NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating microglial senescence in central nervous system health and disease
Funder: Wellcome Trust

Abstract: Neurodegenerative diseases cause progressive loss of nerve cells in the brain, resulting in impaired cognition and/or movement. There are currently no treatments for these diseases and therefore, another approach to developing treatments is required. With ageing, dysfunctional or “senescent” cells accumulate in the body and are involved in various neurodegenerative diseases. Microglia are specialised immune cells in the brain responsible for keeping surrounding nerve cells healthy. Microglia can become senescent, meaning they struggle to maintain nerve cell health. We hypothesise that senescent microglia regulate neurodegeneration. However, how senescent microglia differ in ageing and neurodegenerative disease is unknown and it is unclear how senescent microglia contribute to neurodegeneration. I will explore this using immunofluorescence, whereby senescent microglia and associated neurodegeneration can be identified by staining cells with specific markers. I will also induce and prevent microglial senescence specifically, using two specially designed mouse models, and assess neurodegeneration. It is also unknown what causes microglial senescence but ageing and long-term inflammation throughout the body likely contribute. I will investigate how microglia become senescent in mouse models undergoing ageing or long-term inflammation. This work aims to improve understanding of the role of senescent microglia in neurodegeneration and provide alternative targets for treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Profiling neuroinflammatory signatures of disease heterogeneity in C9orf72-associated ALS-FTD
Funder: Wellcome Trust

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) lie on a disease spectrum. Individuals affected by these conditions may have problems with movement (symptoms of ALS), thinking and behaviour (symptoms of FTD), or a combination of both. Even families with the same genetic cause, such as a C9orf72 mutation, can develop very diverse disease symptoms and there is currently no way of predicting how someone will be affected. This uncertainty is not only difficult for patients; it also affects our ability to conduct clinical trials, as some treatments may only work on a subset of patients, and disease heterogeneity may confound outcome measures. It has recently been suggested that neuroinflammation influences disease presentation along the ALS-FTD spectrum. I aim to explore this by creating a cohort of deeply clinically phenotyped post-mortem brain tissue. I will investigate neuroinflammatory gene expression in key tissues, aiming to create a holistic image of neuroinflammatory dynamics along the spectrum. Finally, I will validate my findings in a human stem cell-derived model and explore specific therapeutic approaches to target neuroinflammatory dysregulation. These studies will help shed light on methods to treat individual patients and symptoms, improving the outlook for clinical trials in this field.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating mechanisms and rescue of a novel microgliopathy caused by dysfunctional LRRC33/NRROS
Funder: Wellcome Trust

Abstract: Recent discoveries have suggested a dysfunctional immune system of the brain plays a significant role in a set of diseases known as microgliopathies. New disorders of this type are still being identified, but ones which have so far been uncovered lead to significant brain damage and decreased lifespan. Our group has discovered a developmental microgliopathy-like disease in a patient caused by a defect in a protein named LRRC33. However, we do not fully understand the impact this defect has on the brain’s immune system, how it affects different types of brain cells, and how it leads to disease onset. We aim to investigate these questions using a combination of animal models and patient post-mortem tissue. We will also seek to determine whether we can repair brain damage in our animal disease model by suppressing the brain’s immune system. Strategies such as these, along with improved knowledge of the biology of the disease, could potentially lay the foundations for development of treatments for these microgliopathies, of which there are currently none.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating mRNA transport granule composition and transport dynamics in motor neurons
Funder: Wellcome Trust

Abstract: Neurons transport messenger RNA (mRNA) over long distances within RNA transport granules, which are made of one or more mRNAs coated by RNA binding proteins (RBPs). It is thought that such granules bind directly to motor proteins for transport, however, recent studies show that they can ‘hitchhike’ onto intracellular organelles for indirect mobilisation. The overall goal of my PhD is to uncover how these two distinct pathways are integrated to ensure coordinated transport along neuronal axons. Moreover, I will determine how these pathways are affected in motor neuron disease (MND). Specifically, I will focus on the RBP named Staufen, which is an important component for RNA granule assembly and transport, and which has been suggested to contribute to MND onset and progression. I aim to identify the mRNAs transported via either route under normal conditions and in MND. I will use a novel method in which proteins representing each transport pathway are modified by an enzyme that “tags” nearby proteins. Tagged proteins and associated mRNAs can thus be identified and used to investigate RNA granule composition associated with each transport pathway in healthy and diseased neurons.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The effect of dominance status on hypothalamic processing of social stimuli
Funder: Wellcome Trust

Abstract: Social hierarchies are ubiquitous among animals. They ensure efficient allocation of resources such as food, shelter, and mates, and reduce the need for physical confrontations within a group. Recent research has uncovered how representations of social status are learned and encoded in the brain, specifically in cortical areas. These representations of social status inform which social behaviours are shown by animals at different levels of hierarchy. For instance, subordinates are more likely to exhibit social avoidance and defensive behaviours such as fleeing, and show more restraint when presented with rewards. Despite these findings, it remains unclear how cortical representations of social status affect downstream areas that are more closely linked to controlling status-specific behaviours. My PhD project will investigate how cortical representations of dominance status affect the processing of social stimuli in hypothalamic areas, and how this leads to altered social behaviour in dominant vs. subordinate males. This work will help explain how social status is translated into appropriate social behaviour by specific brain circuits, and how dysregulation of these processes might contribute to maladaptive behaviours.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: NEUROLOGICAL
Title: The mechanical regulation of chemical signaling in axon pathfinding in the developing Xenopus laevis brain
Funder: Wellcome Trust

Abstract: During nervous system development, neurons extend their axons over long distances to predefined targets. Research from the last decade has revealed a plethora of chemical signals that are involved in instructing axon guidance. However, it is now becoming increasingly evident that axons also respond to the mechanical environment that they grow in and this affects axon guidance. Moreover, crosstalk occurs between chemical and mechanical signalling. Thus, a holistic understanding of axon guidance would involve understanding both chemical and mechanical guidance cues and the crosstalk between them. A variety of chemical signalling cues which mediate attraction or repulsion are known to regulate axon pathfinding. These include Slits, Semaphorins, Netrins and Ephrins. However, chemical guidance cues do not act alone. The mechanical environment that the axons grow in, also influences axon pathfinding. One of the ways axons respond to the mechanical environment is through mechanosensitive ion channels (e.g. Piezo1). My PhD project aims at exploring the crosstalk between mechanical and chemical signalling in axon pathfinding, using the optic tract (OT) of Xenopus laevis as a model system.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Sources of relaxation differences in quantitative MRI
Funder: Wellcome Trust

Abstract: Magnetic resonance imaging (MRI) it is a powerful technique which allows brain tissue to be explored indirectly. Despite more than 40 years of innovation, the standard clinical MRI protocol remains largely unchanged: a set of 3 images influenced by ‘relaxation’ phenomena, namely how quickly tissue returns to equilibrium when perturbed by a radiofrequency pulse. Radiologists detect pathology through differences in relative intensity. While recent advances can estimate relaxation times directly, facilitating quantitative MRI, the biophysical origins of differences in relaxation times are poorly understood. In brain tissue, differences in cell size, orientation and make-up have all been posited, but their contributions have not yet been fully characterised. I will use computer simulations and real MRI experiments to tease-apart these mechanisms. This will include validating the specificity of different imaging parameters in animal-models using histology and further evaluating their sensitivity in the human brain at different stage of development. My aim is to make quantitative MRI more interpretable, boosting its clinical utility both in neuroscience and medicine.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Patient-derived monoclonal antibodies as a precise tool to understand the pathophysiology of Caspr2-antibody encephalitis
Funder: Wellcome Trust

Abstract: The production of autoantibodies by our immune system can be protective. In some cases, it can result in brain inflammation with memory disturbances and seizures.My work aims to understand the basis of these disorders by studying a prototypical condition associated with antibodies against Caspr2. To study Caspr2-antibodies, I clone out patient antibodies from their blood and cerebrospinal fluid and study their characteristics using a suite of biochemical techniques. I will relate this to the properties of the cells which make these antibodies, also isolated from blood and cerebrospinal fluid, to address questions about the underlying immunology such as which cells first make the antibodies and which cells carry the most harmful antibodies. After cloning, the antibodies will be subjected to in vitro tests to study their effects on nerve cells. Those with most potent effects will be injected into mice to observe their influence on memory, mood and seizures. In addition, real-time recordings of epileptogenic activity in awake animals will be used to investigate how the antibodies can lead to seizures. These studies will utilise patient-derived antibodies as a powerful tool to decipher their relative contributions to human neurological illness and offer directed future methods to target their production.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mechanisms of neurodegeneration and repair following demyelination in zebrafish
Funder: Wellcome Trust

Abstract: In the neurodegenerative disease multiple sclerosis (MS), the lipid-rich layer surrounding nerve fibres known as myelin is lost, in a process known as demyelination. While this is thought to contribute to neuronal loss seen in MS, it is not clear exactly how neurons respond to demyelination, which prevents targeting key mechanisms that could be responsible for neurodegeneration in disease.In animal models of demyelination, it has been observed that synapses, the structures that allow neurons to communicate with one another, are lost. Synapses are also affected in MS, which could contribute to clinical disability and cognitive impairment. We expect that synapse loss is an early feature of the neuronal response to demyelination, and if prevented, may protect neurons from degeneration. In this study, we aim to understand mechanisms of synapse loss and neurodegeneration after demyelination, and to determine if they are direct effects of demyelination or mediated by immune cells that respond to demyelination. We will employ zebrafish as a model, because we can follow individual neurons and synapses before, during and after demyelination using live imaging. This research will allow us to investigate the relationship between demyelination and synapse loss and identify strategies to prevent neuronal loss from ocurring.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Structural and molecular investigation of neuronal adenylyl cyclases underlying synaptic plasticity
Funder: Wellcome Trust

Abstract: Long-lasting changes in strength between synapses are a key element of learning and memory. The intracellular second messenger cyclic AMP (cAMP) plays a key role alongside Ca2+ in coordinating such synaptic plasticity. cAMP signalling operates in localised ‘nanodomains’ that are centred on the enzymes that synthesize cAMP – adenylyl cyclases. In neurons, two Ca2+-sensitive cyclases (AC1 and AC8) are particularly important in signalling underlying synaptic plasticity. These enzymes are relatively understudied, partly due to technical hurdles. I will take advantage of novel crosslinking approaches, and state-of-the-art mammalian cell expression systems to overcome these hurdles and study the enzymes in three ways. First, I will use crosslinking of extracts from rat cerebellum (where the cyclases are abundant) to identify and characterise their molecular interactions. Second, I will employ inducible expression in suspension cultures of mammalian cells to express large amounts of the cyclases. This will enable me to study their three-dimensional structure – a key step in fully understanding their function. Third, I will use a high-throughput assay to screen for novel ligands of neuronal cyclases. This multidisciplinary approach will address a basic element of neuronal signalling that is critical in brain regions including the cerebellum, hippocampus, and the striatum.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Generative models for biological methods of control
Funder: Wellcome Trust

Abstract: Behavioural phenotypes are highly relevant to many diseases, particularly those involving neurodegeneration, such as Friedreich’s Ataxia or Parkinson’s disease. While these behavioural phenotypes arise from low-level molecular and cellular processes, they are highly complex. As a result, identifying structure within behavioural data can be challenging. Generative models are a type of model which are able to generate new instances of data, unlike discriminative models which can only discriminate between existing instances. As a result, these models must solve the more complex problem of whether a given data instance is likely, as opposed to what classification it most likely belongs to. This means they must learn the underlying distributions of the data itself, often capturing more meaningful correlations as a result. Building generative models of behaviour can therefore offer deeper insight into the structure of behaviour, as well as a means of analysis through synthesis, where the ability of a model to successfully reproduce naturally observed behaviour provides further validation of the model. These models can also be used to investigate the impact of disease on behaviour through attempts to ‘corrupt’ the model’s underlying processes and compare the output to experimental data obtained from individuals with a particular disease.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Investigating hypoxia-induced immunometabolic changes in microglia in the context of vascular cognitive impairment and cerebral small vessel disease
Funder: Wellcome Trust

Abstract: Small vessel disease (SVD) is a chronic brain disease that causes vascular cognitive impairment (VCI). Insufficient oxygen delivery to the brain occurs in SVD and causes damage to parts of the brain containing bundles of nerve fibres, termed the white matter, as well as activation of the immune cells of the brain, microglia. We think that microglia act to reduce the white matter damage, thus slowing the disease progression. We also think that this protective immune response relies on energy provided through adjustments in microglial cellular metabolism, however this has never been investigated. Therefore, in my PhD I aim to characterise how microglial metabolism changes when oxygen levels are low, to understand how these changes relate to white matter health and to investigate whether they are controlled by the microglial receptor TREM2. I will also look for molecular signatures of metabolically altered microglia in brain tissue from people with SVD and from rodent models of SVD/VCI. Finally, I will try to manipulate microglial metabolism in an effort to improve white matter health and cognition in a rodent model of SVD/VCI.These studies will increase our understanding of immune responses in SVD/VCI and will contribute to identification of potential therapeutic targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Mitochondrial dynamics and synaptic health in Alzheimer's disease
Funder: Wellcome Trust

Abstract: Alzheimer’s disease (AD) arises through the aggregation of amyloid-&beta; (a cleavage product of APP) and tau protein throughout the brain. The build-up of these proteins can result in harmful changes to neuronal functioning and health, including dysfunction of mitochondria, which are responsible for energy production within the cell, and changes to the way neurons communicate with each other at synapses. My project aims to express AD-causing mutant forms of APP and tau proteins in primary neuronal cultures to generate a sped-up model for neurodegeneration in AD. Upon validating these models with regards to neuronal health and production of neurotoxic proteins, the models will then be used to investigate the changes to mitochondria morphology and proteins controlling this. Using a mixture of protein biochemistry, immunofluorescence imaging and potentially electrophysiology, I will detect changes that occur when either or both of these neurotoxic proteins are expressed to dissect each proteins’ role in mitochondrial dysfunction. Further to this, the cellular localization, surface expression and activity of synaptic proteins including AMPA receptors and CB1 receptors will be investigated following expression of these neurotoxic proteins. This work could help to find new points of intervention to slow dementia in AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Identifying Epigenetic Drivers of Abnormal Neuro-Immune Interactions Which Influence Hippocampal Ageing
Funder: Wellcome Trust

Abstract: The ability to form long-term memories is a fundamental property of the brain. Age-associated memory impairment negatively impacts quality of life, with approximately 40% of people aged 65 or older experiencing significant memory impairment. Both ageing of the hippocampus and the immune system appear to contribute to age-associated memory decline and interventions targeting the immune system can at least partially rescue age-related memory decline. We and others have identified transcriptional changes in hippocampus-resident immune cells, which may trigger abnormal neuroimmune interactions in the aged hippocampus. We hypothesise that changes to cell's transcriptional control mechanism's, known as epigenetics, which are known to accumulate over time, are responsible for these transcriptional changes. The primary aim of this project is to use 10x Genomics Single-Cell Multiome-sequencing to identify epigenetic and transcriptional changes that occur in individual nervous and immune system cells of the hippocampus during ageing. This data will be used to identify potential transcription factors that drive these epigenetic changes. We will target these factors to test if we can restore cognitive function in aged mice. This work will identify neuroimmune mechanisms underlying age-related cognitive decline and suggest novel therapies for cognitive impairment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The role of perineuronal nets in the selective resistance of motor neurons to cell death in Amyotrophic Lateral Sclerosis
Funder: Wellcome Trust

Abstract: Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease is an incurable illness. Cells in the brain and spinal cord called motor neurons (MNs) control muscle movements, for example, walking, swallowing and breathing. Over the course of ALS, many MNs die leading to progressive muscle loss. For unknown reasons, certain MNs do not die as ALS progresses. Perineuronal nets (PNNs) are mesh like structures that wrap around many MNs. Loss of PNNs has been associated with worsening ALS disease progression. The status of PNNs in areas where cells do not die is unknown. • · We aim to understand if PNNs influence the ability of certain MNs to evade cell death. To achieve this, we will assess the integrity, composition and stiffness of PNNs from areas where cells did not die in human post-mortem samples • · We aim to create a 3D model of these PNNs in a dish to try and understand the impact of changes to the integrity, composition and stiffness on MNs viability We hope that this research will clarify what role, if any, is played by PNNs in the selective resistance of MNs to cell death in ALS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Modelling neuroinflammatory mechanisms of Amyotrophic Lateral Sclerosis pathogenesis using human iPSC-derived glial cells
Funder: Wellcome Trust

Abstract: Inflammation of the CNS and the consequential neuronal responses play pivotal roles in Amyotrophic Lateral Sclerosis (ALS). Gliosis, the accumulation of functionally altered glial-cells, is frequently observed in ALS brain however, its role in disease pathogenesis remains elusive. Microglia in particular, the immune cells of the brain, are key regulators of neuronal function that maintain homeostasis and orchestrate the innate immune response. Microglia-neuronal interactions may be central to triggering pathology at the earliest phase of the disease, amplifying existing damage and spreading it to neighbouring neurons. Crucial gaps in the study of ALS aetiology remain: What is the specific microglia state induced by pathological TAR-DNA-Binding-Protein (TARDBP) mislocalisation? What is the effect of this molecular switch on neighbouring cells? How do TARDBP mutations in microglia affect their inflammatory state and their homeostatic functions? Our approach to study the effects of mutant TARDBP protein on microglia physiology using patient stem cells will be critical for aiming at disease-specific molecular targets that could regulate the pro-inflammatory response as well as pathological protein accumulation. We expect to gain important insight at microglia subtypes and states unique in ALS, leading to a refined disease model and uncovering novel drug targets for the treatment of ALS.


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