NIHRDataInsights/HRCSData huggingface dataset:
Title: RNA-scaffolded RNP condensation, its physiologic regulation, and therapeutic modulation
Funder: Wellcome Trust

Abstract: Ribonucleoprotein complexes (RNPs) play key roles in RNA regulation. Many mRNAs, especially those localised to neuronal axons or dendrites, promote the condensation of RNPs into microscopically visible complexes, often referred to as ‘RNA granules’. Mutations in RNA-binding proteins (RBPs) that cause diseases such as amyotrophic lateral sclerosis (ALS) often affect the biophysical properties of RNP condensation. Most work to date has focused on protein-protein interactions within condensates. Recent discoveries however, indicate that long RNA molecules can provide scaffolds for RNP condensation via their secondary structures, methylation status and repetitive, cooperative interactions with collections of RBPs. Here, we will build on our collaborative experimental and computational experience in high-throughput RNA technologies to uncover the principles underlying RNP condensation, with a focus on the role of long-range RNA secondary structures in vivo. We will establish new approaches based on CRISPR-Cas13 to modulate RNP condensation on NEAT1, a well-known RNA scaffold. We shall then apply these techniques together with computational modelling to interrogate the roles of long-range RNA structures in RNP condensation on 3’UTRs, and thus in the regulation of localised mRNA activities. Finally, we will assess whether, by modulating the structured RNA scaffolds, we can neutralise aberrant RNP condensation in ALS.

Lay abstract: Protein-RNA complexes play key roles in controlling gene expression. In neurons, many RNA molecules travel to the long extensions formed by neurons, called axons or dendrites, where they enable gene expression to be regulated in response to local stimuli, which contributes to formation of memories and to regeneration of neurons. Mutations that initiate diseases such as amyotrophic lateral sclerosis (ALS) often disrupt the regulation of these localised RNAs. We will study the unique properties of protein-RNA complexes that assemble on the localised RNAs by using high-throughput technologies, with a focus on the role of RNA structures. We will establish new experimental and computational methods to gain insights into the roles these structures play in healthy and diseased neurons. Thereby, we aim to develop new therapeutic approaches that could neutralise the effects of genetic mutations in ALS, in order to re-establish the appropriate regulation of neuronal RNAs.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Principles of synapse-astrocyte networking in the brain
Funder: Wellcome Trust

Abstract: Astrocytes are emerging as active contributors to the operation of synaptic circuits, in health and disease. Whilst important aspects of synapse-astroglia signalling are being revealed at a pace, the underlying principles are poorly understood. Whether this signal exchange system adapts to the changes associated with learning and memory remains an enigma. Building upon our recent findings and several methodological breakthroughs, the overall aim here is to establish the causality of cellular mechanisms engaging astroglia in brain circuit operation. We will focus on cortical circuitry, combining single-cell electrophysiology, two-photon excitation imaging and uncaging, time-resolved and super-resolution fluorescence microscopy, cell-targeted genetic optical sensors, in situ and in vivo, with high-end cell and network modelling. Firstly, we will establish rules that shape functional identities and co-operation among presynaptic sites carried by individual axonal circuits. Secondly, we will determine how these presynaptic identities are influenced by the astrocytes they trespass. Thirdly, we will find out how astroglial microenvironment contributes to use-dependent local circuit remodelling. Fourthly, we will unravel basic principles of functional micro-compartmentalisation and signal integration in astrocytes. Finally, we will explore models of astrocytes and neuron-astroglia networks, to reveal theoretical principles upon which astroglia can influence information handling by brain circuits.

Lay abstract: Astroglia, which have long been considered auxiliary brain cells, have emerged as active contributors to the neural circuit operation, in health and disease. Whilst important aspects of synapse-astroglia signalling are being revealed at a pace, the underlying principles are poorly understood. Whether this signal exchange system adapts to the changes associated with learning and memory remains an enigma. Building upon our recent findings and several methodological breakthroughs, the overall aim here is to establish the causality of cellular mechanisms engaging astroglia in brain circuit operation. We will employ a multi-disciplinary experimental strategy, ex vivo and in vivo, to establish rules that shape functional identities and co-operation among synapses on individual axonal circuits, and to determine how these presynaptic identities are influenced and remodelled by the astrocytes they trespass. We will use high-end computational models to translate our findings into theoretical principles underpinning astroglial contribution to information handling by the brain.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Speeding-up genetic neurodegenerative disease research through sequencing standardisation, cross-border patient recruitment and new geographically-diverse datasets.
Funder: Innovate UK

Abstract: **Speeding genetic neurodegenerative disease research through genetic sequencing standardisation, cross-border patient recruitment and development of ethnically and geographically diverse disease datasets.** Genetic neurodegenerative diseases (GND) such as Motor Neurone Disease(MND), Frontotemporal dementia(FTD), Lewy Body dementia, Alzheimer's disease affect over 250m people globally. There are hundreds of GNDs, with thousands of identified genetic causes, however less than 200 approved treatments for these conditions currently exist. Taking up to 15 years and ~£119m to bring to market, potential therapies often show promise in Phase 2 trial results, then prove to be ineffective in the subsequent, larger-scale Phase 3 trials. GND clinical trials in particular take a significant amount of time, resources, and funding to recruit the right patients at the right stage of disease, with many failing due to poor recruitment and engagement. Trials in GND can take many years to show efficacy due to the progressive nature of disease, so engagement and delivering value to participants is a key requirement. With this in mind, in November 2021 the UK GOV committed £375 million over the next five years in research funding to help people living with neurodegenerative diseases live longer, healthier lives. We intend to support and complement this research with the development of a new patient recruitment, engagement, and research tool, providing researchers and drug discovery companies with timely access to global GND patient pools and rich multimodal datasets (genomic/phenotype/health record) for AI-driven drug discovery and patient stratification for clinical trials. The project builds upon work with Genomics England on a rare disease patient portal (IUK---project---105415). The platform will be designed to be international, with careful mapping of user-journeys against local laws/regulations, ensuring full compliance. MND will be the project test-case, a genetically complex condition affecting ~250k globally and 5,000 in the UK. The first global research tool for GND, the platform will be multi-lingual, provide global genetic testing capabilities and enable clinical trial recruitment from diverse ethnic and geographic bases, not only for symptomatic patients but also for pre-symptomatic/asymptomatic people who have been identified as at-risk.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: University of Leicester (The) and PJ Care Limited
Funder: Innovate UK

Abstract: To establish a novel methodology and processes that will improve personal care planning and management in Care centres, with the objective to better respond to the needs of residents with neurological conditions.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Machine Learning for Computer-Assisted Neurosurgery
Funder: Royal Academy of Engineering

Abstract: design new machine learning technologies to provide neurosurgeons with accurate and timely information to help plan, deliver and monitor surgical procedures. Neurosurgeons use medical imaging techniques, such as MRI, CT, ultrasound and fluorescence imaging, to identify the best surgical approach and for real-time navigational guidance. These images provide vast amounts of data that must be minutely exploited to be effective. The artificial intelligence systems developed will act as smart virtual surgical assistants, providing interactive, patient-specific decision support that incorporates real-time feedback from the clinical team.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.4 SURGERY
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Chromosomal Single-Strand Break Repair: Mechanisms and Degenerative Disease
Funder: Medical Research Council

Abstract: The aim of the proposed programme is to address critical unanswered questions and new hypotheses concerning mechanism/s of DNA single-strand break repair and the link between this process and human degenerative disease. For example, we will employ molecular and cellular approaches to pursue the new molecular links we have uncovered between the response to DNA strand breaks and the hereditary neurodegenerative disease, ataxia oculomotor apraxia-2. This work will involve the use of siRNA and gene targeting technology in human, DT40, and murine cells, in conjunction with biochemical assays that measure DNA strand break repair and related processes in vitro. The proposed programme is relevant not only to hereditary neurodegenerative disease, however, but also to degenerative pathologies associated with normal human ageing. This is because we have found that loss of the critical DNA single-strand break repair scaffold protein XRCC1 in brain results in premature onset of molecular/pathological hallmarks of ageing, systemically. We will thus also pursue these findings in the new Programme, using not only the cellular model systems described above but also physiological approaches. Finally, we will address key unanswered questions concerning the organisation and importance of DNA single-strand break repair in vivo, focussing on a critical but unidentified role for XRCC1, and on how XRCC1 function is modulated within the context of chromatin by the proteins APLF and PARP-1. To do this, we will again employ a combination of biochemical, cellular, and physiological approaches. Together, the experiments proposed in this research Programme will enable us to address both critical unanswered questions concerning cellular mechanisms of DNA single-strand break repair and also the pathophysiological consequences of not repairing such breaks.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Genomic and biochemical analysis of ageing and age-related disease.
Funder: Wellcome Trust

Abstract: A recent discovery is that mutations in single genes can extend healthy lifespan in laboratory organisms. Furthermore, these effects are conserved over large evolutionary distances, opening the opportunity to use simpler organisms with much shorter lifespans to understand human ageing. Mutations in insulin/IGF-like signalling (IIS) genes can extend lifespan in the worm Caenorhabditis elegans, the fruit fly Drosophila and the mouse. Our collaborative research programme has three aims: 1. Our previous work has both demonstrated robust conservation of the effects of IIS on lifespan in Drosophila and produced a new, robustly long-lived mutant mouse. We shall unravel the signalling mechanisms involved, essential for identification of possible drug targets. 2. We shall identify and manipulate the biochemical processes by which IIS slows ageing, the key to understanding how ageing-related damage is generated and how normal longevity is assured by defence and repair systems. We shall focus on detoxification, autophagy and the proteasome. 3. Ageing is the major risk factor for predominant, lethal diseases: cardiovascular disease, cancer and neurodegenerative disease. We shall test the idea that ageing-related diseases are caused by the same accumulation of molecular damage that drives the ageing process, focussing upon neurodegenerative diseases in the model organisms and humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Establishing an advanced imaging facility for neuroscience.
Funder: Wellcome Trust

Abstract: The past decade has seen dramatic technical developments in microscopy for studying biological systems Many of these use newly developed molecules - recognised in the 2008 Nobel Prize for Chemistry - that emit light of a particular wavelength and/or alter their characteristics when activated by light. Some of these molecules can be attached to proteins inside cells, or on their surface to track protein movements, some signal changes in activity within cells, others release activating molecules or directly activate the cells that contain them. Where once we could only see fine structure in dead, fixed tissue, we can now follow minute components of cell structure and even single molecules as they are transported from one part of the cell to another. We can watch proteins interacting with each other and see the processes that underlie communication between nerve cells - as they happen - instead of inferring what has happened from a static picture after the event. Here we request funding for two microscopes that will allow us to apply these cutting edge techniques to ongoing and new projects that focus on how nerve cells communicate with each other and how and why this communication alters in disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: SEN1 implications in DNA damage: an insight into AOAII.
Funder: Wellcome Trust

Abstract: Human diseases that do not originate from external factors are often caused by mutations in genes encoding proteins that have an essential function for the survival of a single cell, and consequently the entire body. One such essential function is to prevent DNA damage. If genes that code for proteins that guard the integrity of DNA are mutated, cells will accumulate more DNA damage as they age, leading to their premature death. I will investigate the function of a protein that prevents DNA dama ge accumulation. As this protein is known to be involved in gene expression (mRNA production), its involvement in guarding the DNA integrity is not only surprising, but may also reveal connections between mRNA production and DNA damage. It is known that if this protein is mutated in humans, certain brain cells accumulate DNA damage over time and eventually die. To better understand how this protein prevents DNA damage, I will investigate the yeast version of the said protein, because yeast cells grow quickly and are easier to manipulate genetically. Since this human and yeast protein are very similar, knowledge acquired in yeast will translate to humans and thus help understand the human disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Protein quality control: Chaperone-substrate interactions and cellular aggregates.
Funder: Wellcome Trust

Abstract: The health of cells and organisms relies on extensive cellular machinery for ensuring that proteins are maintained in their functional states and that damaged proteins are either repaired or destroyed. Failures of this quality control system lead to conditions termed protein misfolding diseases, in which proteins aggregate and accumulate in cells or tissues. These diseases are very serious for two reasons firstly, the affected protein becomes non functional. More seriously, the aggregation pro cess produces toxic species which cause cell death. These processes underlie many devastating neurodegenerative diseases such as Alzheimers, Parkinsons and the transmissible encephalopathies which include BSE and CJD, and other systemic diseases. The molecular and cellular processes underlying these pathologies are poorly understood. We wish to study the basic mechanisms of protein quality control, at both the molecular and cellular levels. Using low temperature electron microscopy to keep the d elicate biological molecules intact, we plan to image the molecules that help other proteins to fold or dissolve aggregates, as well as the cells in which aggregates are forming. We aim to capture these machines while they are carrying out their functions, and to observe the consequences of protein aggregation in cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Repair of topoisomerase-mediated and oxidative-stress induced DNA damage: novel factors and implications on neuronal function.
Funder: Wellcome Trust

Abstract: DNA topoisomerases (Topos) regulate DNA topology ahead of important cellular processes such as transcription, replication, and repair. Topos generate transient DNA breaks in which the Topo is attached to DNA via a covalent phosphotyrosyl bond. Failure to re-ligate these intermediates leads to persistent DNA breaks, which ultimately needs to be repaired. One such repair mechanism involves the hydrolytic cleavage of the phosphodiester bond between the stalled Topo and DNA. The prototype enzyme for such an activity is TDP1, which is also involved in the repair of a variety of oxidative 3 -termini and mutation of which is associated with the neurological disorder SCAN1. Despite this important catalytic function fulfilled by TDP1, it remains the only human enzyme that displays this activity. Here, we aim to (1) characterise and identify novel mechanisms for the repair of DNA topoisomerase-mediated and/or oxidative stress-induced DNA breaks, using a combined approach of yeast genetics and bi ochemical analysis (employing synthetic oligonucleotide substrates). (2) Define the impact of defective repair of oxidative and Top1-mediated DNA breaks on neural cell fate. In particular, we aim to examine the impact on mitochondrial genome stability, using a combination of biochemical, microscopical, and whole animal approaches.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Mechanisms of Adaptive Sensorimotor Control.
Funder: Wellcome Trust

Abstract: Movement is the only way we interact with the world. Through movement of our limbs, faces, and vocal tract we interact with people and manipulate objects. The effortless ease with which we move masks the true complexity of the control processes involved. This is clearly evident when we try to build machines to perform human control tasks. While computers can now beat grandmasters at chess, no computer can yet control a robot to manipulate a chess piece with the dexterity of a six-year-old child. My research will investigate the mechanisms by which the brain learns about the physical environment and modifies its control to successfully interact with the world. The first research area examines the mechanism by which the sensory information is used to learn new motor skills. The second research area will investigate how the learning process is able to control and tune the sensory information that it receives in order to produce accurate and efficient movement. Together, these projects wil l further our understanding of the process of motor learning and control. Such understanding not only is critical to understand brain function and dysfunction, but it also provides insight into rehabilitation techniques, robotic control and the development of prosthetics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Feelings of pain and pleasure - delineating hedonic sensation in the brain.
Funder: Wellcome Trust

Abstract: In this project, the aim is to find specific regions in the brain important for generating the opposite sensory feelings of pain and pleasure. There is to date no objective measure from the brain where we can predict precisely if someone is experiencing pain or pleasant sensations. One aim here is to develop mathematical tools that can aid in measuring subjective reports related to affective (pain and pleasure) touch sensations. By stimulating the skin of subjects to produce painful and pleasant sensations while using neuroimaging, we can see which parts of the brain are activated by these hedonically opposite sensations. In another project, single skin nerves in humans, dedicated to signal pain, are electrically stimulated directly to test the relationship between how we stimulate and the painful sensation produced. Subsequently, by combining the techniques of stimulating pain nerves and imaging the brain, activity with detailed anatomical information can be related to the correspondi ng affective sensation. These projects open the possibility of coming closer to what signifies hurt or pleasure in the brain, by targeting regions which may alter the hedonic experience, which may be a crucial step towards novel therapies for pain relief.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Title: Mechanisms regulating movement and force generation by cytoplasmic dynein.
Funder: Wellcome Trust

Abstract: Specialised proteins called motor proteins play critical roles in ensuring that growing bodies and nervous systems develop correctly. Motor proteins travel inside our cells and distribute important molecules to their proper places. Motor protein malfunction causes human disease, particularly of the nervous system. Viruses such as HIV can hijack motor proteins and use them for their own ends. It is therefore vital for us to understand how motor proteins are controlled in health and deregula ted in disease. However, this has proved challenging, because it can be difficult to isolate the molecules for detailed study. I intend to solve this problem by isolating and studying the motor machinery from yeast, rather than humans. Because the human and yeast machinery are very similar, I will be able to discover more about how the human motor machinery works. I will study its mechanism in detail by viewing individual molecules using state-of-the art microscopy techniques, and communicate the results via a molecular movie This research will lead to a clearer picture of how motor proteins are controlled, and how failures in this regulation cause disease. In the long term, we may be able to use this information to design synthetic applications for motor proteins.


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