NIHRDataInsights/HRCSData huggingface dataset:
Title: International Mouse Phenotyping Consortium- building a functional catalogue of a mammalian genome
Funder: Medical Research Council

Abstract: The goal of the International Mouse Phenotyping Consortium (IMPC) is to discover functional insight for every gene by generating and systematically phenotyping 20,000 knockout mouse strains. The IMPC set out to accomplish its goals in two phases. Phase 1, funded from 2011-2016, is well established and on target to deliver and phenotype 5000 mouse mutants. Phase 2, from 2016-2021 envisages a ramp up to generate and characterise mutations for the remaining 15,000 genes. The IMPC incorporates 16 major mouse centres around the world that are committed to the delivery of the first phase of the programme. As well as the major production and phenotyping centres, IMPC also incorporates a substantial informatics effort – MPI2 - that underpins the international endeavor. MPI2 comprises three centres (MRC Harwell, EBI, Sanger Institute) each of which has a key role in the coordinated delivery of data acquisition, data analysis and data dissemination. Importance of International Collaboration MRC Harwell was in the vanguard of the planning and initial scientific and business proposals for IMPC, recognizing that the challenge of generating a comprehensive catalogue of mammalian gene function would require the combined efforts of the leading mouse genetics centres worldwide. Moreover, the IMPC members together bring an unparalleled breadth and depth of expertise in mammalian genomics and genetics that has undoubtedly underpinned the rapid progress and success of the consortium to date (as well as delivering locally in every member country extraordinary access to outstanding science and technology developments along the way). The consortium has worked together to set new standards in mouse genetics for reproducibility and as a consequence has realized: 1. The development and delivery of a gold standard collection of validated mouse mutants 2. A set of gold standard phenotyping assays that underpins the reliability and reproducibility of the data produced Systematic broad-based phenotyping is performed by each IMPC center using standardized procedures found within the International Mouse Phenotyping Resource of Standardised Screens (IMPReSS) resource. Gene-to-phenotype associations are made by a versioned statistical analysis with all data freely available through the web portal and several data download features.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Germline and Pluripotency
Funder: Medical Research Council

Abstract: Pluripotency is the capacity of a single cell to form all adult cell lineages. In the mammalian embryo, pluripotency is a transient property that disappears as cells sequentially specialise into differentiated tissues or soma. However, a small number of primordial germ cells (PGCs) are set-aside in early development and are the founder cells of the germline, ultimately giving rise to the gametes – the sperm and egg. Despite the overt specialisation displayed by sperm and egg, it is through combining these two cell types that a new embryo, once again containing pluripotent cells, is produced in the next generation. Furthermore, PGCs are the cells of origin of testicular teratocarcinoma and when placed in culture, in the presence of certain cytokines, they can efficiently undergo conversion to pluripotent stem cells called embryonic germ (EG) cells. These cells have similar properties to embryonic stem (ES) cells derived directly from pluripotent cells in the early embryo. Therefore we have hypothesised that competence for pluripotency appears to persist – to a lesser or greater extent - throughout the germline cycle. Our lab studies the germline cycle in vivo in mammalian embryos, and also in vitro using primary culture systems and pluripotent stem cell models. By studying how pluripotency is regulated both in vivo (predominantly in the mouse) and in vitro (using mouse, rat and, increasingly, human cells) we seek to answer basic questions about the regulation of cell fate and potency. We are also interested in how germ cell development is co-ordinated with the major germline epigenetic reprogramming events, with a particularly focus on DNA methylation. We have started to develop live imaging approaches to visualise germ cells in vivo and in vitro, and we hope to use this to answer a broad range of questions including: how developmental signals influence cell potency and epigenetic processes, the role of physical factors on germ cells and the molecular mechanism of PGC migration. By studying basic questions in stem cell biology, developmental biology, epigenetics and reproduction we hope to inform the treatment of human infertility, such as by in vitro gametogenesis approaches, and more broadly impact the field of regenerative medicine. Understanding the process of teratocarcinogenesis may well inform our understanding of developmental tumours. Understanding how normal development is subverted and how aberrant cells survive and lead to tumours has the potential to impact strategies to improve treatment strategies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Centre for Chemical and Synthetic Biology
Funder: Medical Research Council

Abstract: We have pioneered genetic code expansion methods that allow us to site specifically direct the incorporation of user-defined chemically synthesized amino acids into proteins in living cells. The Chemical Biology Initiative aims to exploit these technologies for quantitatively addressing important biological problems that are challenging or impossible to address by other methods. This program addresses 1) producing and characterizing – biochemically and structurally - the role of post translational modifications in controlling protein function 2) The temporal and spatial control of protein function inside living cells to extract a quantitative understanding of biological phenomena 3) Methods for labeling proteins and mapping protein interactions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The chemical origins of molecular biology
Funder: Medical Research Council

Abstract: A true understanding of biology must include knowledge of its chemical origin, and comprehending the chemical events that gave biology its foundations – cellular format, the central dogma, the genetic code – is therefore a fundamental aspect of natural science. Furthermore, understanding the way in which extant biology arose can inform the design of synthetic biologies. We are interested in using the tools of organic chemistry (synthesis and analysis) to uncover prebiotically plausible syntheses of the informational, catalytic and compartment–forming molecules necessary for the emergence of life. We have previously demonstrated the constitutional self-assembly of pyrimidine ribonucleotides from mixtures of simple building blocks, and we are now exploring similar systems chemistry approaches to the purine ribonucleotides, and ways of assembling RNA from these ribonucleotides with regiocontrol of the internucleotide phosphodiester linkage. We are also interested in the chemical origins of genetically encoded translation, and the abiogenesis of lipids.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The structure and mechanism of Dynein
Funder: Medical Research Council

Abstract: Cytoplasmic dynein is a 1.4MDa complex of proteins that acts as a minus-end directed, microtubule motor. It plays roles in mitosis and carries a wide range of cargos from membrane organelles through to unfolded proteins. Dynein malfunction is associated with developmental disorders and neurodegeneration and dynein is used by viruses, such as herpes, to reach the nucleus and infect the cell. Our goal is to use structural biology to improve our understanding of dynein’s roles in these medical and cell biological processes. We determined X-ray crystal structures of the yeast dynein motor in the absence of nucleotide and a human dynein motor in the presence of a transition state inhibitor (ADP.vanadate). These structures reveal how dynein couples ATP hydrolysis to force production through bending of a long alpha helical bundle called the linker domain. We also demonstrated how dynein uses the relative sliding of alpha helices in its coiled coil stalk to control its binding to microtubules. This work finally shows how dynein, the largest cytoskeletal motor protein, uses ATP to drive movement. We recently used cryo-electron microscopy to determine the first high resolution structure of the dynactin complex, a 1.1MDa cofactor for dynein. Dynactin is built round a short filament of the actin related protein Arp1. We explained how the complex is assembled and how the length of the filament is precisely determined. We also determined how dynein binds to dynactin. We showed that dynein and dynactin assemble around a long coiled coil protein called Bicaudal-D2 which is itself tethered directly to Golgi vesicle cargos. We therefore provide the first description of how dynein selects its cargos. Our future plan is to uncover the rules that govern how other cargos including viruses bind the motor. This should provide insight into how one dynein motor can undertake so many different roles in the cell.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Computational Crystallography
Funder: Medical Research Council

Abstract: Our main aim is to develop state of the art mathematical, computational, statistical, bioinformatics tools for the analysis of Macromolecular Crystallographic (MX) data and Electron Microscopy (EM) maps, and to derive of chemically and structurally consistent atomic models. Focus of our research is on several interlinked, but independent aspects of the Macromolecular 3D structure analysis: 1) Low-resolution MX (3-7A). Most of the existing tools have been designed for medium and high resolution MX analysis. As a result only less than 2% of all structures deposited to the Protein Data Bank have been analysed at lower than 3.5A. There are two problems related to the analysis of such data: a) smeared and noisy electron density resulting from Fourier series termination, high mobility of the molecules and phase errors, b) low ratio of the number of observations to the number of parameters. We are developing several image processing techniques to improve electron densities and Bayesian techniques to transfer information from all or class of macromolecules to low-resolution structure analysis. 2) Modelling processes in the crystals during X-ray experiments. Most of the MX software assumes that data are collected from static crystals. However radiation damage phenomenon demonstrates that they may change during data collection. We have started application of hidden Markov models to address this problem. Developed tools will help to increase reliability of the derived models 3) Automatic and manual model building and analysis of macromolecular structures. Dr Paul Emsley leads this project. His molecular graphics program – COOT is the leading software in the field. 4) Automatic structure solution pipeline. We have developed an automatic structure solution pipeline for initial phasing using molecular replacement. We plan to develop a pipeline for all stages of MX. Decision at every stage will be made using all available information. An integral part of such systems is custom designed database of accumulated knowledge. 5) Semiautomatic ligand design. One of the applications of MX is to enzymatic reaction mechanism study. For this, many inhibitor/substrate - protein crystals are analysed. Accurate ligand description is essential for such analysis. The problem looks deceptively simple however many mistakes in the PDB are due to inaccurate ligand descriptions. We are using computational chemical techniques to improve their reliability. 6) Interpretation of EM models with atomic models and their optimal fit to maps. To achieve optimal fit we aim to use all available information about macromolecules and properties of EM maps that are different in some aspects from MX derived maps. We also plan to combine several experimental techniques to derive reliable 3D models. In particular we are developing techniques for joint analysis NMR/MX and EM/MX data.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Post-transcriptional control of gene expression following toxic injury
Funder: Medical Research Council

Abstract: Following toxic cellular insult mediated by a range of agents (including UVB exposure, cisplatin and TNF related apoptosis inducing ligand, TRAIL, asbestos exposure) there is a reprogramming of protein synthesis. This reprogramming event occurs in addition to transcriptional control, although in comparison to transcription control post-transcriptional regulation has been less studied. From the systems examined thus far, the data suggest that following toxic injury subsets of mRNAs are co-ordinately regulated at a post-transcriptional level. The overall spectrum of mRNAs that are selectively translated under these conditions is specific to the type of toxic injury imposed, thus forming an essential part of the cellular response to toxic exposure. The overall aims of this programme are: A) to combine post-transcriptional and transcriptional profiling data obtained following exposure to different classes of toxic agents, to generate new models to accurately predict the effects of toxic insult; B) to carry out a detailed analysis on the RNA elements and their cognate binding proteins that permit the selective protein synthesis following toxic exposure to determine the mechanistic basis for the response; C) to examine ways in which the response to toxic injury can be modulated to enhance the efficacy of cytotoxic agents.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of microRNAs in the cytotoxic response
Funder: Medical Research Council

Abstract: MicroRNAs (miRNAs) represent a major control point of gene regulation. These small, non-coding RNA molecules regulate gene expression by base-pairing in an imperfect manner to target mRNAs, negatively regulating protein synthesis from the corresponding mRNA1. The MRC Toxicology Unit’s new strategy is to investigate how toxic insult changes gene expression using a systems-based approach. MiRNAs are of fundamental importance to the control of gene expression and thus form a major part of this vision. The objective of this program is therefore to investigate how miRNAs and the enzymes involved in mRNA maturation influence gene expression and DNA repair following situations of toxic insult. This research will integrate into the global understanding of how gene expression is altered under these conditions and in the longer term unveil potential future therapeutic avenues. Aims 1. To determine the changes in miRNA expression, and their effects on gene expression, following a diverse range of cytotoxic insults. 2. To identify the signalling pathways following DNA damage that lead to transcriptional activation of miR-34b/c and how these miRNAs potently inhibit translation of key targets. 3. To investigate whether modulating miRNAs can sensitise cells to chemotherapeutic agents. 4. To determine the role of miRNAs in the onset of the asbestos-induced disease malignant mesothelioma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Budget support for Edward Francis Small Teaching Hospital & University of The Gambia platform
Funder: Medical Research Council

Abstract: The budget provides support for clinical work and clinical research at paediatric unit of Edward Francis Small Teaching Hospital (previously called Royal Victoria Teaching Hospital) and teaching of paediatrics to medical students of university of The Gambia. Edward Francis Small Teaching Hospital (EFSTH) is located in Banjul, the capital of The Gambia and it is the main referral hospital for the country. Patients are referred to EFSTH mainly from the western part of the country and the paediatric unit has 100 beds and admits about 3000 patients annually. Major causes for admission include severe malaria, acute respiratory infection, malnutrition, septicaemia and gastroenteritis. On-going clinical research at the EFSTH includes a surveillance of invasive Haemophilus influenzae type b (Hib) infection in The Gambia to understand its evolving epidemiology; and study of aetiological agents and risk factors for neonatal sepsis in The Gambia. A randomised controlled trial of early kangaroo mother care for hospitalised newborns who have low birth weight is also planned to commence in the fall of 2016. The paediatric unit provides teaching for medical students from University of The Gambian. In addition, medical students from other parts of Africa, Europe and America come to the department for their elective postings.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Post-Translational Modifications in the Radiation Damage Response
Funder: Medical Research Council

Abstract: Posttranslational modifications (PTMs) including ubiquitination and SUMOylation are essential for the DNA damage response (DDR) and DNA replication. The local accumulation of these proteinaceous PTMs at sites of DNA damage and at sites of DNA replication is essential for accumulation and disassembly of DDR and DNA replication proteins and thus paramount for genome stability. Defects in ubiquitin (Ub) and SUMO signals lead to various human diseases including neurodegeneration, premature aging and cancer. The main objective of the group is to decipher the ubiquitin (Ub) and SUMO signals in DDR after ionising radiation (IR) and in DNA replication. To address this objective we study the central component of the ubiquitin-proteasome system (UPS), the AAA+ ATPase p97 (also known as VCP in mammals or Cdc48 in lower eukaryotes). p97 is the Ub-dependent molecular chaperone that, in association with its cofactors (around 30 are known), controls the rate and dynamics of Ub and SUMO dependent protein turnover and degradation. The p97 system (p97+cofactors) is essential for various processes in chromatin biology. My work has identified the role of p97 associated with chromatin for the first time and opened a new arena of research, namely the removal and degradation of chromatin-associated proteins. The Group’s work has further discovered the essential role of p97 in DNA double strand break (DSB) repair after IR, and a direct link between mutations in a component of the p97 system and accelerated aging and cancer in humans. Moreover, we have just identified that p97 cofactor SPARTAN is a DNA-dependent metalloprotease for repair of DNA-protein crosslinks, under-investigated DNA lesions associated with premature ageing and cancer. Based on these findings, we have evidence that a specialised DNA repair pathway exists, which removes DNA-protein crosslinks in vertebrates. By using quantitative proteomic approaches we have identified three p97 sub-complexes, which associate with chromatin after IR. Now, we aim to use biochemical and cell biological approaches in different human normal and cancer cell lines to characterise the p97 system in genome stability. Specifically, we will focus on: (i) characterisation of SPARTAN enzymatic activity and identification of its substrates, and (ii) characterisation of three p97-chromatin associated sub-complexes and how these sub-complexes orchestrate DNA replication and DNA double strand break repair after IR. As components of both the UPS (proteasome inhibitor bortezomib -Velcade®) and DDR (PARP inhibitor olaparib - Lynparza®) are druggable targets and approved cancer therapeutics, investigating the p97 system is of importance to extend our understanding of carcinogenesis and developing novel cancer therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Statistical bioinformatics and genetics
Funder: Medical Research Council

Abstract: We focus our research on gene regulation and biopathways as derived from genetic, phylogenetic, gene expression, and molecular biomarker data. Biological systems of particular interest are stem and cancer cells (human, mouse, and drosophila), blood cells (platelets involved in artherothrombosis), and bacteria (Mycobacterium tuberculosis). Statistical modelling of such systems is challenging. Experimental data as well as other sources of information, such as bioinformatics databases, are challenging. Statistical and mathematical models which are able to represent key features of a biological system, features important for its understanding, prediction, and manipulation, are quite complex. We explore how to combine statistical inference methods, machine learning algorithms, and mathematical modelling to derive useful representations of the biological systems of interest. We will anticipate new technologies for high throughput whole genome sequencing, by developing methods for direct analysis of DNA sequences, as opposed to genetic markers. Integrating evidence from multiple data sources from different levels of organisation of a biological system will enable the discovery of important functional links and the assessment of the predictive import of molecular biomarkers with respect to phenotypes of direct clinical interest. Development of application-specific methods will result in the creation of generic computational tools and software for use by a larger community of bioinformaticians and biologists, not necessarily experts in the detailed statistical background.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Evidence Synthesis to inform health related decision making
Funder: Medical Research Council

Abstract: Decisions regarding health policy are being increasingly informed by the synthesis of evidence from multiple sources. Often available evidence comes from a multitude of heterogeneous sources or studies, may be incomplete, biased, refers to populations different from those of interest, and/or is sparse. Robust statistical methods and epidemiological understanding are then needed to integrate such a patchwork of evidence in a coherent manner to make it useful for decision making. Approaches to such syntheses range from meta-analysis through generalised evidence to decision theoretic methods required for advising on health policies. Our work focuses on developing and statistical methodology to design, fit and evaluate complex models for evidence synthesis. Outstanding methodological challenges include statistical standard setting for inclusion of data sources, model development and criticism, including handling of heterogeneity and biases, detecting, quantifying and resolving possible inconsistency between sources and development of appropriate and accessible computational approaches. Further, the abundance of emerging data sources available, as a result of investment in e-health, means that it is more important than ever to apply rigorous scientific principles to develop models which have a sound and relevant evidence base. In addition, as new types of biomedical information, such as genetic and genomic data, become available, its integration into existing evidence synthesis frameworks will become increasingly important. Our work is inspired by, and applied to, substantive problems in medical research with particular emphasis on infectious diseases, addictions and evaluation of public health interventions.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: GENERIC HEALTH RELEVANCE