NIHRDataInsights/HRCSData huggingface dataset:
Title: COMPUTATIONAL GENOMICS ANALYSIS AND TRAINING (CGAT)AT THE MRC FUNCTIONAL GENOMICS UNIT
Funder: Medical Research Council

Abstract: CGAT will provide expertise and analytical capacity to UK-based research groups planning to use or already using next-generation sequencing data. At the same time CGAT will train post-doctoral researchers in the analysis and biological interpretation of genome-scale data sets. Each project will be highly collaborative, and focused on gleaning important biological conclusions from large data sets. Recent years have seen an accelerating growth in sequencing capacity, whilst sequencing costs have plummeted. As a result, powerful techniques and assays based on DNA sequencing (ChIP-Seq, RNA-Seq, genome resequencing etc.) are being developed that add greatly to the experimental toolkit of biologists and clinicians. However, while becoming increasingly affordable, these new methods require substantial computational infrastructure and expertise that are not available, currently, in many experimental research groups. Indeed, UK-wide there remains a considerable shortage of bioinformaticians able to process these large data sets. CGAT aims to help meet these considerable needs. For each collaboration, CGAT provides expertise in computational genomics, the computational infrastructure and a dedicated post-doctoral researcher. Collaborators contribute sequence data sets and their unique knowledge of their specific research area. Taken together, the result will be high-quality research culminating in high-profile journals under a joint-authorship model. CGAT builds on the experience of the Ponting group in comparative genomics and next-generation sequencing analysis. The group has a strong back-ground in computational sequence analysis and evolutionary biology with a proven track record of translating large scale sequencing data into diverse biological contexts. Post-doctoral trainees in the CGAT group will benefit from in-house training, but also the biological insights of collaborators. Working on a variety of projects, trainees will accumulate expertise in genome sequencing-related fields, as well as high profile publications.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Development of a method for adjusting trial results for biases in meta-analysis: combining generic evidence on bias with detailed trial assessment
Funder: Medical Research Council

Abstract: A meta-analysis of the results from relevant randomised trials is often regarded as the best evidence concerning the effectiveness of a healthcare intervention. In practice, however, randomised trials vary in methodological quality, and flaws in trial conduct can lead to biased estimation of the intervention effect. Two different methods of adjusting for bias in meta-analysis have been proposed recently: method A (from Welton et al.) constructs distributions for biases in the new meta-analysis using generic evidence from an external collection of meta-analyses; method B (from Turner et al.) relies on detailed assessment of the methodological quality of each trial in the new meta-analysis and elicitation of opinion about the degree of bias likely to result, which is used to make trial-specific adjustments for biases. Both approaches have advantages and disadvantages. Our overall aim is to investigate and integrate these two approaches in order to produce a third approach that gains the advantages of both. We will work entirely within a Bayesian framework. We will first examine agreement in predicting the impact of a single methodological flaw (e.g. inadequate/unclear allocation concealment) between methods A and B, and then examine agreement in predicting the impact of multiple flaws. Building on the findings of these investigations, we will develop an integrated approach to addressing within-study bias in meta-analysis, combining generic evidence and detailed study information. Three different possible approaches to integrating the methods will be considered: data and opinion will be formally combined in a Bayesian analysis; or experts will be asked to choose ranges for biases on the basis of both the trial's Risk of Bias table and the generic bias distribution for all studies within the same bias profile, either qualitatively or quantitatively. We will provide two full case studies to compare methods A and B and one or more of the integrated approaches.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular insights into ubiquitin remodelling factor p97(VCP) in DNA damage response and genome stability
Funder: Medical Research Council

Abstract: Our preliminary screen with siRNA against 13 members of UBX-family identified several candidates that strongly affect repair by homologous recombination, as measured by the dr-GFP reporter assay. We will establish which other p97-adapters are involved in processing of K48-ubiquitin signal at sites of DSB, and thus in DSB repair. We will use both laser micro-irradiation assays developed in our laboratory or ultrasoft X-ray (USX) micro-irradiation to induce DNA damage. This assay will screen for UBX-proteins that are relevant for the function of p97 at sites of DSB. p97 is detected at sites of DSB after laser treatment, where it forms IR-dependent complex with RNF8 and K48-polyubiquitinated substrates. Now our goal is to understand the interactome of p97 and DSB related proteins. For this purpose we will isolate p97 complex from chromatin under different genotoxic conditions (e.g. exposure to IR or treatment with HU) and analyse p97 adapter interactome and substrate proteome by mass spectrometry. The complex formation between p97, its adapters and DSB repair proteins will be further analysed to define these interactomes and find out their cellular relevance. p97 together with its adapter DVC1 and E3 ubiquitin ligase RNF8 have an essential role in DNA replication and replication-related repair. We aim to understand how the p97-DVC1-RNF8 cascade orchestrates DNA replication. We will use standard techniques in the DNA replication field such as FACS analysis, pulsed-field gel electrophoresis, DNA fibre assays and confocal microscopy to establish the mechanism by which p97-DVC1-RNF8 regulates DNA replication and thus genome stability, and disorders such as Werner-like premature aging syndrome in human.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: CCP4 - Collaborative Computing Project in structural biology
Funder: Medical Research Council

Abstract: The overarching aim of the proposal is to transform the ability of biologists to pursue International level structural research. We have chosen this theme because we recognise that structural biology is evolving to tackle increasingly complex and exciting biological projects. This emphasis on biology has inevitably decreased the amount of training in X-ray|crystallography. The gap in expertise is the most serious for the most difficult projects. Achieving our aim will enable biologists to undertake more challenging problems, to get the best from their data, to accelerate the computational process and to produce more reliable insights. |The project has four objectives.|1. Development of new methods for reliably and automatically building accurate atomic models for structures at limited resolution (Post 1).|2. Development of software to handle the next generation of X-ray detectors and to extract diffraction data from images from poor crystals (Post 2).|3. Development of new expert wizard based software and databases to guide the inexperienced user to get the most from the data by presenting not only information but strategy for progress, whilst still allowing the experienced user the flexibility that is the hallmark of CCP4 (Post 3).|4. Translation of the software developments of the first three objectives, and those of other CCP4 staff and contributors, into robust, well supported, and widely used tools for Industry and Academia (Post 4). This will demonstrate successful technology transfer.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Rare disease use of clinical trial simulation for the chioce and optimization of study designs/Priomedchild Call/ER
Funder: Medical Research Council

Abstract: Background: Rare diseases are defined based on their low incidence, less than one in 2,000. Whereas randomized controlled trials (RCTs) are currently the gold standard for drug evaluation, there is still no general validated approach for the assessment of (orphan) drugs in this field.|Objectives of the CRESim (Child-Rare-Euro-Simulation) project: To develop a platform performing trial modelling and simulation in order to identify optimal trial designs in children for the evaluation of (orphan) drugs tailored to different types of rare diseases.|Methods: In silico approach using RCT modelling and Monte Carlo simulation, implemented for different categories of rare diseases in pediatrics. Several RCTs with different experimental designs will be modelled and simulated, and the different designs will be compared in terms of trial duration and precision of the estimation of the treatment effect.|Expected Outcomes: Improvement and optimization of the development of new orphan drugs.|Dissemination of results: Dissemination will target those involved in drug development (i.e pharmacologists, therapeutic specialists, methodologists and statisticians), and in drug registration (public health decision makers), and registration authorities (EMEA and national agencies).


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: ERA-Net Priomedchild Call for proposals
Funder: Medical Research Council

Abstract: Understanding the pharmacokinetics (PK) of drug metabolism in children is essential in determining therapeutic dosages and avoiding adverse events. However to obtain paediatric PK data particularly in the 0-2 year old age group is technically challenging. We therefore propose to develop and validate new approaches to obtain paediatric PK data in this age group using three model drugs viz. paracetamol, spironolactone and midazolam with the ultrasensitive bioanalytical technique, Accelerator Mass Spectrometry (AMS), which can measure parent drug and metabolite concentrations in very small volume blood samples.|AMS requires the administration of a microtracer of 14C-labelled drug and hence all the necessary ethical, legal, regulatory and scientific procedures will need to be developed to allow AMS studies in the paediatric population. Intensive blood sampling procedures will be used in a relatively few paediatric patients (up to 100 patients split across two paediatric clinics) to obtain high quality PK data; these data will be compared with literature PK data where sparse sampling procedures have been used.|Paediatric patients will be recruited in Tartu, Estonia, and Liverpool, UK. The PAMPERS model drugs will be given as part of normal clinical management; in order to facilitate recruitment, we will therefore recruit patients in environments which cause the least discomfort and do not lead to significant changes in clinical procedures, for example in the post-operative period or in the intensive care unit. 14C-Labelled certificated drugs will be provided by PRI, Poland and ethical and project management aspects by groups who have been previously involved in EU funded programmes. AMS bioanalysis will be performed at a new TNO AMS centre in Zeist, The Netherlands. The innovative procedures developed here will provide a better understanding of the utility of AMS to obtain paediatric PK data and could pave the way for AMS studies to be incorporated into Paediatric Investigation Plans. This would ultimately have the benefit of earlier introduction of new therapies to the paediatric population in|a safer, more effective and efficient manner with appropriate dosage regimes.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of base excision repair
Funder: Medical Research Council

Abstract: Base excision repair (BER) is a frontline DNA repair system that is responsible for maintaining genome integrity, thus preventing many human diseases, including cancer. Changes in BER capacity most probably are responsible for many cases of cancer treatment efficiency, since many cancers have altered expression of BER proteins. Although BER enzymes have been studied in detail, the mechanisms involved in BER coordination and regulation are unclear. This knowledge gap is impeding the finding of new cancer therapy targets and the development of novel treatment strategies. We have recently discovered a new mechanism regulating BER capacity and activity by controlling steady state levels of DNA polymerase β and identified the proteins involved. However, our studies have also demonstrated that some other enzymes, including major human AP-endonuclease 1 (APE1), Polynucleotide Kinase Phosphatase (PNKP), and PARP-1 that are involved in BER, and are specifically important for removal of radiation-induced DNA lesions, are regulated by different mechanisms and enzymes. Correspondingly, the major goal of future studies is to uncover the mechanisms and proteins controlling APE1, PNKP, and PARP-1 and to build a comprehensive model for regulation and coordination of the BER response to ionising radiation. Increasing our understanding of the regulatory network for BER could be vital to targeted cancer therapy. The aim of the individual projects would be the purification and identification of new enzymes involved in post-translational modifications of BER proteins and identification of their roles in DNA damage signalling and repair of DNA damage. Specifically, we will study proteins that are involved in post-translational regulation of APE1, PNKP and PARP-1 and are required for their activation and stability. To achieve these goals, we will use purified BER proteins as substrates and establish in vitro assays for post-translational modifications such as ubiquitylation, deubiquitylation and phosphorylation. Using fractionation of human cell extracts by various chromatography techniques, we will purify and identify by mass spectrometry enzymes involved in the post-translational modification of APE1, PARP-1, and PNKP. The identified proteins will be cloned, characterised and their cellular role in the regulation of BER, and their role in the repair of radiation-induced DNA damage will be investigated using siRNA knockdown and overexpression techniques. An important part of our future studies will be the investigation of the signalling pathways linking steady state levels of APE1, PARP-1 and PNKP to the level of DNA damage and understanding the mechanism coordinating the entire BER pathway.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Wellcome Trust MRC Cambridge Stem Cell Institute
Funder: Medical Research Council

Abstract: This award is to facilitate creation of a world-leading centre for fundamental and translational stem cell research at the University of Cambridge. The Cambridge Stem Cell Institute (SCI) will build upon previous Wellcome Trust and Medical Research Council funding by drawing together 30 research teams into a cohesive centre. These groups will ultimately be co-located in a purpose-designed 8000m2 facility to be constructed on the Cambridge Biomedical Research Campus. The overall objective of this proposal is to define the potential of stem cell biology for human medicine. This relies on assembling a critical mass of talent in fundamental stem cell science alongside investigators focussed on translation to medical applications. The Cambridge Stem Cell Institute will be broad-based, well-resourced and intellectually invigorating. Cross-fertilisation between pluripotent and tissue stem cell biology will stimulate basic discoveries and increase capacity to address issues of human health and disease. Based on acquiring a deep understanding of stem cells allied with a clinical perspective, Institute scientists will pioneer innovative therapeutic approaches to unmet medical needs. Platform technologies supported by a Centre grant will enable SCI to recruit and retain the most talented investigators and empower them to make ground-breaking advances in understanding stem cells and their medical applications. Fundamental research will focus at the molecular level on mechanisms of self-renewal, commitment, differentiation and reprogramming. Functional studies will address the role of stem cells in development, repair, ageing, physiology and pathologies including cancer. Disease-specific induced pluripotent stem cells will be exploited to unravel mechanisms of cellular pathogenesis and define drug targets. Strategies to mobilise endogenous stem cells for regeneration will be evaluated in animal models and in the clinic as will approaches based on cell transplantation. The Institute will provide comprehensive training in embryonic and adult stem cell biology and will seek, and offer unique opportunities for, bioindustry interaction and collaboration. Objectives The objectives for SCI are: (i) to uncover fundamental principles of stem cell identity, regulation and function; (ii) to translate this knowledge into new tools for drug discovery and diagnostics; (iii) to pioneer therapeutic approaches based on recruitment of endogenous stem cells and/or cell transplantation strategies.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Confidence in Concept 2012 - Imperial
Funder: Medical Research Council

Abstract: Confidence in Concept Award to Imperial College London. The Confidence in Concept scheme provides awards of £300k-£1m to institutions, to be used flexibly to support the earliest stages of multiple translational research projects. It is intended to accelerate the transition from discovery research to translational development projects by supporting preliminary work or feasibility studies to establish the viability of an approach. Provide up to 10 keywords relating to your research, these help us to classify the programme (see Guidance Notes). Drug, therapy, diagnosis, development, peptide, vaccine, clinical, pre-clinical, testing


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES;5.3 MEDICAL DEVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: UK Biobank pilot imaging enhancement
Funder: Medical Research Council

Abstract: Prospective cohorts, such as UK Biobank, have advantages for the comprehensive and reliable quantification of the combined effects of different types of risk factor on disease. However, they need to involve large numbers of participants because only a relatively small proportion will develop any particular condition. UK Biobank has collected extensive baseline questionnaire data, physical measures and biological samples from 500,000 men and women aged 40-69 at baseline and their health is being followed by linkage to health records. Central adjudication of health outcomes will ensure that consistent definitions are used and facilitate access to the resource. It is now planned to enhance further the phenotyping of 100,000 participants with information from multiple imaging modalities involving Magnetic Resonance imaging of brain, heart, large blood vessels and abdomen, Ultrasound of carotid arteries, and Dual-Energy X-ray Absorptiometry (DXA) of bone and joints. The availability of imaging measures that quantitatively define phenotypes that are closely related to disease will provide substantial power for detecting associations with incident health outcomes occurring during follow-up (as well as allowing cross-sectional analyses with prevalent disease and other measures recorded at baseline). Although imaging measures have been included in other population-based studies, the small numbers of people involved (typically less than 5,000), and the focus of those studies on imaging particular organ systems, has limited their ability to assess associations with incident disease. Integration of complementary imaging data that inform on a range of organ systems from 100,000 UK Biobank participants, along with the detailed non-imaging data collected at baseline (including genotyping and biomarker data), will provide a unique resource for investigating the biological mechanisms of disease. (For example, the risk of developing dementia may be related to imaging measures derived not just from the brain but also from other parts of the body, as well as to genetic, biochemical or environmental information from baseline.) Subject to successful piloting during 2013-14, the main phase of imaging assessments will be conducted in dedicated imaging centres during 2014-2019. After completing imaging in 100,000 participants, these imaging centres could then be used to conduct repeat imaging in a subset of participants to allow investigation of the relevance of changes in imaging measures to particular outcomes (e.g. dementia). As is the case for the rest of the UK Biobank resource, the imaging data will be made available to all bona fide researchers for health-related research that is in the public interest.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE