and environmental risk and modifying factors in the pathogenesis of the disease. We will use existing genetic and pathological knowledge as a starting point to decode affected processes and pathways in different groups of patients with FTD using a multi level approach based on genetic and "omics" data from patients and corresponding animal and cellular models. The biological significance of identified networks will be validated in our cellular and animal models and will pinpoint potential pathomechanisms that are specific to a single FTD-subtype or common to all forms. The results will be utilized to improve the quality of our predictions towards targeted intervention.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Comprehensive Unbiased Risk factor Assessment for Genetics and Environment in Parkinson's Disease
Funder: Medical Research Council

Abstract: Despite the advances in the identification of genes involved in Parkinson's disease (PD), there are still appreciable gaps in our understanding of PD. Therefore we propose a comprehensive approach based on (i) a unique collection of families and (ii) large cohorts of sporadic PD patients for (iii) genetic studies and (iv) assessment of environmental modifiers that will translate into (v) functional validation studies. Using NGS strategies, we will disentangle the complex genetic architecture of PD and better define the underlying functional variants in disease-associated GWAS loci. Newly identified genetic variants are filtered for pathogenic relevance and replicated in large cohorts of PD patients also using the unique resources of the GEO-PD Consortium. Subsequent assessment of disease modifiers includes two complementary approaches: Mendelian randomization, and gene-environment interaction studies. To validate genetic risk variants, functional studies on patient biomaterial will be performed based on (i) the unique expertise for fibroblasts- and iPSC-derived cellular models of PD and (ii) a large repository of biomaterials from carriers of PD-associated mutations. Established readouts allow to study functional effects of identified genetic risk factors and will be used to assign novel disease genes and risk variants to defined pathogenic pathways. Moreover patient-based cellular models will be challenged with environmental risk factors identified as modulators of disease.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Early macrostructural and microstructural cortical changes in Alzheimer's disease: longitudinal and cross-sectional studies of early change
Funder: Medical Research Council

Abstract: Evidence suggests that Alzheimer's disease (AD) is associated with a long period of progressive accumulation of molecular pathology, followed by increasing neuronal damage, before symptoms appear. The best chance of successful treatment may therefore come from offering therapies as early as possible. In order to do so we need to be able to identify those at risk, to stage their disease, and to track progression with robust and precise methods. Although rare, familial AD (FAD) provides a unique opportunity for prospective study of individuals who are cognitively normal but are destined to develop the disease. Whilst rates of brain atrophy increase prior to symptom onset, detecting subtle changes in cortical grey matter may be a more sensitive and earlier marker of neurodegeneration. Recent advances in imaging have led to the development of techniques for high quality macroscopic (cortical thickness) and microscopic (diffusion) measures of cortical change. Whilst by definition asymptomatic, those who have prodromal AD may have subtle cognitive deficits. Novel neuropsychological tests have been able to detect subtle abnormalities in memory, including binding of short-term memory and accelerated long-term forgetting, in other conditions involving mesial temporal cortex. These tests may also be useful in early AD. The aims of this study are: 1. To use serial MRI to investigate cross-sectional and longitudinal markers of early cortical and juxtacortical change using sensitive metrics (cortical thickness and diffusion) in those at-risk of developing FAD, those mildly affected by FAD and sporadic AD, and controls; 2. To evaluate the sensitivity of novel neuropsychological tests of mesial temporal dysfunction at detecting differences in these groups; 3. To evaluate how these markers of early degenerative change compare temporally to one another, and to more established cognitive and imaging outcomes; and how these correlate with molecular markers of AD pathology.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Use of PrP transgenic drosophila to measure mammalian prion infectivity
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: The aim of this proposal is to test the hypothesis that PrP transgenic drosophila are a suitable invertebrate host to measure mammalian prion infectivity. The prion disease we will study is scrapie of sheep. We have already generated ovine PrP transgenic drosophila and have shown exogenous exposure to ovine prions induces a toxic phenotype in these flies. The specific objectives of this proposal are 1. Determine the sensitivity of ovine PrP transgenic drosophila to ovine prion infectivity 2. Use ovine PrP transgenic drosophila to measure prion infectivity in brain, lymphoid tissue and blood from scrapie-infected sheep 3. Strain type ovine prions in ovine PrP transgenic drosophila To achieve these aims, ovine PrP transgenic drosophila, at the larval stage, will be orally fed ovine prions by the addition of scrapie-infected inocula to drosophila feed. The prion inocula will include: brain homogenate from classical (ARQ/ARQ and VRQ/VRQ) or atypical (AHQ/AHQ) scrapie-infected sheep brain material; lymphoid tissue homogenate and time course blood plasma samples from classical scrapie-infected sheep; homogenates of serially passaged, defined prion strain-infected ovine PrP transgenic mouse brains. The prion-induced phenotype of ovine PrP transgenic drosophila will be assessed in post eclosion flies by measurement of locomotor ability using a negative geotaxis climbing assay, together with analysis of disease-associated PrP deposition by IHC and molecular profile by western blot; confocal analysis of PrP in fly brains (+/- Proteinase K) and quantitation of PrP by conformational dependent immunoassay on fly head homogenates. All of the ovine PrP transgenic flies have already been generated for use in this proposal. All of the prion inocula have already been acquired from, and characterised within, previous prion projects within our laboratory. All of the experimental protocols to be used in this proposal are fully established in our laboratory.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: Reduction & refinement in animal models of neuropathic pain: using systematic review & meta-analysis
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Neuropathic pain (NP) is a major clinical problem and current therapies do not provide adequate analgesia for many patients. Subjecting animals to lesions modelling NP, or to tests designed to assess responses to painful stimuli, is inevitably associated with distress and discomfort. We plan to systematically identify all animal experiments modelling NP. Using meta-regression we will provide evidence as to whether less noxious tests are as predictive as more severe alternatives to refine their use to minimise pain and suffering. We will also investigate the effect of experimental duration and post-operative analgesia regimens to reduce the period of suffering of the animals. We will provide precise estimates of the observed variance of different tests. This will identify which tests require fewer animals and allow robust sample size calculations to be performed and reported to reduce the number of animals sacrificed in experiments which are too small for the effect sought or those which use more animals than required. Limitations in the validity of experiments reduce their reliability and may compromise their utility. Preclinical studies rarely report measures to reduce potential sources of bias. We will use meta-analysis to quantify the impact of quality on estimates of treatment effects in the NP literature. We will quantify the impact of publication bias in the NP literature; this will highlight the importance of the issue and encourage the dissemination of all data derived from the use of animals. We will also make the database publicly available; this will enable colleagues to identify whether experiments have already been conducted and reduce the unnecessary replication of experiments. This project will generate robust empirical data without the use of animals. It will contribute towards a reduction in the number of animals used and the refinement of experimental design, tests used and has the potential to reform and improve animal welfare in this field.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL