NIHRDataInsights/HRCSData huggingface dataset:
Title: Dissecting the role of PGC-1a in Drosophila models of familial and sporadic Parkinson's disease: a new therapeutic target in PD?
Funder: Parkinson's UK

Abstract: Parkinson's disease (PD) is the commonest neurodegenerative movement disorder and is characterised by the loss of dopaminergic neurons in the substantia nigra. Most cases of sporadic PD display intraneuronal inclusions known as Lewy bodies composed of aggregated a-synuclein protein. Mitochondrial dysfunction has been widely implicated in PD and a link between a-synuclein and mitochondrial abnormalities has been described. Drosophila melanogaster is commonly used to model neurodegenerative diseases and has provided significant insights into the mitochondrial abnormalities that result from defects in pink1 and parkin. Mutations in these genes are associated with autosomal recessive early-onset PD. Loss of pink1 or parkin function in Drosophila causes various phenotypes including reduced lifespan, locomotor abnormalities, muscle degeneration and mitochondrial dysfunction. It has recently been demonstrated that PGC-1a, a regulator of mitochondrial biogenesis, is a downstream effector of parkin and is becoming increasingly implicated in PD. Indeed PGC-1a gene expression has been shown to be downregulated in parkin mutant mouse models and human PD brain tissue. We will therefore study the role of PGC-1a using familial and sporadic Drosophila models of PD. We will assess whether PGC-1a modifies the mitochondrial abnormalities and other phenotypes associated with pink1 and parkin deficiency or overexpression of a-synuclein. Furthermore, we will use these Drosophila models of PD as a platform of drug discovery to determine whether drugs, which upregulate PGC-1a expression, are able to rescue the neurotoxic phenotypes in these PD models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mis-coordinated Ca2+ signalling in Parkinson’s Disease
Funder: Parkinson's UK

Abstract: Although significant progress has been made in understanding the genetic basis of Parkinson's disease (PD), much of the cell biology remains to be elucidated. Two of the most common genetic risk factors for PD are mutations in genes encoding LRRK2 and GBA1. Both have been linked to the lysosome. Such findings add to the growing appreciation of the importance of lysosomes in the pathology of PD. However the underlying mechanisms are incompletely understood. Much evidence now implicates the lysosome as a mobilizable store of Ca2+. Lysosomal Ca2+ release acts as trigger signal which is amplified by the endoplasmic reticulum (ER) and transmitted to mitochondria. We contend that disruption of this communication at either of the check-points results in cellular dysfunction. Here we test the central hypothesis that deviant lysosomal-ER Ca2+ signalling contributes to PD pathology. Preliminary data obtained through an innovation grant using patient-derived fibroblasts together with recently published findings provide supporting evidence for Ca2+ defects at both the lysosomal and ER levels. The student will ask whether lysosomal proliferation is a novel PD biomarker (Aim 1) and define the basis and consequences of aberrant triggering (Aim 2) and amplification (Aim 3) of Ca2+ signals in LRRK2- and GBA-linked PD. They will use a range of complimentary molecular, cellular and imaging methods brought by this joint application. The successful outcome of this project will provide new insight into the role of Ca2+ in PD pathology with clear scope for the development of novel biomarkers and mechanism-based therapeutic approaches.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Targeted cell-type specific gene expression profiling in a transgenic mouse model of Parkinson’s
Funder: Parkinson's UK

Abstract: Parkinson's is the second most common neurodegenerative disease and a major unmet clinical need in our ageing population. The main pathological feature is a catastrophic loss of dopaminergic neurons of the substantia nigra, resulting in a loss of striatal dopaminergic innervation. While the pathological disease end-state is well described from post-mortem tissue, the early changes in the physiology of the selectively vulnerable neurons are unclear. The proposed project will bring together two cutting-edge transgenic mouse models developed in the Wade-Martins Laboratory at the Oxford Parkinson's Disease Centre, University of Oxford. First, the Laboratory has generated a transgenic mouse model over-expressing wild-type alpha-synuclein from the complete human SNCA locus within a bacterial artificial chromosome (BAC), the SNCA-OVX mouse. This model recapitulates the sequence of pathological events seen in Parkinson’s. Here, the SNCA-OVX mouse line will be crossed to a second transgenic mouse line expressing targeted translating ribosome affinity purification (TRAP) technology to enable profiling of translated mRNAs in specific CNS cell populations. The second transgenic mouse line expresses the EGFP-tagged ribosomal protein L10a under the control of the tyrosine hydroxylase (TH) promoter (TH-bacTRAP) to allow translatome profiling. We will use SNCA-OVX/TH-bacTRAP mice to analyse perturbations in translated gene expression in vulnerable and resistant dopaminergic neurons, as well as to compare total mRNA and translated mRNAs to identify mRNAs under strong translational control. Providing a new powerful tool to investigate translational changes occurring during Parkinson's in vivo, we hope to obtain a more complete understanding of the underlying pathological pathways.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Self-management in dementia: a pilot trial of the development, efficacy and cost-effectiveness of a SM group intervention
Funder: Division for Social Care and Health Research (Wales)

Abstract: Receiving a diagnosis of dementia can be overwhelming, leading to feelings of hopelessness and inability to do anything to alter the situation. However, there is a great deal that individuals and families can do to ensure they live as well as possible with dementia. It is important to harness the resources that people bring to the situation so that people can start to take control over what is happening and work out how to cope and plan ahead. This is sometimes called ‘self-management’. We know that this is helpful in many other long-term health conditions. This study aims to find out how best to support people in developing the capacity for self-management in the early stages of dementia. drawing on the perspectives of people with dementia and carers, we will outline a self-management programme in which people with early-stage dementia and carers participate in a series of weekly group meetings. People attending the programme will be compared to a similar number of people not attending. We will find out whether attending the programme leads people with dementia to feel more in control and to experience greater well-being, and carers to experience less stress, compared to those not attending.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL
Title: TDP-43 and the molecular causes of its pathogenicity in neurodegenerative disease
Funder: Motor Neurone Disease Association

Abstract: TDP-43 is a highly conserved nuclear protein that has recently been identified as a major component of inclusion bodies found in the cytoplasm of neurons in the central nervous systems of patients suffering from both sporadic and familial ALS and frontotemporal lobar dementia, FTLDU. More than 30 dominant point mutations of TDP-43 have been identified in sporadic and familial ALS patients. TDP-43 inclusions have not been detected in the brains and spinal cords of SOD1 FALS patients, implying that the two represent different subsets of ALS causative agents and that these two are likely to cover the majority of ALS patients. The discovery that TDP-43 is a critical factor in ALS pathogenesis is the most significant breakthrough since the landmark discovery of mutations in SOD1 gene in 20% of FALS where we have contributed significantly to identifying the molecular causes of its disease-causing property and are currently working on knowledge-based drug-discovery programme. The discovery of TDP-43 has opened up a new and exciting avenue of exploration for global effort in understanding its disease causing properties at the molecular level and thus finding a suitable cure with wider implications than SOD-ALS. The success of international consortium ICOSA for SOD-ALS research will be repeated for TDP-43 where groups working on different aspects will be able to share data openly. We have recently established the expression systems for both mouse and human TDP-43 with a view of undertaking comprehensive structural studies using solution X-ray scattering and X-ray crystallographic techniques, a prerequisite to a knowledge-based drug-discovery programme and thus finding a ‘suitable cure’.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Translating the effects of new susceptibility genes for AD into disease mechanisms and potential drug screening platforms
Funder: Division for Social Care and Health Research (Wales)

Abstract: Alzheimer’s disease (AD) is a common debilitating disorder, which places a huge burden on the individual sufferer, society and the economy. Identifying and studying genes that contribute to disease development will help us to understand the causes of AD, providing the basis for developing new treatments. Recently, in a study including 60,000 individuals and twenty research cohorts throughout Europe and the US, we identified nine novel genes, that increase susceptibility to AD. There is now an increasing imperative to accelerate the translation of current and future knowledge gained from these AD genes into clinical practice and health policy. This fellowship will test the effects of new susceptibility genes on the processing of beta-amyloid, a protein observed at high levels in the brain of Alzheimer’s patients. It will develop new skill sets across genetics, molecular biology and drug discovery, forging collaborations between research groups within Cardiff University as well as the Severnside Alliance for Translational Research (SARTRE), to create models of AD relevant disease mechanisms, using several forms of human cell lines including cells from Alzheimer’s patients with specific genetic risk profiles, thereby providing a means to screen new therapeutic compounds to translate into clinical practice.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Automatic anomaly detection for brain imaging triage and classification
Funder: Department of Health (England)

Abstract: Modern brain imaging contains vastly more information than historical radiographs, yet its clinically informative output has remained the same: a radiologist's verbal report. As the information content of imaging increases, a void has opened between what we expensively collect and what we actually use. This is both a lost opportunity, and an obstacle to the continued growth of brain imaging. Our technology seeks to close this gap by applying novel computer-assisted algorithms so as to exploit much more of the information in each scan than a verbal report contains. An automatic anomaly map for each scan, indexing the deviation from normality of each point, will assist radiological reporting, allow the application of computer systems that predict clinical outcomes from patterns of anomaly, and guide radiological triage and resource/performance management. Our goal is to demonstrate the feasibility, robustness, clinical, and managerial value of the approach using a large collection of standard brain imaging, and to deliver a pilot system translatable into a full clinical product with a commercial partner. Without changing any clinical pathways or adding new investigations, the system will improve radiological reporting and optimise radiological triage and management, while creating a scalable major new platform for computational imaging analysis.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Novel multimodality imaging techniques for neurosurgical planning and stereotactic navigation in epilepsy surgery.
Funder: Department of Health (England)

Abstract: a) Successful neurosurgery for epilepsy depends on removing the parts of the brain that give rise to seizures, and avoiding damaging areas undertaking vital functions such as language, movement and vision. Current techniques to direct surgery are based on MRI scans to show brain structure, but do not show areas needed for vital tasks, and do not permit interactive simulations of placement of recording electrodes in the brain. b) We have implemented methods to identify critical areas of brain function, connections and blood vessels and display these in 3D. We will develop this system to enable the neurosurgeon to plan the best operative approach for inserting recording electrodes and for planning surgical resections. This information will be made available in the MRI scan guidance system in the operating room so that operations are more precise. c) We will produce a new system that will result in epilepsy surgery being planned more effectively, resulting in a higher cure rate and fewer complications. d) In collaboration with Medtronic, these advances will be applicable across the UK, and globally, with improved accuracy and precision of neurosurgery, so that target removal is more complete and the risk of damaging critical areas is reduced.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.4 SURGERY
Health categories: NEUROLOGICAL
Title: Mechanisms of G4C2-derived dipeptide repeat protein toxicity in ALS
Funder: Motor Neurone Disease Association

Abstract: Amyotrophic Lateral Sclerosis (ALS) is a devastating disease for which currently no cure is available. Research into the mechanisms underlying disease formation is fundamental for the development of novel therapeutic strategies. Alterations in the gene C9ORF72 were recently identified in a high percentage of ALS cases and represent the most common genetic abnormality in the disease. These genetic alterations are due to an aberrant repeat expansion of the C9ORF72 gene, which is thought to cause ALS. Very recently, it has been shown that these alterations can lead to repeat protein species that can accumulate in nerve cells, potentially causing the death of nerve cells. However, the underlying mechanisms are unknown. Here we propose to establish a fruitfly model of these genetic alterations in order to study how these repeat protein species can cause the loss of nerve cells typical for ALS. Because C9ORF72 alterations come together with accumulation of TDP-43, another protein implicated in ALS, we will also use our fly model to investigate the interplay between these C9ORF72-related repeat protein species and TDP-43 as well as other proteins involved in ALS formation and progression. We expect that our project will gain fundamental insights into the pathogenic mechanisms underlying the most common genetic abnormality in ALS. This in turn will identify therapeutic targets that can directly guide clinical research and the development of novel strategies for the targeted treatment of ALS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Motor Neuron Disease Diagnosis: The utility of standard frame rate B-mode ultrasound imaging
Funder: Motor Neurone Disease Association

Abstract: The current diagnostic test for MND involves recording electrical activity from muscles, using a needle electrode, to identify the small involuntary contractions (called fasciculation and fibrillations) that characterize the disease. Although they are not dangerous, many patients find the needles painful and unpleasant. The technique can only be applied to a limited range of muscles and, once a diagnosis has been made, clinicians are often reluctant to repeat the measurement too many times. This means it is difficult to follow the time course of the disease or quantify the benefits of any treatments that may be developed in the future. The small contractions can be seen in ultrasound images, just as ultrasound is used for screening unborn babies, and this offers the possibility of stress free examinations which can be applied to a wide range of muscles and can be repeated as often as needed for clinical or research purposes. A further advantage of ultrasound imaging is that it can provide a picture of the distribution of abnormal activity in the muscle as it enables assessment of a large portion of muscle, whilst needle techniques can only assess a very small region at a time. The first stage of the proposed study is to develop computer-based pattern recognition techniques, to detect and quantify the different involuntary contractions indicative of MND, subsequent work will explore the sensitivity and accuracy of ultrasound as a diagnostic tool compared with conventional needle electrode examination. We will collect data from patients suspected of suffering MND who have been referred for assessment. The results of the consultant’s diagnosis and the ultrasound image analysis will be compared to provide evidence of whether our new approach could reliably identify cases of MND to an acceptable clinical standard. Whilst no patient wants to be diagnosed with MND a great deal of distress, both to the patient and their family, is caused by uncertainty and an early diagnosis would be a considerable help. It also means that specialist help and referral could be made earlier and patients would have more time to achieve personal goals and put personal affairs in order. Improved diagnostic procedures would not only help the patients but would increase the efficiency of clinical neurology departments.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Selective Nanobrush Sensors (SNS) for Label-free Diagnosis of Neurodegenerative Disorders
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Advances in our understanding of disease processes emphasise the need for biosensors that are much more sensitive and selective for their target molecules. The majority of methods for detecting biomarkers in vitro often require fluorophores, electrochemical probes, magnetic beads, or active enzymatic labelling which results in extended and potentially complex steps between sample extraction and detection. This project is the result of the synergy of world-class expertise in nanoscale sensing, biomedical/electronic engineering, and neuroscience to develop next generation biosensors, dubbed the smart nanobrush sensors (SNS), capable of discrimination and monitoring of two exemplar molecules (alpha synuclein, amyloid-beta) in cerebrospinal fluid. The proposed technology is based on the development of aptamer modified solid-state nanopores, tailored for use in vitro. Nanopores are a class of single-molecule detectors that have been used successfully for label-free analysis; However, conventional nanopores lack selectivity, making it challenging to discriminate target molecules in complex clinical samples. The novelty of the SNS relies on the nanopore, having its inner surface coated with aptamer brushes selected to recognise individual biomarkers. The target molecules are identified by transient blockades of the ion current during their transport through the nanopore. The target-aptamer bond is then dissociated by the electric field inside the nanopore, leading to full sensor recovery and simultaneously allowing for quantification of the analyte concentration. The implementation of the SNS will provide 1) a novel tool for accurate and early clinical diagnosis, 2) fundamental insight into neurodegenerative diseases, 3) capability to monitor disease progression. The ultimate aim will be to translate the SNS from a lab-based concept to a clinically viable tool to improve quality of life.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: NEUROLOGICAL
Title: Noninvasive, ultrasound-mediated viral delivery of genes for optogenetic study of brain function
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Optogenetics - genetically modifying cells to make them light-sensitive, in order to observe and perturb physiological processes - has revolutionised systems neuroscience. However, current optogenetic techniques require either highly invasive procedures such as intracerebral infusion of viral constructs, or extensive transgenic breeding programmes. The development of non-, or less, invasive procedures for gene delivery into targeted brain regions would enhance scientific outcomes and improve prospects for long-term translation towards human therapeutic applications. Focused ultrasound, which has been used successfully to deliver small molecule drugs across the blood-brain barrier (BBB), provides a new approach for noninvasive delivery of optogenetic constructs into targeted brain regions. To effectively deliver large molecular weight compounds such as adeno-associated viruses (AAVs) across the BBB, without inflammatory response in the brain, new pulse sequences must be devised. The development of a successful and highly reproducible protocol for noninvasive delivery of genetically encoded sensors such as GCaMP6 would allow in vivo calcium imaging experiments to be performed with no procedure more invasive than a standard tail vein injection. The aim of this project is to develop a novel device for noninvasive delivery of genes into targeted brain regions, and to demonstrate its use by noninvasively labelling cerebral cortex with the calcium sensor GCaMP6s, and imaging neuronal activity through the skull with a two photon microscope.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL