NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Medical and Regulatory Genomics
Funder: Medical Research Council

Abstract: We use computational approaches to reveal the interdependencies between transcription, chromatin and the underlying genomic sequence - and to investigate transcriptional control mechanisms and their disruption in disease. We have an established track record in studying the roles of chromatin structure in mutational spectra, and in how tumour genomes evolve during cancer progression. We aim to test hypotheses addressing three broad aims. Our first aim is to reveal new functional interactions between chromatin structure and transcriptional activity. We still lack a convincing and quantitative account of the relationships between nuclear organisation, chromatin structure and expression dynamics over time. Developing such models will have important consequences for our understanding of noncoding variation in disease. Our second aim is to understand the roles of chromatin structure and mutational bias in the evolution of regulatory sites, within the catastrophe strewn genomes of tumours, and during the evolution of isolated human populations. Using a novel approach we have demonstrated unexpectedly high mutational loads at active regulatory sites in most cancers, relative to matched control sites. We are extending this approach to allow us to test the hypothesis that certain site classes accumulate lower levels of mutation than expected, suggesting purifying selection in tumours. Classes showing unexpected increases or decreases of mutational load, suggesting selection in specific tumour types, may suggest new candidate targets for therapeutics. In parallel we will extend our regulatory mutational load metrics to comparisons between isolated human populations (eg from the Shetland archipelago) and cosmopolitan populations, to detect regulatory site classes with unexpected loads, correlated to phenotypic traits. We aim to gain novel insights into the impact of rare regulatory variants on quantitative traits relevant to disease predisposition, ultimately aiding the development of ‘personalised’ medicine based upon genome sequencing. Finally, we aim to explore the frequencies and roles of regulatory domain lesions in developmental disorders and cancers. Structural variants (SVs) are known to play critical roles in tumourigenesis, but there are currently no methods to reliably disentangle mutational bias from selection operating on SVs in cancers. Such methods are essential to establish which SVs host potential new therapeutic targets, and which are simply well tolerated by tumours. We are developing new models based upon experimental measurements of the mutational spectra in relevant cell types, to estimate the expected spectra in tumours, and rigorously infer candidate breakpoints that may be under selection.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Award Title: Membrane protein biosynthesis and quality control
Funder: Medical Research Council

Abstract: Our Programme conducts research into the general areas of protein folding, maturation, and quality control. We are addressing at the molecular and mechanistic level three inter-related questions. How are proteins properly matured to their final functional form? How does the cell recognise and degrade the products of mistakes in the maturation process? How do failures in protein maturation and quality control contribute to disease? The first two questions are being addressed using biochemical reconstitution to identify the key machinery that aids in the maturation and degradation of membrane proteins. Once identified, the individual pathways are studied in isolation using biophysical and structural methods to understand how they operate. The third question is addressed by determining how perturbation of maturation or quality control pathways affects the physiology of intact cells and whole organisms. We investigate different types of proteins, but are particularly interested in integral membrane proteins that are assembled at the endoplasmic reticulum. We anticipate this research to have long-term impact on human health for two reasons. First, membrane proteins, an area of particular interest to our Programme, play crucial roles in nearly all areas of human physiology and are major targets for most currently available drugs. Thus, understanding their biosynthesis may lead to new ways of regulating their functional expression to alter physiologic pathways for health benefit. Second, defective protein processing and degradation play central roles in several diseases including Cystic Fibrosis, Alzheimer’s disease, and Prion diseases. Understanding cellular quality control of the proteins in these diseases could therefore open potential avenues for future therapeutic strategies.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Metabolic Characterization of Natural Killer T Cell responses to sterile, hypoxic injury
Funder: Wellcome Trust

Abstract: It has been described that ischemia-reperfusion injury (IRI), such as during organ transplantation, evokes damaging sterile inflammation and secondary tissue injury that is dependent on iNKT cell activation, but the underlying mechanisms remain elusive. Similarly, in sickle cell disease (SCD) mice, RBC sickling and widely disseminated microvascular ischemia can be triggered by hypoxia/reperfusion (H/R), presenting a global and scalable model of sterile, NKT-mediated inflammation. We propose here to use state-of-the-art metabolic methodologies to investigate the response to hypoxia and reperfusion (H/R), which ultimately causes NKT cell activation and tissue damage in SCD. Mice carrying the human sickle cell alleles are available and were crossed with NKT-deficient Ja18 mice, thus generating our novel Sickle-Ja18 mouse model which exhibits reduced tissue damage in response to H/R. Together with in-vitro co-culture experiments, we will explore (1) the intrinsic and (2) APC-mediated mechanisms of sterile inflammation caused by hypoxia and reperfusion in the context of sickle cell disease with the ultimate goal to identify metabolic mechanisms downstream of ischemia to interfere with disease pathogenesis. We anticipate that this research will increase our understanding not only of SCD, but also the pathology of IRI, organ transplantation and sterile inflammation.

Lay Abstract: Ischemia-reperfusion-injury (IRI), the tissue damage caused after a period of lack of oxygen, evokes damaging inflammation and is a major concern for example in liver transplantation. IRI leads to sterile inflammation, but the underlying mechanisms remain elusive. Recent advances found a key role for iNKT cell activation, a type of innate T-lymphocytes. Mice with sickle cell disease, in which damaged red blood cells cause widely disseminated IRI, can be used as a scalable model of sterile, NKT-mediated inflammation. We will investigate how the response to hypoxia and reperfusion causes NKT cell activation and tissue damage in sickle cell disease. Two hypotheses will be explored: the change in oxygen levels has an effect on (1) antigen presentation to NKT cells, and (2) on the differentiation into different NKT cell types. We will explore these hypotheses with the ultimate goal to identify metabolic mechanisms downstream of ischemia to interfere with disease pathogenesis.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Metaphors we listen with: the neural correlates of timbral brightness investigated by pitch-timbre interference and fMRI
Funder: The British Academy

Abstract: Brightness is among the most studied aspects of music perception, and arguably among the most important musical cues actively shaped by performers, composers, and audio engineers. Psychoacoustically, sounds described as bright exhibit a high-frequency emphasis in the spectrum and sounds with more high-frequency energy are described as bright. However, relatively little is known about the neural mechanisms that facilitate those metaphorical descriptions. Do sounds seem bright because our auditory and visual systems communicate directly, or because they each link to a supramodal area where a higher level, more abstract representation of what brightness entails is coded? Interactions between numerical value and brightness level of digits have been shown to modulate activity in the parietal lobe, an area previously implicated in magnitude processing. Implementing an analogous auditory paradigm of pitch-brightness interactions, this study will investigate by fMRI whether they implicate the parietal lobe or, alternatively, visual areas.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: EAR;NEUROLOGICAL
Award Title: MicroRNAs in Branchial Arch Development
Funder: Wellcome Trust

Abstract: Embryonic development of the face and neck is a complex process. In vertebrates it begins with the formation of temporary segments called branchial arches. Within these segments, cells must express the correct genes to properly form various structures and tissues, such as the jawbone. Furthermore, these genes need to be expressed at the correct time and in the correct segment. This requires precise regulation, and one mechanism by which cells can accomplish this tight control is using microRNAs. MicroRNAs are known to be involved in important developmental processes, but no studies have profiled the full collection of microRNAs expressed in developing branchial arches. In this project we aim to identify key microRNAs that function during mouse branchial arch development. We will achieve this using a technology called small RNA-sequencing, which will allow us to determine the abundance of all microRNAs expressed in each stage and time. Following this, we will use computational programs to predict the genes they may regulate and later validate these predictions in the lab. This project will identify new contexts for which microRNAs function in and increase our understanding of the precise regulation in place during facial development.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Microglial spatiotemporal diversity and role in susceptibility and resilience to neurodegenerative disease
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK.  Funding details for UK DRI programmes will be added in 2019. Microglia have important developmental, homeostatic and neuroimmune functions and growing evidence supports that aberrations in each of these broad functional roles can contribute to neurological dysfunction across the lifespan, including dementia-causing neurodegenerative disease1. The discovery of neurodegenerative disorders where the primary disease-causing mechanism appears to be a fault in microglial function (“microgliopathies” e.g. Nasu-Hakola disease (NHD) caused by TREM2/TYROBP mutations2 and HDLS/POLD caused by CSF1R mutations3) supports causative roles and the broader concept that neuronal degeneration can be driven in a non-cell autonomous manner. Mutations in TREM2 and other microglial-enriched genes also increase risk of AD and amyotrophic lateral sclerosis (ALS)4, and recently we and others at UoE (Prof Seth Grant) showed the predominance of microglial and neuroimmune changes within the global tissue-level transcriptomic response in AD and other proteinopathies5,6. Studies using experimental neurodegeneration models showing altered disease trajectory in mice deficient in TREM27,8, inflammasome components9, or with pharmacological modulation of microglial proliferation10-12 further support disease-modifying roles of microglia / neuroinflammation. Microglia and related CNS myeloid cell types also sense and transduce body-to-CNS signals triggered by systemic inflammatory processes (e.g. infection, chronic vascular/metabolic disease), some of which themselves are risk factors for and modifiers of neurodegeneration. Recent studies have also described aberrant synaptic pruning in AD-like pathology13.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Mind Wandering and Metacognition in Children
Funder: The British Academy

Abstract: Mind wandering poses a serious threat to children’s learning. Failing to attend to instruction because of task-unrelated thoughts may impede children's chances of acquiring crucial skills or knowledge. The link between mind wandering and learning has been studied extensively in adult student populations. Yet, despite its clear educational significance, there is a striking evidence gap on the impact of mind wandering on learning in children. The proposed research will address this important research gap by conducting an examination of 5-8 year-olds’ meta-awareness of mind wandering and their understanding of how mind wandering can impact on learning. Outcomes of this work will provide a springboard for the development of new interventions geared toward detecting and refocusing lapses of attention in educational settings.


Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: MENTAL HEALTH
Award Title: Miniature microscopes for ultra-high frame rate imaging in freely moving animals
Funder: Wellcome Trust

Abstract: We propose to develop the first miniaturised microscopes for high-speed (kHz) voltage imaging in freely moving animals. Voltage changes that mediate neuronal computations, and electrical signalling in non-neuronal tissues, are too fast to observe with miniature microscopes currently used for imaging in freely moving animals. To address this, we will build miniature microscopes that use Single Photon Avalanche Diode (SPAD) sensor technology to obtain frame rates > 10 fold higher than existing systems.   Our proof-of-principle ex-vivo data shows that SPAD sensors can image sub-threshold and spiking activity of neurons reported with genetically encoded voltage indicators (GEVIs). As the sensors used for these experiments have a similar footprint to the standard CMOS sensors in current miniature microscopes, it will be feasible to use SPADs to image fast electrical signalling even in freely behaving animals.   Our goals are: 1. To develop miniature microscopes that incorporate our established SPAD technology, along with custom made drivers and control software, to image 10s of neurons in freely moving animals. 2. To develop a second system using state-of-the-art SPAD sensors to image 100s of neurons in freely moving animals. 3. To validate the systems by recording from genetically identified neurons during spatial exploration and action selection.

Lay Abstract: Precise electrical signalling at a millisecond time scale is critical for healthy functioning of the brain and organs such as the heart. Future advances in understanding functions and disorders of the brain, and electrical activity in other organs, will require new tools to resolve fast electrical signals in identified cells in freely moving animal models.  Recently developed fluorescent indicators enable electrical signals to be observed with microscopes. However, because current microscopes able to do this are bulky they can only be used with animals that are restrained, which severely limits their usefulness. To address this, we propose to develop miniature microscopes that by incorporating novel imaging sensors will be capable of extremely high frame rate imaging of the electrical activity of populations of neurons, or other cells, in freely moving animals. By facilitating widespread adoption of these systems we expect to transform investigation of electrical signaling during complex behaviours.

Research Activity Codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health Categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Award Title: Mining the Past
Funder: Wellcome Trust

Abstract: This is a project to conserve, catalogue and exploit the archives of the National Union of Mineworkers (NUM). It presents the opportunity to develop a nationally significant archive for occupational and industrial health at the MRC and a Midlands network for coal related archive collections. The NUM records are currently held in poor conditions at the union’s headquarters in Barnsley. The project involves the removal of the archives to professional conservation facilities for drying and cleaning prior to storage at the MRC. It includes the sorting and cataloguing of the collection for research use as well as a public engagement programme. The project will:
 
  • Remove the collection to Harwells for conservation treatment
  • Re-box, sort and summarise the collection for immediate access and use in promotional activities
  • File/item list the collection for full online catalogue access
  • Select and digitise items for research, teaching and exhibitions.
  • Develop a project website
  • Co-host seminars with the Centre for the History of Medicine (Warwick) on coal, industry and health
  • Develop a Midlands network of coal related archive collections for future collaboration, education and outreach activities
  • Use the NUM archive as a focus for the development of a national industrial health and welfare archive


Research Activity Codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: MitoCluster: an integrated phenotyping and mouse model generation platform for mitochondrial disease and dysfunction
Funder: Medical Research Council

Abstract: Primary mitochondrial diseases (PMDs) caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA) that impair energy production, affect 1/4,300 in the UK. Despite causing severe disability and shortened lifespan, management is primarily symptomatic. This reflects incomplete understanding of underlying pathogenesis and few reliable, non-invasive biomarkers to diagnose and monitor disease progression. The UK is at the forefront of PMD clinical and scientific research. MitoCluster is well-positioned to connect this world-leading expertise with mtDNA genome editing (mtGE) and deep phenotyping skills, to create a multi-site UK-wide platform for much-needed PMD mouse model generation, breeding and phenotyping. Aim 1 (WP1) will generate a refined phenotyping platform, including measures of muscle fatigue and weakness, the leading targets of drug development given impacts on quality of life. We will combine in-cage assessments at Mary Lyon Centre with biochemical, imaging, metabolomics and single-cell sequencing at partner sites. Aim 2 (WP2 and 3) will generate 6-9 novel mtGE mouse models using two approaches: (1) phenotype-first, in which breeding of heterozygous mitochondrial mutator (PolgA+/D257A) mice results in random heritable heteroplasmic mtDNA mutations - lines are selected via measurable phenotypes; (2) targeted, based on programmable nuclease (mtZFN) or cytosine base editing (DdCBE) methods to obtain predefined deleterious mtDNA mutations. These will be subject to deep phenotyping through our refined platform (WP1) and undergo combined single-cell mtDNA/RNA-Seq in different tissues over time, to generate a publicly available atlas of somatic heteroplasmy dynamics. We will harness our strong Pharma partnerships to evaluate the impact of existing and novel compounds in a whole organism context (Aim 3) and develop and deliver courses in mtGE model generation and maintenance (Aim 4), to grow the UK skills base across academia and industry.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Mitochondrial dysfunction: Understanding how dysfunctional mitochondrial redox metabolism underpins pathology
Funder: Medical Research Council

Abstract: Reactive oxygen species (ROS) produced by mitochondria cause oxidative damage that impairs the ability of mitochondria to make ATP and to carry out their metabolic functions. They may participate also in cellular redox signalling pathways. One important aspect of our work is to investigate how oxidative damage to mitochondria contributes to human pathologies. We have worked out a way of targeting small bioactive molecules, such as antioxidants, to mitochondria in order to counter the effects of ROS and to examine the effects of doing so at cellular and whole animal levels. The bioactive molecule is attached chemically to a lipophilic cation such triphenylphosphonium. These cations accumulate selectively, first in the cytosol, driven by the plasma membrane potential, and then several-hundred fold in the matrix of mitochondria, driven by the membrane potential across the inner membrane. A second important aspect is to determine whether and how mitochondrial ROS alters the activities of proteins in putative signalling and protective pathways by reversibly modifying the redox state of critical protein thiols in mitochondria. We use a range of free radical and proteomic approaches to identify the proteins involved, and to identify the cysteine residues and any redox modifications. Finally, we take this information and use it to rationally design potential therapies for diseases that arise from mitochondria dysfunction. Currently our main focus for therapy is the ischaemia/reperfusion injury that arises from stroke and heart attack.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Mitophagy Signalling in Health and Disease
Funder: Medical Research Council

Abstract: A major focus of this research is to decipher the signals that regulate autophagy under physiological conditions and we are particularly interested in the autophagy of mitochondria, a process termed mitophagy. Mitochondria, the key energy-generating organelles of the cell, have the potential to cause great cellular harm and death when they become damaged, in part due to uncontrolled release of cytochrome c and production of reactive oxygen species. Because of this, a failure in mitochondrial quality control has strong links to diseases such as cancer and neurodegeneration. One critical quality control pathway that is emerging is mitophagy, the clearance of mitochondria by autophagy. Autophagy is a catabolic process whereby a membrane compartment, termed an autophagosome, engulfs excess, impaired and/or toxic components and delivers them to the lysosome for degradation. It is now evident from cell-based work that mitochondria can be specifically incorporated into autophagosomes, but how and where this occurs physiologically is still poorly defined. Addressing these issues is vital, not only for understanding the aetiology of diseases such as Parkinson’s, but also because mitophagy has great potential as a therapeutic tool. Our work has revealed for the first time that mitophagy occurs at a high rate in specific cells and tissues in vivo under normal conditions, including those of clinical relevance such as dopaminergic neurons in relation to Parkinson’s. However, we do not know the signalling pathways controlling these instances of mitophagy. Our objective is to resolve the mechanisms that regulate physiological mitophagy, delineate the relevant signalling pathways and to determine how these mechanisms relate to development of disease. Using a combination of biochemistry and cell biological techniques, we will molecularly define how the autophagy initiating ULK1 kinase complex becomes activated to drive mitophagy and in turn determine when and where this becomes important in vivo.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: GENERIC HEALTH RELEVANCE