NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigation of the genetic and functional determinants of disease progression in Progressive Supranuclear Palsy
Funder: Medical Research Council

Abstract: Progressive Supranuclear Palsy (PSP) is a rapidly progressive neurodegenerative disorder. As in many other neurodegenerative diseases, to date, there have no effective disease modifying therapies for treating PSP. In cancer medicine, effective therapies are directed against specific biological pathways whose dysfunction drives the progression of the disease. We feel that the same principle should be applied to neurodegenerative disorders, in particular, studying genetic variation that drives disease progression. Whilst PSP is a sporadic disorder, it is likely that an accumulation of common genetic variants alter the risk of developing PSP and influence the rate of disease progression. Our project aims to be the first to discover the genetic determinants of disease progression in PSP. We will achieve this through single nucleotide polymorphism (SNP) genotyping of ~1000 PSP cases. Clinical and genetic data from pathologically diagnosed cases will be obtained from the Queen Square Brain Bank and our collaborators. Clinical and genetic data from clinically diagnosed cases will be obtained from a UK wide, prospective study of atypical parkinsonian subjects (PROSPECT study), for which Prof Morris is the chief investigator. This data will be used to carry out a genome-wide association study (GWAS) to identify genetic predictors of PSP phenotype and the rate of disease progression. We will then use our GWAS data, along with summary data from the original PSP case-control GWAS, to conduct transcriptome wide association studies (TWAS) to discover SNP-gene expression-disease risk and SNP-gene expression-disease progression associations. Finally, we will study the functional implications of progression GWAS 'hits' using CRISPR/Cas-9 technology in induced pluripotent stem cell models. We hope that this project will eventually lead to the development of drugs that directly target dysfunctional biological pathways to slow down, or even stop, the progression of PSP.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: TRP channels and white matter function in health and disease
Funder: Medical Research Council

Abstract: The importance of myelin is highlighted by the severity of disabilities observed in diseases in which it is damaged, such as Multiple Sclerosis (MS). I have shown, by simulating ischaemia in fresh rodent brain slices, that Ca2+-evoked myelin decompaction can be mediated by TRPA1 channels. TRPA1 channels were identified because the Ca2+ influx was inhibited by specific TRPA1 blockers and by global genetic knockout. It is vital that we increase our understanding of the role it plays in demyelinating diseases, as TRPA1 expression is heterogeneous, and many pathological substances activate it. Project aims: AIM 1 Generate and characterize oligodendrocyte-specific TRPA1 knockout mice. Using inducible TRPA1 knockout mice (Sox10-CreERT2 x floxed TRPA1), we will investigate the role of TRPA1 specifically in oligodendrocytes lineage cells in myelination and myelin pathology. We will use these mice in the following aims. AIM 2 Determine whether TRPA1 is a valuable drug target in demyelinating diseases. 2.1 Does oligodendrocyte TRPA1 activation impede white matter function in optic nerve ischaemia? 2.2 Does TRPA1 also cause myelin damage in white matter stroke in vivo? We will cause stroke in mice in vivo by occluding the middle cerebral artery with a filament. 2.3 Do agents that cause myelin damage in other diseases, do so via oligodendrocyte TRPA1 activation and/or upregulation? By patch-clamping oligodendrocytes, immunostaining, immunoblotting and qPCR, we will test whether endogenously- and exogenously- derived TRPA1 agonists raise [Ca2+]i in myelin, increase TRPA1 expression or cause cell death. 2.4 Does TRPA1 activation cause myelin damage in a model of MS? In collaboration with Kenneth Smith we will use the LPS injection mouse model of MS, which results in type III lesion formation. AIM 3 Investigating the mechanism of TRPA1-mediated white matter damage through patch-clamping and imaging intracellular ions with ion sensitive dyes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Development of a cot-side optical biomarker of brain tissue health following neonatal hypoxic-ischaemic brain injury.
Funder: Medical Research Council

Abstract: Intrapartum-related events are the 4th leading cause of childhood mortality worldwide. Infants exposed to a perinatal insult typically present with neonatal encephalopathy (NE) that is treated with hypothermia, which prevents adverse outcome in only ~50% of infants. There is an urgent clinical need to detect those neonates at most risk and who may benefit from adjunct therapies. We aim to address this by developing a novel optical instrumentation that will allow non-invasive, in-vivo, at the cot-site measurements of brain oxygenation, blood flow, metabolic rate of oxygen and mitochondrial function. This instrument will use: (1) broadband near-infrared spectroscopy or Broadband NIRS that has the capacity to measure brain vascular oxygenation and mitochondrial function. By measuring the light attenuation at many different near-infrared (NIR) wavelengths, one can estimate the vascular haemoglobin oxygenation and the redox state of mitochondrial respiratory chain enzyme, cytochrome-c-oxidase (CCO). (2) diffuse correlation spectroscopy or DCS has the capacity to measure cerebral blood flow (CBF). DCS uses a single wavelength of NIR light that measures brain blood flow by quantifying temporal fluctuations of light fields emerging from the tissue surface. Measurements of brain tissue CCO with Broadband NIRS and of CBF with DCS have been successfully but independently applied to monitor NE. For the first time we will combine them into a single instrument. The measurements will then be integrated using our computational model of brain tissue physiology. We will assess the instrument through a series of hypoxic-ischaemic studies in the neonatal preclinical model and validate its predictive capacity to quantify the level of brain injury using a series of multimodal measurements (MRS, EEG, Histology). Finally we will move beyond of proof-of-principle to a clinical observational study in NE infants both during the acute (Days 1-3) and post-acute phases (Days 4-7).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: The developing human pain connectome and brain dynamics of infant pain: sex differences, pain history and skin-to-skin care
Funder: Medical Research Council

Abstract: This proposal aims to study the structural and functional development of pain networks in the human infant brain, focussing upon the dynamic interactions between brain oscillations and pain. We will record resting and noxious evoked activity in the brains of premature and term infants of 28-42 weeks corrected gestational age in the neonatal units at UCLH and St Thomas' Hospital, using electrophysiology and magnetic resonance imaging. We will: (i) map the developing human pain structural and functional networks using existing data and our own acquired diffusion weight (DWI), structural (MRI) and functional (fMRI) brain images and (ii) record brain oscillations and nociceptive event related potentials (nERPs) using non-invasive electroencephalography (EEG) to analyse the dynamics of these networks. Data will be entered into a unique open access database and will be used to test these hypotheses: 1. The pain connectome matures over the last trimester of gestation. 2. Functional pain dynamics (the interaction between brain dynamics and an incoming noxious stimulus) undergo distinct developmental changes over the perinatal period. 3. Sex differences in the developing pain connectome and functional pain dynamics are apparent from birth. 4.Pain history, that is the frequency, intensity and timing of painful events, alters the development of the pain connectome and functional pain dynamics in the newborn brain. 5. Care-giver skin-to-skin contact diminishes or alters the functional pain dynamics. The data will provide novel insights into the development of pain processing in the human brain, how these interact with ongoing brain oscillations and how they may be modified by intrinsic and contextual factors. The results will provide a brain-based rationale for designing effective methods of pain control in neonatal intensive care.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: CoEN: Gut microbes, Neuroinflammation and Alzheimer's disease: determining the immunoregulatory role of gut microbiota on brain and behaviour
Funder: Medical Research Council

Abstract: Chronic low-grade inflammation (inflammaging) is a key feature in Alzheimer's disease (AD). Recent reports suggest that an altered gut microbiota can promote a brain inflammatory response. Partner 3 has shown an association between pro-inflammatory gut microbiota and A pathology in AD patients. However, the mechanisms by which changes in gut microbiota composition mediate the neuroinflammation, neuroplasticity changes and cognitive dysfunctions in AD remain unknown. We propose that the inflammaging in AD is precipitated by an altered gut microbiota. In our research programme, we will (1) stratify an inflammatory signature in faecal samples from AD and mild cognitive impairment (MCI) patients, (2) investigate how gut microbiota influence neuroplasticity, neurogenic processes and cognitive behaviour using fecal microbiota transplantation from AD/MCI patients to a novel animal model of chronic low-grade hippocampal inflammation, (3) identify a gut microbiota/inflammation signature modulating neural stem cell health/hippocampal neurogenic process using a novel in vitro parabiosis assay employing human neural stem cells growing in presence of patients' serum. Our results will inform how a gut microbiota and inflammatory pattern signature in AD/MCI patients may be used as a biomarker to classify disease stage and prognosis, which may offer future individualised therapeutic intervention for AD.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: CoEN Developing preclinical and clinical biomarkers of NRF2 pathway activation for therapeutic application in neurodegenerative diseases.
Funder: Medical Research Council

Abstract: There is an urgent need for effective neuroprotective therapies for neurodegenerative disorders including motor neuron disease and Alzheimer's disease. The heterogeneity and complexity of these disorders have proved major challenges for therapy development. However, in both disorders neuronal injury involves a combination of age-related attenuation of protective responses; oxidative stress; mitochondrial dysfunction; dysregulation of proteostasis and neuroinflammation. In the presence of such cellular stresses, an up-regulation of the NRF2 signalling pathway increases the expression of an array of cytoprotective genes. This response is attenuated during ageing and also in MND and AD, as well as in models of these disorders. Compelling evidence has emerged from robust model systems, with major contributions from the two teams underpinning this application, that NRF2 activation has positive benefits in protecting neurons from injury in MND and AD. The overall objectives are to develop multiple biochemical, transcriptomic and imaging biomarkers in robust animal models of MND and AD and linked with evaluation in human biosamples and imaging studies, to determine target engagement and indices of therapeutic efficacy of two NRF2-activating compounds (S-apomorphine and dimethyl fumarate) for future translation into human experimental medicine studies. Such 'translational biomarkers' are regarded as critical parameters for successful drug development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: CoEN: Investigating chromatin landscapes in neurodegenerative disease models
Funder: Medical Research Council

Abstract: In line with the aims of this "pathfinder" call, we will investigate the role of chromatin remodelling in neurodegenerative processes and test the hypothesis that development of pathology in human neurodegenerative diseases is modulated, at least in part, by short- and long-term chromatin responses to specific tissue challenges. In particular, we will investigate restrictive and permissive chromatin changes in animal models that mimic pathologic features of Parkinson's disease, prion disease and tauopathies. Chromatin changes and ensuing transcriptional alterations will be analysed over time prior to, during and after the development of pathology (e.g., protein aggregation and neurodegeneration). Bioinformatic analysis will help identify similarities as well as differences across disease models and elucidate metabolic/toxic pathways involved in cell-specific vulnerability. Our present lack of disease-modifying intervention for human neurodegenerative diseases is due to a limited knowledge of pathogenetic mechanisms. Although chromatin remodelling could be one of these mechanisms, it remains relatively unexplored from the experimental and translational standpoints. This proposed study is designed to provide key insights into the dynamic nature of neurodegenerative diseaseassociated chromatin alterations and will constitute the seed for further work aimed at targeting these epigenetic modifications as a novel therapeutic approach.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: CoEN 4007- Is prion like propagation of alpha synuclein aggregation associated with a ferroptotic cell death
Funder: Medical Research Council

Abstract: Cytoplasmic inclusions of aggregated alpha-synuclein (alpha-syn) are the major constituent of Lewy bodies; a pathological hallmark of synucleinopathies including Parkinson's disease (PD). Within certain biological environments alpha-syn self promotes aggregation and neuronal death in a prion-like mode of action. In alpha-syn mutations (i.e. familial PD) and various posttranslational modifications increase the propensity for aggregation, preventing the monomer from functioning as a key regulator of synaptic and endosomal vesicle trafficking. This disrupts dopamine compartmentalization and iron importation, leading to harmful dopamine auto-oxidation and iron accumulation; both prevalent features in PD. Recently, we have shown that a novel regulated necrotic cell death pathway called ferroptosis, defined by iron-dependent lipid peroxidation, is predominant in pro-oxidant models. Our current hypothesis is that alpha-syn dysfunction promotes ferroptosis via iron and dopamine dyshomeostasis, leading to a cellular environment that generates a conformational form of alpha-syn required for prion-like propagation. We aim to demonstrate a pivotal interplay between alpha-syn, iron and ferroptosis using translational studies to genetically and pharmacologically modulate ferroptosis together with clinical longitudinal studies in patients. Outcomes are expected to identify relevant wet (cerebro-spinal fluid) and dry biomarkers (MRI) as well as pave the way to future innovative therapeutic strategies based upon upcoming anti-ferroptotic drugs.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Neuropathological and amyloid peptide differences between DS and familial AD with duplications and missense mutations in APP gene
Funder: Medical Research Council

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of amyloid plaques mainly constituted of extracellular amyloid beta peptides (Abeta) deposits in brain parenchyma and intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau protein. Additionally Abeta can be found deposited in blood vessel walls as cerebral amyloid angiopathy (CAA), a major cause of intracerebral hemorrhage. While the presence of amyloid plaques in postmortem brains is common to all AD cases including sporadic, familial and Down syndrome (DS, trisomy of chromosome 21, with overdose of the Amyloid Precursor Protein (APP) gene on Hsa21), CAA is a more prominent phenotype in familial cases with either APP duplication or certain (but not all) point mutations. The nature and mechanisms underlying these pathological and clinical differences between APP causes of AD remain unclear. We propose a unique study specifically focusing on rare and poorly studied patient groups focusing on rare and poorly studied, but potentially very informative patient groups - those with APP mutations and duplications and DS - to elucidate differences that may provide important clues for treatment. We plan to investigate the diversity of clinical and neuropathological phenotypes associated with the diversity of alterations in the APP gene by studying endo-lysosomal alterations and Abeta species neuropathological differences in human cases, novel mouse models, and in several cell types derived from iPSC lines reproducing various diseases to unravel pathophysiological mechanisms involved in specific Abeta deposition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The development of better models and therapies for chronic neurodegenerative disorders of the CNS
Funder: Medical Research Council

Abstract: The pathological features of PD are known to involve selective neuronal subsets in the central, enteric and autonomic nervous systems, all of which appear to follow a stereotypic spatiotemporal pattern of alpha-synuclein pathology. To date though it has not been possible to model this distributed yet selective pathology preclinically (especially the CNS and enteric involvement in the same animal). My present proposal tackles this problem and builds on my extensive pilot data showing that a single systemic delivery of misfolded, wild-type human alpha-synuclein pre-formed fibril results in an evolving pathology that involves both the central and enteric nervous systems, with corresponding functional deterioration over 6 months, in a pattern of deficits and pathology that is, similar to that reported in people with pre-motor PD. Now I wish to further characterise this model over a longer time frame (up to 16 months) to evaluate pathological progression in this model to a stage equivalent to that seen in the clinic when patients have overt motor PD. This will be done, using clinically relevant assessments (including gastrointestinal, olfactory, motor, and cognitive function). As I have already shown the presence of progressive alpha synuclein pathology and neuroinflammation in the brain in my pilot data, this model will enable me to study the long-term benefit of cell therapy in the presence of host-to-graft propagation of pathogenic alpha synuclein. Furthermore, I will use induced neurons (iNs) directly transdifferentiated from sporadic PD patients to screen for novel therapeutics targeting alpha-synuclein pathology. As cell therapy by itself is unlikely to deliver benefits to the nonmotor symptoms of PD, identification of compounds with therapeutic potential on alpha-synucleinopathy can potentially complement the benefits of cell therapies to provide disease-modifying treatment for PD.


Research activity codes: 5.1 PHARMACEUTICALS;6.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Investigating the effects of CAG repeat structure and MSH3 variants on the molecular biology of Huntington's disease
Funder: Medical Research Council

Abstract: Huntington's disease (HD) is an autosomal dominant central neurodegenerative condition that causes involuntary movements, behavioural and psychiatric problems, and dementia. HD is slowly progressive over many years and life-shortening. There are no disease-modifying treatments. HD is caused by an expanded tandem CAG repeat in exon 1 of the HTT gene. Longer repeat lengths (over the disease threshold of 35) are associated with earlier onset of disease symptoms, but there is considerable variation. Some of this variation is heritable. Recent genetic studies have shown that variants in or near DNA repair genes can be associated with altered age at onset of symptoms. We have extended these data by sequencing the whole exomes of 500 HD patients with very early or late onset disease, after accounting for CAG repeat length. We have discovered a number of rare coding variants associated with altered age at disease onset. These include variants in the CAG repeat structure and damaging variants in DNA repair genes such as MSH3 and FAN1. The aim of this MRC-NIH partnering award is to probe the molecular mechanisms underlying these genetic observations, in collaboration with Dr Karen Usdin at NIH. We will synthesise artificial DNA substrates containing the variant CAG repeat structures and test them in assays of MSH2/MSH3 (MutSbeta) function: DNA-MutSbeta binding, nucleotide binding and ATPase activity. In addition, we will produce MSH3 containing some of the damaging variants identified by exome sequencing, and assay these in the MutSbeta systems described above. The protein-DNA assay systems described above are already established in Dr Usdin's laboratory and so combining this expertise with novel genetic variants will enable us to expedite our investigations of pathogenic mechanisms in HD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: How heterogeneous are oligodendroglia from normal human brain and spinal cord?
Funder: Medical Research Council

Abstract: The intricacies of the human brain are probably what define us as human, and the oligodendrocytes of the brain are vital in maintaining this. These cells form the myelin sheaths around nerve axons, allowing fast saltatory nerve conduction, and metabolic support to the underlying axon. Myelination is mostly postnatal, and can be disrupted around birth, due to genetic abnormalities or premature birth, in adulthood in diseases such as multiple sclerosis and in old age, either in normal ageing, or in other neurodegenerative diseases. We used to consider all oligodendrocytes as very similar, but we now know that they likely exist as different subtypes, depending on their developmental source, final location, the age and sex of the human, and the presence of neurological disease. This heterogeneity can now be studied in individual cells or nuclei by RNA sequencing, comparing each cell to another within and across humans, from post mortem tissue, using bioinformatics, with validation using immunohistochemistry/immunofluorescence and in situ hybridisation on such tissue. In this project, we will extract oligodendroglial nuclei, from precursors to myelinating cells, from human post mortem brain and spinal cord tissue from male and female fetuses, young adults and old adults, from forebrain, cerebellum and spinal cord, and perform single nuclei RNAseq. We will then analyse these data, pooled with our previous data, and any published and HCA data to better define oligodendroglial subclusters. We will validate them with our previous markers and new markers, and then study the similarities and differences between our sample sets. These differences may define functional differences which confer differential vulnerability to disease or ageing, in central nervous system regions, in males and females. In the future, we can repeat this with disease samples, improving target pathway discovery for white matter disease therapeutics.


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