NIHRDataInsights/HRCSData huggingface dataset:
Title: Non-invasive monitoring of human pluripotent stem cell differentiation into midbrain dopaminergic neural cells
Funder: Medical Research Council

Abstract: An emerging regenerative medicine therapy for Parkinson's is cell replacement therapy (CRT) with midbrain dopaminergic (mDA) cells differentiated from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs). Clinical trials have started in Japan with iPSC-derived mDA cells in 2018. The process of hESC/hiPSC differentiation is complex and heterogeneous. Furthermore, it is well described that different iPSC lines can respond differently to the same differentiation protocol. Here we propose to establish tools for non-invasive monitoring for mDA differentiation by interrogation the secretome of cells as they are converting from pluripotent cells to committed mDA progenitor cells. We have identified a number of secreted molecules, including TFF3, CORIN, PDGFC, SERPIN F1, and NRP1, that increase in conditioned medium during the early stages of mDA differentiation. In this project we will determine how robust these, and other markers, are at predicting mDA differentiation efficiency across two laboratories (Edinburgh and Kyoto) and for multiple hESC and hiPSC cell lines. We will further use unbiased proteomic methods to discover novel biomarkers for mDA cells, and importantly markers of non-mDA cells (Kyoto). Single-cell RNAseq will be use to define the heterogeneity of cells present in a transplantable mDA population with a known biomarker profile (Edinburgh), and the transplantation of these cell populations with be assessed a rat lesion model of Parkinson's (Cardiff). One of the deliverables of this project is a multiplexed assay system to simultaneously measure multiple positive and negative biomarkers of mDA differentiation that will be of high value to academic and commercial efforts toward cell replacement therapy for Parkinson's.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: CoEN5025 NANOSYN: Unravelling synaptic pathology in Alzheimer's disease and Dementia with Lewy bodies using super-resolution microscopy
Funder: Medical Research Council

Abstract: Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) are the two most common causes of dementia, characterized by neuronal loss and abnormal protein aggregates. In AD, the pathological hallmarks are extracellular aggregates of amyloid beta (Ab) and intracellular aggregates of hyperphosphorylated tau (ptau). In DLB, the hallmark is aggregated alpha-synuclein (alpha-syn) in the neuronal soma and processes. Synapse loss is an early and key feature in both diseases. However, the characterization of synaptic damage in humans has remained elusive due to the lack of sensitive techniques to resolve these small structures. In this project, we will apply 2 super-resolution microscopy techniques (Array Tomography [AT] and Single-Molecule Localization super-resolution Microscopy [SMLM] approaches, such as STORM and DNA-PAINT) to systematically investigate synaptic damage in single synapses in 5 human brain regions affected by AD and DLB pathology. We will use a unique collection of human brain samples collected in Edinburgh and Barcelona ready for AT/SMLM. We will compare the localization of oligomeric and fibrillar forms of Ab, ptau and alpha-syn at millions of synapses across several brain regions. This project will apply the latest technology to unravel this key phenomenon and could lead to the development of more specific treatments aimed at restoring synapses in these common dementias.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Auditory Cognition in Alzheimer's Disease
Funder: Medical Research Council

Abstract: Hearing loss in midlife is the biggest risk factor for dementia but the reasons for this are unclear. Hypotheses include peripheral hearing loss causing social withdrawal or an increased cognitive loading of the brain, both increasing the risk of dementia. I propose that the neural pathways for central hearing, specifically Auditory Working Memory (AWM; the ability to keep non-speech sounds in mind over seconds), and pathology due to Alzheimer's disease (AD) interact at the level of the hippocampus (HC; an early target in AD) in the medial temporal lobe. Impoverished AWM may be an early sensitive indicator of cognitive symptoms of AD in midlife due to reduced HC function. This project aims to provide the neuroscientific link between new tests of AWM that engage the HC and provide a proof-of-principle that AWM can be used as an indicator of cognitive decline in AD. 1. Cognitive neuropsychological studies will aim to show that structural changes to specific medial temporal lobe regions, such as the HC, worsen AWM performance. 2. Functional neuroimaging studies, in participants from midlife with a range of central hearing ability, will show that AWM performance is correlated with activity in specific HC subfields, such as CA3. Clinically, this project aims to identify novel preclinical markers of AD in midlife in the form of hearing tests. Scientifically, this proposal will establish how central hearing is related to cognitive decline in AD by providing mechanistic links based on medial temporal lobe neuroanatomy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: CoED5013 Innate Memory-related blood Biomarkers as a proxy of microglia-mediated neurodegeneration to predict early AD progression (ADIMB)
Funder: Medical Research Council

Abstract: Inflammation is a driving force in Alzheimer's disease (AD) and besides brain resident microglia, other innate immune cells from periphery, including dendritic cells (DCs), may have a role in AD pathogenesis and progression. Recent evidence indicates that following exposition to various stimuli, host innate immune cells undergo a mechanism of inflammation enhancement named innate memory (IM), which could contribute to neurodegeneration. DCs, a unique type of migratory innate immune cells that induce and regulate immune responses and inflammation, are subjected to IM reprogramming and orchestrate brain immune surveillance. In AD patients, DCs are dysfunctional and show pro-inflammatory profiles, thus when recruited to brain could contribute to neuropathology and promote neurodegeneration, reflecting the progression of disease. Aim of this project is to study AD patients at early disease stages in order to assess their blood levels of DCs as an index of cell recruitment to brain and define the IM status of their DCs in terms of enhanced inflammatory cytokine recall responses and epigenetic modifications following in vitro stimulations. The identified peripheral immune changes will be related to microglial activation, amyloid load and symptomatology to identify new peripheral biomarkers potentially helpful for diagnosis and disease progression tracking.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigation of the role of the snoRNA U8 in human health and disease
Funder: Medical Research Council

Abstract: Ribosome biogenesis is an evolutionarily conserved process required for protein production in all living cells. Ribosomal RNA (rRNA) is transcribed as a precursor, and then subjected to extensive processing and post-transcriptional modification with the help of small nucleolar RNAs (snoRNAs). snoRNAs are divided into two major classes, box C/D and H/ACA, based on the presence of conserved sequence elements and differential protein interactions. Whilst some box snoRNAs modify rRNA, either by 2'-O-methylation (2'-O-Me) (C/D) or pseudouridylation (H/ACA), the box C/D snoRNA U8 is involved in precursor (pre)-rRNA processing. Of note, non-canonical actions of snoRNAs are also being increasingly recognised, but are much less studied. Understanding the function of snoRNAs addresses a biological question fundamental to human health. Our project explores snoRNA biology in health and disease through a focus on the snoRNA U8, informed by our identification (Jenkinson et al. Nat Genet 2016;48:1185-92) and characterisation (Badrock et al. Am J Hum Genet 2020 AOP) of mutations in SNORD118, encoding U8, as the cause of a Mendelian disease of the cerebral vasculature called leukoencephalopathy with calcifications and cysts (LCC). Interestingly, in addition to its role in ribosomal biogenesis, clinical observation, in vitro analyses and in silico modelling suggest to us that U8 might play a previously unsuspected role in telomere maintenance. To investigate the role of U8 in human health and disease, we will use a combination of clinical phenotyping, Mendelian and population genetics, specialised in vitro assays, and our zebrafish animal model. The derived data will inform our general understanding of snoRNA biology, and the pathogenesis of LCC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Unravelling dorsal root ganglion as an intrinsic filtering device
Funder: Medical Research Council

Abstract: This project builds on our recent discovery that spinal somatosensory ganglia actively filter peripherally-born action potentials traveling along sensory nerves to the CNS. We aim to answer three main questions: i) how peripheral nociceptive input is filtered by the spinal ganglia; ii) why this filtering is more efficient in nociceptive nerve fibers as compared to those transmitting non-pain-related sensory inputs; iii) how this filtering changes with the development of chronic neuropathic pain. Our ultimate goal is to unravel basic principles of ganglionic filtering in order to develop new or improve existing therapeutic interventions. We will use iDISCO tissue clearing and light sheet microscopy in combination with genetic labelling of DRG neurons with defined and distinct sensory modalities to obtain accurate morphometry of the DRG-localised segments of the fibers. This will be further supplemented by generating a database of biophysical parameters of different fiber types obtained by electrophysiology. These measurements will generate parameters for realistic computational modelling of the t-junctional filtering in different types of afferent fibers. We will then use mouse neuropathic pain models in combination with in vivo electrophysiological recordings to directly measure changes in filtering efficiency in neuropathic animals. We will integrate these data with the computational modelling to obtain comprehensive understanding of the effect of neuropathy on peripheral pain processing. Fulfilling our research aims will identify basic principles of transmission of sensory signals through the spinal ganglia and how this transmission changes in chronic pain; ultimately this research will inform current and future therapeutic interventions for treatment/control of chronic pain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Multi-scale brain network mechanisms of working memory and short-term memory
Funder: Medical Research Council

Abstract: The aim of this project is to resolve multi-scale oscillatory brain networks underlying human STM and WM. To this end, we will record neuronal activity over the whole brain at millisecond temporal resolution with combined magneto- and electroencephalography (M/EEG) during STM and WM tasks. We will localize cortical sources of neuronal activity using MNE for inverse transform and use cutting-edge network analysis to map 1) large-scale within-frequencies network synchronization (PS networks) and 2) cross-frequency coupling (CFC) networks that are correlated with STM and WM task performance using in-house developed data-analyses softwares. Graph theory will be used to identify the extent of synchronization and the most central hubs (brain regions) and connections of the networks. This approach will reveal the most important brain regions and connections for STM and WM task performance. As M/EEG yields only correlative evidence, we will use TMS-EEG to stimulate the most important hubs (brain regions) and connections identified with M/EEG to test if network synchronization is causally and mechanistically related to WM and STM performance. To estimate the effect of TMS on synchronization, we will analyse concurrently recorded EEG data using the same approach as used for M/EEG data. M/EEG and TMS-EEG data will be collected from the same sample N= 30 healthy participants. The analysis in a common framework allows the offline integration of information from multimodal neuroimaging (MEG-EEG-TMS). This establishes if the large-scale PS and CFC networks play a causal role in memory.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: MICA: M102, A Combined NRF2 and HSF1 Activator for the Treatment of Motor Neuron Disease
Funder: Medical Research Council

Abstract: The overarching aim of this project is to complete the CMC (chemistry, manufacturing and control), preclinical toxicology package and develop clinical response biomarkers for a promising new treatment, M102 , for motor neuron disease (MND), a rapidly progressive, fatal neurodegenerative disorder. We have identified M102, a CNS penetrant small molecule dual activator of the NFE2-related factor 2 antioxidant response element (NRF2-ARE) and heat shock factor 1-heat shock element (HSF1-HSE) transcription factor pathways. M102 targets multiple genetically validated pathogenic mechanisms in MND including redox imbalance, inflammation, mitochondrial dysfunction and altered proteostasis. By targeting multiple pathways we expect to significantly increase the probability of clinical success. This is demonstrated by a preclinical efficacy package which includes neuroprotective effects in two MND-related animal models (SOD1G93A and TDP43Q331K transgenic mice) as well as in patient-derived astrocyte/motor neuron toxicity assays from SOD1, C9orf72 and sporadic MND patients. We have conducted a series of non-GLP pharmacokinetic and toxicological studies which indicate that M102 is likely to have sufficient safety margins in clinical studies following completion of GLP toxicological studies. We will also develop the response biomarkers for M102 to support its clinical development in MND patients. Completion of the proposed study will allow the initiation of phase 1 studies in healthy volunteers to evaluate the safety and pharmacokinetics of M102, and subsequent Phase 1b studies in MND patients to evaluate biomarker responses and early efficacy. These will be funded through further public or private funding. Ultimately, the data generated will be used to leverage further investment by our Industrial Partner, Aclipse One, to progress through to large efficacy studies and approval for MND.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Elucidating the interlinked roles of spastin and protrudin in axonal degeneration and regeneration
Funder: Medical Research Council

Abstract: This project will characterise in neurons the functional relationship between spastin and protrudin, two proteins implicated in CNS axonal degeneration and regeneration. Mutations in spastin are the leading cause of the axonal degenerative condition hereditary spastic paraplegia, while protrudin enhances CNS axonal regeneration. These proteins interact at the endoplasmic reticulum (ER) to regulate membrane traffic processes that depend on ER-endosome contacts. The functional significance of this interaction was unknown until our recent work demonstrated that spastin inhibits protrudin in non-neuronal cells. Cells lacking spastin or its binding partners IST1 or CHMP1B (both atypical endosomal sorting complex required for transport-III [ESCRT-III] proteins) develop highly polarised phenotypes identical to those observed on protrudin expression and which require protrudin for their formation. However, important questions remain regarding the role and molecular mechanisms of action of this pathway in human neurons, HSP pathogenesis and CNS axonal regeneration: 1. Is the inhibitory relationship that we have discovered between spastin, ESCRT-III proteins and protrudin present in neurons? Specifically, what functions of protrudin are affected and by what mechanisms? 2. Do spastin and the ESCRT proteins inhibit protrudin in the special context of its role in promoting axonal regeneration, suggesting acute inhibition of these proteins as a novel strategy to promote regeneration? 3. Are pathological effects of spastin abnormality in neurons mediated by increased activity of protrudin, suggesting protrudin inhibition as a novel therapeutic strategy for spastin-HSP? We will answer these questions, predominantly using human induced pluripotent stem cell-derived neuronal systems. In doing so we will elucidate molecular cellular mechanisms that link axonal degeneration and regeneration, and identify potential treatment strategies for both.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The roles of functionally defined populations of lamina I projection neurons
Funder: Medical Research Council

Abstract: Neuropathic pain is common, potentially debilitating and difficult to treat. Our limited understanding of CNS pain pathways has been a major impediment to developing new therapies. Projection cells in lamina I of the spinal cord convey pain and temperature information to the brain and contribute to symptoms of neuropathic pain. These cells are heterogeneous, and several studies have tried to assign them to functional classes. We have recently shown that projection cells belonging to two largely non-overlapping populations, defined by expression of the receptors Tacr1 and Gpr83, differ in their responses to noxious and thermal stimuli, implying that they underlie different aspects of pain and temperature sensation. Building on these findings, we will first provide a comprehensive functional classification of lamina I projection neurons by defining physiological and morphological properties of cells with each of these receptors, as well as those that express both or neither receptor. We will test the prediction that these populations differ in the local neuronal circuits that they engage, focussing on the roles of different types of excitatory interneuron, as well as the involvement of opioid receptors, which modulate nociceptive information. We will also identify those cells that acquire novel responses to brushing of the skin when inhibition is blocked, and are thought to underlie mechanical allodynia after nerve injury. We will then use synaptic silencing to test the prediction that these projection cell populations contribute to different symptoms of neuropathic pain. Finally, we will test whether a well-known type of lamina I projection cell, those responding only to skin cooling, correspond to the cells that lack Tacr1 and Gpr83, and we will define their location in dorsal horn circuits. The project will provide valuable information about spinal cord circuits involved in neuropathic pain, and should assist in the development of new treatments for this condition.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: MICA: Whole genome sequencing in multiple sclerosis
Funder: Medical Research Council

Abstract: Genome-wide association studies have been fabulously successful at identifying common genetic variants that influence susceptibility to multiple sclerosis (MS); the majority of which have been found to lie in non-coding regulatory regions of the genome that are active in immune cells. Despite this success there has been little progress translating these discoveries into high value targets for drug development. The primary aim of this project is to release this logjam of knowledge by fine mapping these associations. To do this we will combine genotypes from newly typed patients with existing data from previous genomewide association studies, together with case and control data from UK Biobank. This UK based data set (15,000 cases and 400,000 controls) will provide unprecedented power to establish manageable sets of credible SNPs for each association. We will then annotate these emerging variants using the extensive and growing array of epigenetic data generated by the International Human Epigenetics Consortium (IHEC). Leveraging Biobank and IHEC resources in this way we anticipate being able to further refine the credible set to <5 variants for more than half the associated loci. The resolution achieved will be further boosted by whole genome sequencing in 3,600 of the cases and by comparing, contrasting and combining data from other immune mediated inflammatory disease and relevant endophenotypes, such as immune cell counts; many of these traits are influenced by the same genetic variants that determine the risk of developing MS. The knowledge we will generate will not only transform our understanding of the genetic architecture underlying susceptibility to MS but more importantly will enable the translation of these genetic associations into meaningful biological insights that will in turn promote the development of safe and effective rational treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: MRC Transition Support award CSF Kathryn Peall
Funder: Medical Research Council

Abstract: Aims 1.Functional characterisation of midbrain dopaminergic (mDA) and striatal medium spiny neurons (MSNs) using already established Myoclonus Dystonia (SGCE mutations) patient derived and genetically edited embryonic cell lines. 2.Transcriptomic analysis of differentially expressed genes in mDA and MSN monocultures. 3.mDA and MSN co-culture evaluation combining wild-type (WT) and knock-out (KO) lines. Background Dystonia is a common and disabling movement disorder. Poor understanding of its pathophysiology has led to few effective treatments. MD is one of few genetically determined dystonias caused by autosomal dominant mutations, providing a unique opportunity for investigation. Previous work suggests network disruption underlies dystonia pathogenesis with the nigro-striatal junction and cerebral cortex being regions of importance. Work to date with this fellowship has demonstrated a hyperexcitable and more elaborate dendritic arbor phenotype in cortical neuronal cells, and developmental phenotype in mDA and MSNs lines. Methodology mDA and MSN neuronal cultures will undergo electrophysiological analysis using single cell patch-clamp and network-based multi-electrode array approaches. In addition to determining baseline excitability, chemical compounds will be used to manipulate components of the dopaminergic neurotransmission pathway (e.g. Dopamine transporter inhibition with nomifensine). Differential gene expression, using RNA-seq, will provide further insights into the impact of loss of epsilon-sarcoglycan expression. Finally, mDA and MSN co-cultures involving WT/WT, KO/KO and WT/KO combinations will provide further understanding of the contributions of intrinsic neuronal and exogenous factors. Scientific and Medical opportunities This functional characterisation will provide detailed insights into the cellular mechanisms in key brain regions underpinning dystonia, informing future studies including identification of novel therapeutic targets.


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