NIHRDataInsights/HRCSData huggingface dataset:
Title: A super-resolution multi-scale in vitro and in vivo imaging platform at Harwell: building models of development and disease from molecules to mammals
Funder: Medical Research Council

Abstract: We have identified three developments to our current facilities to make the proposed multi-scale in vitro-in vivo platform world-leading: Firstly, to purchase a top-of-the-range 3D super-resolution microscope that combines structured illumination microscopy (SIM) with fluorescence localisation microscopies such as stochastic optical reconstruction microscopy (STORM) for live cell imaging to satisfy the strong demand for this technology at the earliest opportunity. Secondly, to establish a 4D ultrafast OCT system to provide much needed access to high-throughput in vivo imaging of embryonic and adult organ systems. Not only there is an urgent need in our communities to have access to these systems but their availability is also essential to make the proposed multi-scale platform internationally competitive. Our choice of commercial super-resolution system has been directed by the ideal of imaging live cells in real-time. However, all the microscopes available have a number of technical limitations that require making one or more of the following compromises: between spatial and temporal resolution, between speed, resolution and imaged sample volume and between photodamage and resolution. The third development we propose is to build the first truly 3D super-resolution microscope that will obtain images with a resolution of <20 nm both axially and laterally and that will collect data from a 3D volume of cell dimensions in a single shot rather than imaging planes within the sample individually. This microscope will be able to image multiple targets within the entire cell volume at this resolution in all three spatial axes and subsecond temporal resolution. At this time scale a wealth of new science will become accessible as we will be able to follow with nanoscale resolution in real-time a multitude of cellular process and molecular interactions as they occur. This will make the proposed imaging platform internationally leading.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: The structural biology of synaptic connectivity: understanding the extracellular organizers of neurotransmission
Funder: Medical Research Council

Abstract: Central nervous system neurons engaged in excitatory synapses are connected by an intricate protein network that spans the synaptic cleft, provides structural support and modulates neurotransmission. The key target of this proposal is to understand the molecular structures, principles of higher order organization and functional mechanisms of two prototypical trans-synaptic assemblies. We will focus on complexes built around type IIa receptor protein tyrosine phosphatases (in particular RPTPsigma) as well as Delta-type glutamate receptors. Our key questions are: What are the rules of assembly in these trans-synaptic complexes? How dynamic are such structures? How do they influence synapse formation, stability and synaptic transmission? We will combine structural biology techniques (X-ray crystallography, cryo-electron tomography) and quantitative live cell fluorescence microscopy to define the architecture of these complexes in an environment as close as possible to physiological, i.e. a cell membrane context. We will create structure-guided mutant constructs and test them in synapse formation assays and other functional paradigms (electrophysiology in whole cells and brain slices, and mouse models) in collaboration with specialist laboratories. Furthermore, by exploiting the modular architecture of soluble "synaptic organizer" proteins, we will use structural information to create molecules with novel intermolecular interaction properties through domain recombination. As an alternative, similar tools will be designed by specifically crosslinking nanobodies raised against synaptic receptors. These macromolecular probes may allow the manipulation of the number and properties of excitatory and inhibitory synapses in neuronal circuits and the implementation of novel rules of synaptic communication and homeostatic plasticity, revealing the importance of specific neuronal connections.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: MRC/UVRI Medical Informatics Centre
Funder: Medical Research Council

Abstract: The integration of epidemiological methods-including large-scale, multi-centre studies and pooled analyses of observational and interventional studies-with genomic and computational technologies has provided new insights into the biology of a broad range of diseases, including human and pathogen genomic diversity, and their risk factors. These advances in genomics create new opportunities and challenges for researchers in sub-Saharan Africa (SSA). Given the marked genomic diversity among human and pathogen populations in SSA,1,2 understanding the genomic basis of these diseases and their risk factors in populations of African descent will provide: 1) additional insights into disease aetiology; 2) new opportunities for disease surveillance; and 3) potential therapeutic and public health intervention strategies. If countries in SSA are to benefit from developments in genomics and medical informatics, there is a need to strengthen capacity, training and collaboration across the region, and with northern partners, to ensure SSA researchers can play a full part. To capitalise on these technological advances and to ensure the efficient utilisation of data resources in clinical epidemiology and large scale genomics across SSA from existing and on-going research programmes, and as part of the MRC/UVRI Uganda Research Unit on AIDS, we propose to develop the MRC/UVRI Medical Informatics Centre (MIC) in Entebbe, Uganda (panel 1). The planned centre will house a computer cluster and build on established strategic collaborations with UK research centres. These UK centres will provide scientific and logistical support to develop infrastructure and computational processes, cloud computing and human research capacity, as well as supporting pan-African and north-south research partnerships (Africa-UK medical informatics consortium).


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Structure, mechanisms, regulation and assembly of ATP synthase
Funder: Medical Research Council

Abstract: The F-ATP synthases in eubacteria and mitochondria are rotary machines with many common features. We will build on past achievements to extend fundamental knowledge about them and provide a basis for putting that knowledge to practical use. The mechanism of their catalytic domains is well understood, but how rotation is generated from the transmembrane proton-motive force is less clear. We will provide a molecular explanation of the generation of rotation. We intend to exploit mechanistic differences between human and bacterial enzymes to develop new drugs. One difference concerns their mechanisms of regulation. The mitochondrial enzyme is regulated by the inhibitor protein, IF1; in vitro, it inhibits ATP hydrolysis and not ATP synthesis, but its in vivo role is unclear, except that it inhibits the hydrolase activity of assembly intermediates. It may also inhibit in vivo ATP synthesis by a mechanism that we will investigate possible involving other unidentified proteins. Different regulatory mechanisms operate in eubacteria; for example in Mycobacteria, the enzyme can only make ATP and not hydrolyze it, but we do not yet know how hydrolysis is prevented. Eubacterial and mitochondrial enzymes differ also in their subunit compositions. They have a common core set to allow them to make ATP, but the mammalian mitochondrial enzymes have a "supernumerary" set of seven membrane proteins, each with a single predicted transmembrane alpha-helix. Six of them participate in the formation of a non-specific pore, called the mitochondrial permeability transition pore (PTP) which opens in response to high concentrations of Ca2+ inside mitochondria and leads to cell death, linked to many human diseases. Therefore, we will characterize the structure and properties of the PTP, and develop it as another drug target. As part of a wider collaboration we will study how the human ATP synthase is assembled.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Multiple imputation by chained equations for data that are missing not at random: methods development for randomised trials and observational studies
Funder: Medical Research Council

Abstract: Awareness of the problem of missing data has increased in recent years, and multiple imputation is increasingly used to handle it. Standard implementations of multiple imputation make a missing at random (MAR) assumption, which cannot be tested from the data and can rarely be confidently justified. Hence analysis based on the MAR assumption should usually be supplemented by sensitivity analyses exploring departures from MAR. For example, the US National Research Council's report on The Prevention and Treatment of Missing Data in Clinical Trials (2010) highlighted "methods for sensitivity analysis and principled decision making based on the results from sensitivity analyses" as an area of statistical research where progress is particularly needed. Multiple Imputation by Chained Equations (MICE) is a popular way to implement multiple imputation, but efforts to do missing not at random analyses have lacked a principled foundation. Finbarr Leacy's PhD research has identified the problem, and shown that the solution is to include missingness indicators in all imputation models. The proposed research aims to extend knowledge of this procedure. We aim to understand how the method works in longitudinal data, comparing its simple implementation with simple implementations of pattern-mixture models and selection models. We then aim to extend the method to realistic complex data sets, including different variable types, complex analysis models and large numbers of variables. Alongside the methods development, we will apply the method in case studies, including exploring predictors of self-harm in the ALSPAC study and re-analysing longitudinal randomised trials in smoking cessation and weight loss. To do this we will develop and implement methods to elicit the magnitude of departures from MAR. Finally, the project will provide user-friendly software in R and Stata, and disseminate the methods and software in tutorial articles and short courses.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Pathway complexities of protein misfolding in neurodegenerative diseases: a novel approach to risks evaluation and model development
Funder: Medical Research Council

Abstract: Recent work by us and others has suggested that non-cell autonomous mechanisms play an important role in the development of most human neurodegenerative diseases. Protein aggregates may form in a localized fashion, from where they spread to distant brain areas, giving rise to clinical symptoms. Together with the existence of a pre-symptomatic, prodromal phase, this opens up novel therapeutic avenues. We propose to use transcriptome sequencing (RNA-Seq) to identify gene expression changes in cells exposed to aggregates of tau protein and alpha-synuclein. Nothing is known about such changes. Seeding will use either aggregated recombinant P301S tau or aggregated A53T alpha-synuclein, in conjunction with lipofectamine. Under these conditions, close to 100% of cells form aggregates 48 h after seed exposure. We developed the relevant cell line models over recent years. We will use untransfected HEK293 cells to investigate if the seed itself leads to transcriptional changes. Transcripts whose expression changes will be identified and their role in the seeding process studied. Total RNA will be isolated using an RNeasy kit (Qiagen) and its quality controlled using a Bioanalyzer (RNA integrity number >9). Library generation and sequencing will be carried out using the Illumina Truseq kit at the Beijing Genomics Institute in Hong Kong. Reads will be aligned to the human genome using TopHat and the transcriptomes assembled using Cufflinks, before being merged. The reads and the merged assemblies will then be fed to Cuffdiff, which calculates expression levels and tests the statistical significance of observed changes. Data analysis will be performed using CummeRbund. Statistically significant changes (p<0.005) will be extracted from CuffDiff2, based on a Poisson model distribution corrected for both count uncertainty and count overdispersion.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing turnkey computational pipelines to analyse next generation sequencing data
Funder: Medical Research Council

Abstract: ultrastructural description of its nervous system provide unique opportunities to link the molecular and circuitry bases of behaviour. One sophisticated C. elegans behaviour is aggregation. The de Bono lab has used forward genetic screens to identify hundreds of mutant strains with defects in this behaviour. Each strain contains ~ 100 de novo mutations. A challenge is to identify which one mutation (it is almost always only one) causes the selected behavioural phenotype. To address this issue, I am designing and optimising a fully-automated bioinformatics pipelining tool that uses Whole Genome Sequencing (WGS) data from all mutant strains in an integrated way in order to filter out background mutations and pinpoint the genomic location of the causal mutation. Mutations selected by the pipeline will then be validated experimentally. I expect that this new bioinformatics tool will be available for all projects involving the detection of nucleotide variants, independently of the model organism chosen or the phenotype studied.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: PREDICTING OUTLIER PHENOTYPES FROM SNPS BASED ON MOLECULAR BIOLOGY AND EVOLUTION
Funder: Medical Research Council

Abstract: One of the major goals of human genomics and medicine today is to reach the stage of personalized medicine. That is, tailoring the diagnosis, prognosis and treatment of diseases to a specific individual. The connections between gene expression and various human diseases have long been made . The central challenge in genetics is to predict differences in the phenotypes of individuals by using knowledge of their genetic variation. Rapid advances in sequencing technologies have brought individual human whole-genome sequences within reach. However, the possibility of predicting phenotypic variations from genomic data of individuals through molecular biology presents an opportunity to bring novelty to the field. In recent years, acquiring one’s genetic data (such as SNP values) to learn more about his or her own disease risks and biology is becoming easier and more prevalent through direct to-consumer genetic testing. These companies allow users to acquire their allele calls at 0.7 M SNPs across the genome. We set out to build a phenotype predictor, which is web-based tool, that would allow users to input their measured SNP variants, and obtain predictions of their phenotypic traits. This project is to bring together our previous research on genetic variant analysis and functional and phenotype prediction. Our model will apply both research areas to personal genomics, by connecting phenotype to genotype through molecular biology aiming at generating a method to be applied to traits or diseases that have significant genetic component, thus broadening our understanding of the gene-gene interactions within such disease models. This method will help, not only predict traits, but may also lead to the discovery of novel SNPs which can be validated using molecular biology approaches in a later stage


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: NPIF Rutherford Fellowship
Funder: Medical Research Council

Abstract: During replication, DNA is unwound to expose single strands as a template for DNA synthesis. However, the propensity of single stranded DNA to form secondary structures poses a challenge to the smooth progression of the replication fork. Certain sequences are particularly prone to secondary structure formation, for instance G quadruplexes (G4) and triple helix forming DNA (H-DNA). Accumulating evidence suggests these structures form readily during replication in vertebrate cells, but are actively countered by a complex network of enzymes. Over 700,000 sites in the human genome are capable of G4 formation, so these structures pose challenges to replication forks potentially as frequently as naturally occurring DNA damage. Moreover, failure to maintain processive replication at secondary structures is associated with both genetic and epigenetic instability. However, the full range factors that promote secondary structure resolution during vertebrate replication is not known, and the in vivo coordination of existing enzymes and the forms of secondary structures upon which they act is also poorly understood. This project will investigate this area using a combination of RNAseq in mutants of known factors, and which have had secondary structures artificially inserted, as well as techniques that identify the location of R-loops (DNA-RNA hybrid triple helixes that may be formed in association with other secondary structures) to provide a comprehensive view of how these challenging DNA replication impediments occur and how they are handled. This will be ultimately important for understanding the circumstances under which structure-forming DNA sequences contribute to human pathology, for example in inherited syndromes, such as Werner or Bloom syndrome, or in cancer, in which replication stress may lead to widespread dysregulation of gene expression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: The rigorous development, implementation, and evaluation of the effectiveness and cost effectiveness of community-based interventions and policies, especially in relation to inequalities in health.The facilitation of two-way knowledge flows between r
Funder: Medical Research Council

Abstract: This award has two aims: • The rigorous development, implementation, and evaluation of the effectiveness and cost effectiveness of community-based interventions and policies, especially in relation to inequalities in health. • The facilitation of two-way knowledge flows between research in the social and public health sciences, and relevant policymakers and practitioners. In all known societies health risks, health-related behaviours, physical and mental health, and life expectancy tend to vary between social groups. Inequalities in health exist across a range of social and demographic indicators including income, social class, occupation and parental occupation, level of education, housing condition, neighbourhood quality, geographic region, gender and ethnicity. Inequalities are evident in many health outcomes, including mortality, morbidity, self-reported health, mental health, death and injury from accidents and violence. There is a considerable body of research documenting trends in inequalities and examining explanations for their existence and persistence. However, there is a lack of evidence about the effectiveness and cost effectiveness of policies, programmes, and projects to improve environments, and to reduce health burdens, unhealthy behaviours, and inequalities in health. This award will fund four five-year postdoctoral researchers whose fellowships will focus on developing and/or implementing and evaluating community-based interventions and/or policies designed to narrow the gap between deprived and vulnerable groups and the rest of the population. A secondary aim of these fellowships is to develop multidisciplinary research skills and capacity in collaborative population health science. The award will also fund a part-time knowledge broker tasked with generating early intelligence on research opportunities and policy/practitioner needs for research in particular fields, and providing two-way communications between researchers and policymakers and practitioners, in order to enhance the policy relevance of our work, and its translation into policy and practice.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE
Title: Centre for Health service and Academic Partnership in Translational eHealth Research (CHAPTER)
Funder: Medical Research Council

Abstract: Background: The four health informatics research centres (HIRCs) were developed in isolation from one another. At their collective birth (March 2013), however, the Centres wish to grasp the opportunity to multiply their activities by creating a single UK institute (the ‘Farr Institute for Health Informatics Research’). Vision: To harness the knowledge from health records data to improve the health of patients and communities by establishing a pre-eminent interdisciplinary UK health informatics research institute. The Farr Institute will be concentrated in the four Centres, act as the nexus of the wider UK Institute network and make the UK the come-to place for data-intensive, translational health science. Aim: The aim of the Farr Institute is to integrate and scale, at the UK level, the work of the four Centres. The Institute will thus provide a new UK-wide focus for each of the workstreams in the Centres: e-infrastructure, research, capacity and public engagement. Objectives for the capital spend (i) E-Infrastructure: To establish an outstanding UK e-infrastructure across the Centres. Specifically by establishing a co-ordinated approach to safe havens for the storage and analysis of detailed, individual-level health data, and the formation of digital laboratories for larger scale research across the Centres and their collaborators. (ii) Research: To enhance research productivity across the UK by widening access to well-described datasets through a prominent UK-wide portal, bringing new datasets to the research community and enhancing communication. The Institute will widen research partnerships beyond the four Centres, developing strategic UK links between academia, industry and the NHS. (iii) Capacity: To develop a UK-wide co-ordinated offering for training and capacity development to address the acute skills shortage in health informatics research. (iv) Public engagement: To engage the public and patients across the UK and locally, in a novel range of activities to enhance public trust in the use of health records for research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);7.4 RESOURCES AND INFRASTRUCTURE (DISEASE MANAGEMENT);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE