NIHRDataInsights/HRCSData huggingface dataset:
Title: Towards a Collaborative Computational Project for Electron cryo-Microscopy (CCP-EM) and bridging the gaps between structure determination methods
Funder: Medical Research Council

Abstract: The Partnership will address three broad areas: It will provide a forum for planning a Collaborative Computational Project (CCP) in cryoEM, and for developing a roadmap for future software developments. It will support the users of software for cryoEM through dissemination of information on available software, directed training and improvements to the useability of software. Finally, it will provide support for software developers, including porting, optimisation and distribution of software. These aims will be achieved through two computational scientists based at the Research Complex at Harwell, directed by 7 investigators from a range of relevant disciplines. The PdrAs will establish the necessary infrastructure in terms of web site, software development environment, and collaboration tools. Together with the named investigators, they will consult with the whole community on software requirements. Some software is available from the applicants, and some from other UK groups. The PdrAs will write additional programs, scripts and workflows as necessary, although we stress the aim is not to replicate existing programs but rather ensure their optimum use. The areas to be covered include single particle reconstruction, helical reconstruction, tomography, and electron crystallography. In addition, there will be strong links to the macromolecular crystallography community through the involvement of CCP4, and the NMR community through CCPN. These established collaborations provide useful experience for the development of a CCP in cryo-EM. In addition, we will look specifically at bridging the gap between these techniques in order to support multi-disciplinary studies, for example by facilitating data transfer. We will also liaise with the Electron Microscopy Data Bank in the areas of validation, deposition and annotation.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: The transcriptome of haemogenic endothelium in zebrafish embryos
Funder: Medical Research Council

Abstract: In the vertebrate embryo, haematopoietic stem cells arise in the ventral wall of the dorsal aorta via an endothelial intermediate, the haemogenic endothelium. Little is known about the molecular programme that drives this process. Here, we propose to analyse in detail the transcriptome of the haemogenic endothelium and to compare it to that of non-haemogenic endothelial cells. For this purpose, we make use of a novel unique transgenic zebrafish line that allows us to isolate haemogenic endothelial cells from the zebrafish embryo by fluorescence-activated cell sorting. Total RNA will be prepared, mRNA reverse transcribed and amplified. Amplified cDNAs are used to generate a library for SOLiD sequencing. Genes up- or down-regulated in haemogenic endothelium in comparison to non-haemogenic and arterial endothelial cells will be verified by quantitative RT-PCR and RNA in situ hybridisation. Genes verified to be differentially expressed will be examined further in loss- and gain-of-function experiments to study their role in the process of haematopoietic stem cell formation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Functional dynamics of endogenous phosphatidylinositol-5-phosphate 4-kinases
Funder: Medical Research Council

Abstract: Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are enigmatic inositol lipid kinases whose function is currently believed to be to regulate the cellular levels of their substrate, PI5P, an inositol lipid found at low levels in the cytoplasm and the nucleus of animal cells, and whose function has so far been associated with stress-activated signalling pathways. We have, primarily by the novel tehnique of genomic tagging in DT40 cells, made a series of discoveries about the three mammalian isoform, PI5P4Ks alpha, beta and gamma that throw a new light on their functional interrelationship. The isoforms form stable heterodimers in vivo randomly (that is, the three isoforms will dimerise in proportion to their relative concentrations). Moreover, we have discovered that they have very different ezymatic activities, with alpha being much more active than beta, which is in turn much more active than gamma. Given that these isoforms each have distinct intracellular locations, our current hypothesis is that cells express different quantities of the three PI5P4Ks to target the active alpha to different locations: to cytoplasmic membranes (alpha/alpha), to the nucleus (alpha/beta) or trafficking vesicles (alpha/gamma). This project aims firstly, to explore the dynamics and functions of the interrelationship between genomically tagged PI5P4Ks alpha and beta in DT40 cells, principally by using a wide gamut of cutting edge fluorescent technologies including FCS, FCCS, Raster image CS and Time-resolved Anisotropy. These, together with electron microscopy, degron-tagging and chemical biology will not only provide unprecedented insight into how this relationship works and functions in vivo, but throw more general light on the mechanisms of isoform-targeted localisation as a general evolutionary strategy for localising cell signalling pathways. To extend the study to the third isoform, PI5P4K gamma, which DT40 cells lack, we will use a close human equivalent, Nalm-6 cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Next-Generation Transgenesis in Zebrafish.
Funder: Medical Research Council

Abstract: We propose to make a large set of creERT2 and lox based lines which will be useful to many Zebrafish researchers including those in the fields of stem cell biology, regeneration and cancer. We will make more than 15 tissue-specific creERT2 transgenes to drive recombination in a range of precursor and differentiated cell types. We will make a set of 3 lineage tracing lines which will enable researchers to permanently label individual cells and their descendants and follow their behaviour (migration, division and differentiation) throughout the life of the animal. In addition, we will make a set of lox based transgenes that will enable researchers to up- or downregulate the activity of more than 7 pathways permanently in a given cell (PathM lines). The following pathways will be targeted in the first instance: FGF, WNT, BMP, Notch, Hedgehog, Hippo, JAK/STAT. Four more PathM lines will be generated at the request of the Zebrafish community. All lines will be freely available as soon as they are established and with the appropriate material transfer agreement(s) in place. We will establish a website to publicise the resource, aid in distribution and to provide a discussion group for trouble-shooting. Our overall aim is to galvanize the use of the Cre/Lox system in Zebrafish research and in doing so provide many new tools for biomedical research.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: IDENTIFICATION OF NUCLEAR PATHWAYS THAT ARE CAUSALLY INVOLVED IN NUCLEOLAR TARGETING OF NF-KAPPAB/RELA.
Funder: Medical Research Council

Abstract: Objective 1. Identification of the COMMD1 complex that ubiquitinates RelA in response to aspirin. Approaches that will be used to complete this objective include depletion of candidate proteins using siRNA followed by immunocytochemistry to detect nucleolar translocation of RelA and Ni-agarose precipitation of 6HisUb followed by anti-RelA western blot analysis to detect ubiquitination of the protein. We will also use a proteomics approach to identify novel, aspirin-induced, COMMD1 binding proteins. GST-COMMD1 will be isolated from cells +/- aspirin. COMMD1 binding proteins will be identified by SDS PAGE and mass spectrometry of excised bands. Immunocytochemistry, western blot analysis and qRTPCR will be used to analyse the effects of aspirin on components of the complex and the mechanisms by which aspirin causes increased cellular levels of COMMD1. Objective 2. Identification of the lysine residues of RelA that are ubiquitinated in response to aspirin and the nature of this ubiquitination. Deletion and site directed mutagenesis will be used to identify domains and lysine residues of RelA important for ubiquitination. We will use ubiquitin-mediated fluorescence complementation (UbFC) assays, expression of mutated ubiquitin and linkage specific antibodies, to identify the ubiquitin linkages important for nucleolar translocation of RelA. Objective 3. Identification of proteins that transport ubiquitinated RelA to the nucleolus. We propose a novel proteomic approach to identify proteins that specifically bind to aspirin-induced, ubiquitinated RelA which involves a combination of isolation of ubiquitinated RelA and stable isotope labelling of amino acids in culture (SILAC). Once binding proteins are identified, techniques outlined in objective 1 will be used to determine their role in aspirin-mediated nucleolar translocation of RelA.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of membrane trafficking and signalling by clathrin light chain phosphorylation
Funder: Medical Research Council

Abstract: The overall aim of this proposal is to understand how endocytosis regulates intracellular signalling. Increasing evidence supports the idea that the rate of flux of signalling molecules through the endocytic pathway plays a key role in their downstream signalling output, thus providing one possible mechanism for how a single signal can give rise to multiple outcomes depending on cellular context. Clathrin plays a major role in intracellular trafficking, forming clathrin coated vesicles at the cell surface, at the Trans-Golgi Network, on recycling endosomes and also establishing microdomains for sorting material from early to late endosomes. Here we propose to study the role of clathrin light chains (CLCs), which have been highly conserved in evolution but whose function is relatively unknown. This proposal builds on our novel findings which have revealed that CLCb has a newly-discovered role in endocytic trafficking and that differential phosphorylation of CLCb plays key roles in the endocytosis of physiologically important G protein-coupled receptors (GPCRs) involved in both platelet regulation in the cardiovascular system (P2Y receptors) and pain and reward in the central nervous system (mu opioid receptor). Our working model is that CLC phosphorylation modulates endocytic flux and this may be physiologically relevant for the transit of signalling molecules along the endocytic pathway. We have already identified G-protein coupled receptor kinase2 (GRK2) as a potential kinase to phosphorylate CLCb. Building on these novel observations we will use a combination of cell biology assays and fluorescence microscopy to explore the role of CLC phosphorylation on the endocytosis and downstream signalling of GPCRs. We will also analyse the role of CLC phosphorylation, and the kinases involved, in other trafficking and signalling pathways.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Spending wisely: Investigating survey mode effects in discrete choice experiment responses
Funder: Medical Research Council

Abstract: Surveys of patient or public preferences are used in health economics research. While in-person interviews are recommended for preference elicitation research they are expensive and researchers have used mail or increasingly internet surveys instead. The survey mode may affect who responds to the survey, how respondents answer the questions and their ability to provide accurate responses. Only one health economics study has investigated the effect of survey mode on the data obtained. This study aims to investigate the effect of survey mode on responses to a questionnaire asking the general population about their preferences for health care. We will compare four survey modes: internet panel survey, mail survey, mail invitation to complete an internet survey, and in-person interviews. The surveys will elicit preferences for a health care good relevant to the general population: the use of community pharmacies for managing minor illness. No previous research has compared all four survey modes in a preference elicitation study. An identical questionnaire will be used to collect data across the four survey modes and data collection for each mode will take place at the same time. For each mode, we will consider three measures of data quality (sample representativeness, response rate, response validity). We will test if the elicited preferences are significantly different across modes, and will also compare the survey cost across modes. To achieve the study aims, the proposed research has five objectives: to test if respondents to each mode are representative of the general population to test if the elicited preferences are significantly different across modes to explore the use of statistical techniques to account for differences in respondent characteristics across modes to test if response validity varies across modes to compare research costs across survey modes.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: The SITAR method of growth curve analysis for growth assessment in translational medicine and life course epidemiology
Funder: Medical Research Council

Abstract: The SITAR method of growth curve analysis summarises individual growth patterns of e.g height or weight in three parameters (size, tempo and velocity) that are estimated as subject random effects, plus a cubic spline estimate of the average growth curve. It explains over 95% of the age-specific variance in the outcome measure, and as such is an effective summary of individual growth patterns. The subject-specific random effects can then be related to earlier growth-affecting exposures or later health outcomes. Thus it is relevant in translational medicine and life course epidemiology. The aims of the project are (i) to further develop the SITAR methodology, (ii) to apply it to a series of existing growth studies, and (iii) to develop a SITAR software library in the R statistical language for its wider dissemination. Methodological developments will include exploring P-splines as an alternative to B-splines for the average curve, and deriving standard errors for the random effects. The application studies are collaborations involving a mix of observational and experimental data, covering height, weight and BMI in infancy, puberty and all childhood, and they include the British 1946, 1958, ALSPAC and Millennium birth cohorts. The R library will enable other statisticians and epidemiologists to apply the method relatively simply. SITAR can also be applied to cross-sectionally based median curves of say height versus age, as used in growth charts. SITAR allows such median curves from different growth references to be superimposed, which is useful for merging charts and for understanding differences in the underlying reference populations.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Driving up the quality and relevance of research-based knowledge through the identification and use of core outcomes: the COMET Initiative
Funder: Medical Research Council

Abstract: A 'core outcome set' (COS) is a set of outcomes which should be measured and reported, as a minimum, in all clinical trials for a specific condition. COS could have implications across all areas of research in health and health care, reduce heterogeneity between trials, lead to research that is more likely to have measured relevant outcomes, and be of potential value in clinical audit. COS would enhance the value of evidence synthesis by reducing the risk of outcome reporting bias and ensuring that all trials contribute usable information. COS will increase the efficiency of the research process. The COMET (Core Outcome Measures in Effectiveness Trials, http://www.comet-initiative.org.uk) Initiative brings together researchers interested in the development and application of COS. The objectives of this 2-year project are to consolidate and develop the ongoing COMET Initiative, which is supported by many stakeholders. There are three workstreams (section 3.3): core activity, research, and strategic development. We will systematically search for and classify studies that have determined which outcomes to measure in clinical trials, and include them in a publically available internet-based resource. Our research objectives are (i) to undertake a survey of COS developers to understand their choice of approach, to describe their experience of COS development and implementation, and to identify priority areas for methodological research, and (ii) to undertake feasibility work for methodological projects alongside COS development. The results of our work will provide a useful, central resource for clinical trialists, systematic reviewers, trial funders, regulators and guideline developers, so they may identify existing core outcome sets in specific clinical areas. Our feasibility studies will benefit other academics working in the fields of consensus methodology research. The project has implications across all areas of research in health and healthcare.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Enhancing the CONSORT initiative: renewal of intellectual support for the CONSORT Group
Funder: Medical Research Council

Abstract: The explicit primary goal of the CONSORT Group is to foster and facilitate proper reporting of randomized trials, primarily through developing guidelines for reporting the findings of completed trials. The work of CONSORT is of extreme relevance to the quality and value of clinical research across all medical areas. Research projects require considerable care in planning and execution if they are to contribute usefully to scientific knowledge and the care of people. However, serious deficiencies in the reporting of trials in the form of journal articles are well-documented. Randomized trials are the focus of particular scrutiny because of their important direct link to health care. The CONSORT Statement (1996, 2001 and 2010) presented recommendations for the proper reporting of randomized trials. Despite clear evidence that CONSORT has helped to improve reports of randomized trials the quality of reporting is still unacceptably low. In 2005, the CONSORT Group successfully received five year funding to support its activities from the Health Technology Assessment Research Methodology Programme in the UK. The support provided by the current grant has greatly benefitted the CONSORT Group and helped us to be very productive in recent years. The CONSORT Statement is an evidence-based reporting guideline, however, to maintain its credibility it must remain up to date. That funding is coming to the end and we now seek a renewal to enable us to support and enhance the work of the CONSORT Group. We outline four broad, interlinked areas of planned activity relating to the CONSORT Statement and its extensions: to continue to refine and update the CONSORT guideline and its extensions; to continue efforts to improve the implementation of and adherence to the CONSORT Statement and its extensions; to conduct relevant research relating to how randomized trials are reported; and to provide vital infrastructure to support the activities of the CONSORT Group.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Enhancing the QUAlity and Transparency of health Research: The EQUATOR Network
Funder: Medical Research Council

Abstract: The EQUATOR Network is an international initiative that seeks to improve the reliability and value of the published health research literature by promoting transparent and accurate reporting. The main focus of our activities is to support scientists, editors, and peer reviewers in writing and publishing well reported research studies that are easy to appraise and use in further research, clinical practice and policy-making. Indirectly, EQUATOR supports the improvement of the design and conduct of future research studies. The EQUATOR Network developed a unique online Library for Health Research Reporting that pulls together all guidelines for reporting health research studies. We promote rigorous research reporting, introduce available reporting guidelines, and support their use through a wide range of activities. Our research programme informs all aspects of the EQUATOR work, such as further Library development, teaching activities, and assisting in the development of new reporting guidelines. Examples of our recent projects include a systematic review of reporting guidelines; a survey of reporting guideline developers; publication of guidance on how to develop reporting guidelines; a survey of journals' instructions to authors and peer reviewers (ongoing); and development of a tool assessing the quality of reporting guidelines (ongoing). The EQUATOR Network is seeking continuation of its MRC financial support for the period of 2011 - 2014 to further advance its programme. This proposal outlines specific deliverables and activities for the next three years. The main outputs include: - Upgraded online Library for Health Research Reporting - First two of the EQUATOR 'signature' courses (for methodology editors; for research students) - Manual for the development of reporting guidelines - Research report summarising the use of reporting guidelines by journals - Database of evaluations of reporting quality across health research specialties


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Designing and analysing multi-arm multi-stage clinical trials with one or more endpoints
Funder: Medical Research Council

Abstract: Multi-arm multi-stage designs are a broad class of designs in which several active treatment arms are compared to a common control. Their advantage over traditional 2-armed studies is that, on the one hand, a common control group is used yielding smaller expected sample sizes compared to multiple 2-armed trials and allowing direct comparisons of all active arms under the same study conditions and, on the other hand, that decisions about effective and ineffective treatments can be made at early interim analyses. Although some work on designing these trials in simple situations (e.g. play-the-winner designs) is available no adequate methods are available for many situations of practical interest (e.g. multiple endpoints). Moreover methods for adequately estimating the treatment effect and finding the corresponding confidence intervals in such trials are not available beyond two stages. This proposal aims to 1. develop statistical designs for multi-arm multi-stage designs that use intermediate endpoints for treatment selection; 2. develop and evaluate methods for estimating the treatment effect and corresponding confidence intervals in multi-arm multi-stage designs with treatment selection and obtain their confidence intervals; 3. develop statistical methods for multi-arm multi-stage designs with multiple endpoints; 4. develop an open-source software package and associated training tailored to clinical trialists and applied statisticians working on clinical trials.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE