NIHRDataInsights/HRCSData huggingface dataset:
Title: Cell-to-cell communication in the brain and tissue-specific phenotypes of mitochondrial disease
Funder: Medical Research Council

Abstract: Mitochondria are cellular organelles primarily involved in energy production. They are considered to be key to the function of eukaryotic cells. Nevertheless, mitochondrial diseases often only present in adulthood with tissue-specific symptoms. This means that cells and tissues must have coping strategies which temporarily maintain normal function when confronted with mitochondrial dysfunction. The overall objective of the research programme is to investigate whether the interactions between different cell types may render tissues more, or less vulnerable to mitochondrial disease. The project will be focused on the brain, which is particularly vulnerable to mitochondrial disease, but also shows strong regional differences in its susceptibility. The main hypothesis is that cell-composition and crosstalk between cells with different metabolic demands, such as neural stem cells (NSCs), neurons and glia, may affect the response to mitochondrial disease. Specific questions and objectives: 1. Which metabolic pathways support NSC function in vivo? To understand how metabolic interactions between cell-types in the brain are affected by mitochondrial disease, the project investigates how mitochondria contributes to the metabolism of NSCs under physiological conditions. The focus is on NAD+ and ATP, and those pathways that provide necessary substrates to support oxidative phosphorylation. Inhibiting known human mitochondrial disease genes within NSCs allows to study how rewiring of NSC metabolism in vivo compensates for the altered metabolic demands of mitochondrial dysfunction. 2. How does mitochondrial disease affect interactions between NSCs and glial cells? To gain insight into how mitochondrial dysfunction impacts on different cell types in the brain, we will obtain cell-type specific expression profiles in response to mitochondrial dysfunction and screen which metabolic pathways in glial cells provide substrates to support NSC metabolism. 3. How does mitochondrial disease affect nuclear metabolism in the NSC niche? The nuclear genome also has specific metabolic demands. To determine how mitochondrial dysfunction affects nuclear metabolism, we use genetically encoded sensors to measure subcellular distribution and study subcellular localization of metabolic enzymes in response to mitochondrial dysfunction. Elucidating generic mechanisms of the tissue-wide response to mitochondrial dysfunction will lead to better insight into metabolic origins of neurodegenerative diseases and cancer and has the potential to uncover novel therapeutic approaches.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Mitochondria in neurodegeneration: Investigating the role of mitochondria and metabolism in the cause and therapeutic targeting of neurodegenerative diseases
Funder: Medical Research Council

Abstract: Neurological disorders (NDs) are now the leading cause of disability in the world, with dementia recently becoming the number one killer in the UK (www.ons.gov.uk). Progress in developing effective therapeutic treatments is hampered by our incomplete understanding of disease aetiology. The decades-long survival of adult neurons requires the coordination of many biological processes, and mitochondrial dysfunction has long been recognised to play a causative role in many NDs. While mitochondria provide the cellular energy required by these cells and protect them by buffering cytoplasmic calcium, they also produce many of the molecules that cause cellular damage and sequester an arsenal of cell death-inducing factors. Thus, mitochondria require exquisite homeostatic processes to keep them intact and prevent potentially catastrophic disruption. Mechanisms of mitochondrial quality control have emerged as important contributors to neurodegeneration. The goal of the Mitochondrial Neurodegeneration group is to understand the causes and consequences of the breakdown in mitochondrial homeostasis on whole-organism or tissue vitality and survival, with a particular focus on pathogenic mechanisms of NDs such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We use a combination of the powerful genetic techniques in Drosophila with molecular, cell biology and biochemical approaches in vivo and in mammalian cells. Greater insights into the mechanisms of mitochondrial homeostasis will deliver a better understanding of the pathogenic causes of NDs and help guide therapeutic developments to combat them.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Redox Control of Sleep
Funder: Medical Research Council

Abstract: Our work in Drosophila showed that rising sleep pressure activates two dozen sleep-inducing neurons with projections to the dorsal fan-shaped body (dFB). Sleep need is encoded in the electrical excitability of these neurons, which fluctuates because two potassium conductances, voltage-gated Shaker (Kv1) and the leak channel Sandman, are modulated antagonistically. As a consequence, dFB neurons are electrically silent during waking and persistently active during sleep. The critical dFB-intrinsic transducer of sleep pressure is Shaker's beta-subunit, an aldo-keto reductase with a stably bound NADPH cofactor. During waking, the mitochondria of metabolically idle dFB neurons release reactive oxygen species and/or aldehydic breakdown products of peroxidized lipids, whose reduction by the beta-subunit flips the cofactor to the oxidized form. This slows the inactivation of the associated potassium conductance, boosts the repolarizing force that restores the resting membrane potential after a spike, and so enables tonically active neurons to fire at higher rates-precisely the changes required to induce sleep. Exogenous substrates for reduction or oxidation by beta-subunits thus offer a potential new mode of intervention in sleep disorders. We will explore this mechanistic concept in three objectives: 1) We will investigate the role of potassium channel beta-subunits-and, in particular, their oxidoreductase activity-in the regulation of mammalian sleep. We will analyze sleep in Kcnab knockout mice and localize sleep-control regions by focal viral transduction of wild-type beta-subunits. 2) We will test if lipid peroxidation products serve as endogenous substrates for beta-subunits and study the stoichiometry and regulation of the oxidoreductase reaction. 3) We will develop high-throughput target- and cell-based screens to explore the wider chemical space of beta-subunit substrates, as an initial step toward characterizing the sleep-modifying potential of hits.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: TO REPAIR OR TO DIE: THE CELLULAR RESPONSE TO RIBOSOMOPATHY-CAUSING MUTATIONS
Funder: Medical Research Council

Abstract: Reduced dosage or activity of individual ribosomal protein (RP) is associated with a class of diseases collectively known as ribosomopathies. Our recent studies suggest that the pathology of ribosomopathies does not follow from reduced or altered protein synthesis. We have shown that, in a Drosophila model of a human ribosomopathy, RP deficiency leads to the accumulation of unfolded proteins, the formation of protein aggregates, and cellular stress. Remarkably, within an RP-deficient tissue (composed of genetically identical cells), some cells undergo apoptosis while others are able to withstand the stress and contribute to functioning organs and appendages. Here we propose to discover, at the molecular level, how RP deficiency is sensed to activate the proteotoxic stress response and how this is further transduced to determine the decision between cell death and repair. We will use a combination of proteomics and transcriptomics to identify the proteins involved in this response both in Drosophila tissues and in human IPS cells (some obtained from patients and others engineered by CRISPR/Cas9). The pathways and molecules that are common to both systems will then be investigated functionally to distinguish those that are cytoprotective from those that are maladaptive. We expect that this work with uncover means of stimulating repair and alleviating cellular stress thus suggesting new therapeutic avenues for this class of disease. In a final work package, we will explore how our findings translate to neuropathologies associated with ribosomopathies and more broadly to age-related proteinopathies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Developing environmentally sustainable best practices for human brain imaging
Funder: Medical Research Council

Abstract: The rapid increase in the accessibility to high performance computing has accelerated large-scale analysis of complex medical imaging data. This has particularly impacted the study of the human brain by enabling application of novel computational methods to imaging modalities such as MRI, PET and CT. The computational study of the human brain has, in turn, led to the development of elaborate pipelines operating on vast amounts of data which are being adopted globally. As a consequence, the computational costs of such neuroimaging pipelines have increased considerably. The increasing storage and computational requirements of neuroimaging pipelines translate into significant increase in the corresponding energy- and carbon- costs. In this project, we aim to assess the carbon footprint of computational neuroimaging pipelines and present basic measures to reduce these costs in some instances. As the first objective, we will adapt existing carbon-tracking tools for neuroimaging pipelines, which we hope will first provide an insight into the carbon-intensity of these pipelines. We will build tools to measure the energy costs of running specialised computation infrastructure used in research data centres. We also aim to 1.) develop a slurm-based job scheduler that can utilise the instantaneous carbon intensities of local power grids to modulate and reduce the energy costs of neuroimaging pipelines 2.) investigate the usefulness of image derived phenotypes in tasks where using massive amounts of raw image data can be computationally expensive. 3.) systematically explore the loss in precision compared to the gains in carbon efficiency. Finally, as neuroimaging pipelines comprise several intermediate steps, we also aim to assess different alternatives and configurations of these steps. This we hope will serve as a guiding framework when deciding the trade-off between a specific choice of method and its corresponding carbon cost.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: RNA Networks
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative founded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Ribonucleoprotein complexes (RNPs) coordinate all regulatory stages that an RNA passes through, while the RNAs also regulate the functions and homeostasis of bound proteins and often acts as a scaffold for assembly of large RNPs such as spliceosome or ribosome. To understand how RNPs assemble and function, we develop techniques that integrate biochemistry and computational biology to obtain a comprehensive map of interactions between proteins and their RNA partners within cells, as well as the functions of these interactions. This includes the individual-nucleotide resolution UV crosslinking and immunoprecipitation of protein-RNA complexes (iCLIP) and its hybrid variant (hiCLIP), which reveal protein-RNA and RNA-RNA contacts that drive the assembly of RNPs. We use these methods to study how the sequence and structure of RNAs defines the composition and function of RNPs, and how the composition of RNPs changes in biology and disease. Genetic studies have identified mutations that disrupt RNPs in a variety of neurologic diseases, particularly the amyotrophic lateral sclerosis (ALS). We wish to understand how these mutations disrupt the appropriate assembly and function of RNPs, thereby initiating the molecular cascade leading to such diseases. Disease-causing mutations tend to disrupt the regions of proteins that are intrinsically disordered but are essential for assembly of protein-RNA condensates, which form through large numbers of weak contacts. By studying a protein implicated in ALS, we found that its condensation properties are linked to multivalent protein-RNA interactions, which led us to study how RNP condensates depend on the arrangements of RNA sequences and structures. We now aim to understand how changes introduced by mutations or post-translational modifications of disordered regions modulate RNP condensation with spatiotemporal precision, how changes in RNP condensates alter protein homeostasis upon stress and aging, and how this can eventually lead to neurodegenerative diseases. Based on our findings, we are developing new therapeutic strategies to prevent disease progression at an early stage.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Delineating the cell intrinsic mechanisms of peripheral nerve regeneration
Funder: Medical Research Council

Abstract: Peripheral nerve injury (PNI) is common and can be physically, psychologically and socioeconomically challenging. Microsurgical nerve repair remains the only clinical intervention yet seldom leads to adequate recovery. Aims: To assess the underlying neurobiology driving regeneration by determining the sites of microtubule nucleation in in vitro, ex vivo and in vivo models of PNI, thus enabling the development of centrally acting therapeutics targeted to the intrinsic regenerative machinery. Objectives: 1. Determine the spatio-temporal control of regeneration using high-resolution live-cell imaging. 2. Identify sub-cellular structures involved in axonal elongation following PNI. 3. Examine the intracellular response to nerve repair in an in vivo model. Methods: Adult rat dorsal root ganglia in vitro and ex vivo tissue cultures will undergo genetic transfection via electroporation. Fluorescent DNA constructs or siRNAs will be delivered to the nucleus allowing for visualisation and manipulation of specific sub-cellular structures within the neurons. Combining this with high-resolution fixed and live-cell imaging will allow for in depth assessment of the spatial and temporal dynamics of peripheral nerve regeneration at the cellular and sub-cellular level. An in vivo rat model of PNI with microsurgical repair will be used to examine the intracellular response to repair and, in particular, response to delayed intervention. Impact: This work will enhance understanding of the neurobiological processes of peripheral nerve regeneration as well as identify targets for the development of novel therapeutics and eventual clinical translation. My models provide an ideal system on which to test therapeutics in their early stages and may provide knowledge on why nerves of the central nervous system are unable to regenerate. Thus, this project will impact basic and translational scientists, clinicians and also those in fields outside of peripheral nerve repair.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: The Co-development of a comprehensive sleep management programme in commercial drivers
Funder: Medical Research Council

Abstract: Optimising daytime vigilance among workers in safety-critical industries can deliver benefits to public health, productivity, and personal wellbeing. Commercial drivers are exposed to occupational and lifestyle challenges which degrade sleep quality and increase daytime fatigue. For most drivers, chronic symptoms fall below the threshold of DVLA notifiable excessive daytime sleepiness. Survey data indicates that > 30% of HGV drivers admit falling asleep whilst driving, and falling asleep at the wheel accounts for 20% of serious collisions. Our own research showed that commercial drivers reported high levels of sleep deprivation and poor sleep quality. Benefits of improved sleep in this at-risk occupational group would be direct (immediately reducing daytime fatigue and improving vigilance) and indirect (through improved cardiometabolic health and daytime stamina). The driving safety of those meeting diagnostic criteria for sleep disorders (e.g. Obstructive Sleep Apnoea) is addressed by current protocols, but no such procedures exist which address the impact of irregular sleep patterns, insufficient sleep duration, and poor sleep hygiene practices. The design and development of our proposed intervention involves collaboration from different layers within the complex system of change: drivers and their immediate environment; employers; and the legal framework governing the work environment. The aim of our proposed study is to co-develop, and provide, an app-based sleep management intervention. The intervention will be grounded in cognitive behavioural therapy principles, accompanied by additional motivational techniques. The study will involve obtaining expert evidence on the interface of sleep and work safety, focus groups with drivers and industry stakeholders addressing sleep, wellbeing and safety, development of the prototype app and usability testing, and app feasibility testing.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Exploring glial roles in sculpting brain development
Funder: Wellcome Trust

Abstract: Although two broad cell types, neurons and glia, compose the brain, neurobiologists have tended to focus on neurons, the electrically excitable cells that process information. Glia were thought of primarily as neuronal support cells. Recent work challenges this view and shows that glia play essential roles not just in supporting neuronal function but also in instructing their development. I propose three aims to address how glia regulate two key aspects of brain development, neuronal birth and neuronal identity: (i) A major challenge in neurobiology is defining the origin of neuronal identity (and thus diversity). I will investigate how signals sent by glia to naïve precursors determine the unique neuronal fates that these cells adopt. (ii) Although the brain has little regenerative potential, under restricted circumstances differentiated glia can act as stem cells to generate neurons. I have identified one such example and will probe the signals that reprogramme glia to generate neurons. (iii) I will explore how different glial types differ in their regulation of neural development. I will begin with a systematic survey of the signals released by different glial-subtypes and then manipulate these while evaluating their effect on neighbouring neural precursors and neurons.

Lay abstract: Our brains are composed of two main cell-types, neurons and glia. Neurons, the electrically excitable cells that process information, have been studied intensely but glia were thought of as support cells and often ignored. Excitingly, I have recently shown that glia play essential roles in instructing brain development. Their dysfunction may therefore underlie or exacerbate many brain pathologies, underscoring the need to understand their normal roles. Overall, we aim to determine, at the cellular and molecular level, how glia regulate neural development. Conservation of biological processes enables us to investigate this question in the fruit fly, where we can make use of modern genetic and molecular techniques to ask how signals from glia regulate neuronal production, how glia can be reprogrammed into neurons and how different types of glia differ in their functions during brain development. Our work will improve our understanding of nervous system regeneration and neuro-developmental disorders.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Characterising the interaction between the RNA binding protein, Syncrip, and poly(A)-RNA
Funder: Wellcome Trust

Abstract: SYNCRIP is a gene required for the correct development of neurons within the brain and spine. Mutations in SYNCRIP are linked to hereditary neurodegenerative disorders, such as spinal muscular atrophy, which can be fatal to babies in their first few years of life. In the cell, SYNCRIP encodes for the protein, Syncrip. Syncrip binds to the tail of specific messenger RNA molecules (mRNA) – the molecules that convey genetic information from DNA to the ribosome, where they are translated into protein. Binding of Syncrip prevents the translation of the bound mRNA molecules. The question I want to answer during my PhD is how Syncrip recognises the tail of these molecules, which is a repetition of the same nucleotide, adensosine, and has been named poly(A). To do this, I will produce the protein Syncrip in the lab and examine its interaction with poly(A). I will use NMR to determine the shape and motions of Syncrip before, during and after the binding event. Furthermore, I will use mass spectrometry to identify the parts of Syncrip directly involved in poly(A) binding. This work will explain how Syncrip can regulate genes in healthy cells and how mutations can affect binding and regulation in disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Investigating Centriole Positioning and Orientation Within Cells
Funder: Wellcome Trust

Abstract: Our bodies are made of cells positioned relative to each other in order to make functioning tissues and organs. Within each cell is a pair of barrel-shaped structures called centrioles that help form the “skeleton” of each cell, giving the cell structural integrity as well as positioning information. “Top” and “bottom” of each cell is distinct (i.e. the cell is polar), therefore they are able to pattern themselves appropriately to form larger scale structures. My project centres around how centrioles orient themselves within a cell, such that the cell achieves proper polarity allowing certain structures, like cilia, to form in the right place relative to other cells. To do this I will use the Drosophilaembryo which has many centrioles, all aligned with one end facing the cell cortex with each centriole appearing as a ring. By measuring the percentage of oriented ring-like centrioles upon introduction of genetic mutations and injected drugs, I will elucidate the key proteins and/or cellular pathways that keep centrioles oriented, allowing them to then establish and maintain cell polarity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL