NIHRDataInsights/HRCSData huggingface dataset:
Title: Children's Health State Preferences Learnt from Animation (CHILDSPLA)
Funder: Medical Research Council

Abstract: There are three stages to this study. (1) In the first we will develop a set of characters and short animations which can be used to obtain information from children regarding how they feel on a range of dimensions of health. Animation can show pain in purely visual terms using exaggerated visual metaphor but crucially can also convey great subtlety of emotion. For example, huge, red throbbing thumbs, constellations circling a knocked head, bodies that turn to green rubber when feeling nausea, heartbeats that race so hard they visibly distend the chest cavity etc. The animated character is the totally controllable puppet of the animator, and like an actor it can sit in a chair in a way that suggests it is uncomfortable there, relaxed, dejected, excited. Also, the performance that is created can be refined indefinitely as it is an artefact in a way that a captured live performance is not. (2) In the second stage we will develop an alternative to traditional questionnaires. The underlying hypothesis is that the use of animated questionnaires with touch screen data entry will have several advantages over traditional data collection with hard copies of text-based questionnaires. However, there are a number of sources of any differences between these methods and we shall establish the contribution of the use of animation itself; the presentation of information graphically; and the use of a touch screen to enter information. (3) The final stage is to develop and test a method of eliciting health state preferences from children. It is not proposed within this project to undertake a definitive valuation of health states using a representative child population but rather to develop the method by which this could be done in a future project and to produce evidence to demonstrate its feasibility.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Functional study of mitotic checkpoint in human embryonic stem cells
Funder: Medical Research Council

Abstract: Human embryonic stem cells (hESCs) have the ability to self-renew indefinitely and differentiate into all types of tissue in the body. Thus they provide an unlimited source for cell transplantation therapy to treat degenerative diseases and for drug discovery. However, these pluripotent stem cells are susceptible to gaining chromosomal abnormalities during in vitro culture, which may make them unsafe to use in regenerative medicine. Aurora kinases are key regulators of cell division and may be highly expressed in many cancer cells. Three mammalian Aurora kinases, including Aurora kinase C, a germline specific Aurora kinase, are expressed in hESCs. Our previous studies in mouse oocytes and embryos showed that over expression of Aurora kinase C promoted securin degradation and chromosome separation, whereas perturbing its function leads to abnormal cell division. In this study, we will use small molecule inhibition, siRNA knocking-down and mRNA over expression to disrupt the function of Aurora B and C and study the short-term and long-term effects on hESC apoptosis, self-renewal and differentiation. The results will provide insights into the function of mitotic checkpoints in hESCs and help inform approaches to reduce or prevent the occurrence of karyotype abnormality in hESCs and improve their genome stability.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Cytokine-induced changes in transcription factories
Funder: Medical Research Council

Abstract: Human nuclei contain 3 RNA polymerases defined by the sets of genes they transcribe. Core activities of each polymerase have been purified and their structures determined. All are part of larger complexes (e.g., polymerase II is found with activities involved in capping, splicing, and polyadenylation), and we have shown these are organized into still larger 'factories'. [We define a factory as a site containing at least 2 polymerases engaged on different templates, and the reason for having all factories is the same: to enhance production by concentrating relevant machines and raw materials in one place.] Hitherto, it has been impossible to isolate factories as they are so tightly bound to the underlying structure. As caspases deconstruct nuclei during apoptosis in vivo, we reasoned they might release factories in vitro - and this was the case. After running released factories in 2D gels, we can now partially purify the 3 complexes with apparent molecular masses of >8 MDa. We also developed a related method that does not involve fixation - 'native' 3C (chromosome conformation capture) - that allows us to catalogue genes attached to isolated factories. Our primary aim is to use these techniques to characterize some contents of factories - the active sites of transcription; we will analyze their nascent transcripts and genes (using high-throughput sequencing). We also wish to (i) analyze how their contents change when two medically-important cytokines (TNFalpha, TGFbeta) activate responsive genes, (ii) characterize a sub-set of factories producing the micro-RNAs that act as immediate effectors, and (iii) insert different test sequences at one specific site in the genome to see how they modify local and global gene activity. We also have a more general objective: we proposed a model for the organization of human chromosomes during interphase (active transcription units cluster into factories), and we plan to see if this model is correct.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Deciphering the molecular mechanism of HD-PTP function in endosomal trafficking
Funder: Medical Research Council

Abstract: Down-regulation of activated mitogenic receptors such as EGFR, is crucial to control the duration of signalling responses, and failure to turn them off is directly associated with cancer. Essential to this process is the internalization, ubiquitination and transport of the activated receptor for subsequent degradation in the lysosome. We discovered that a novel regulator of this process is the tumour suppressor His Domain Phosphotyrosine Phosphatase (HD-PTP). HD-PTP is essential for sorting ubiquitinated cargo at the early endosome and its loss blocks transport of EGFR leading to accumulation of ubiquitinated proteins on endocytic compartments. We demonstrated that HD-PTP binds to key proteins of the endosomal sorting machinery (ESCRTs) and effectors of EGFR signalling. This provides a crucial link between receptor signalling and transport, to control the location and duration of signalling. Defining in detail the specific interactions of HD-PTP with endosomal partners is central to understand the molecular mechanism that sustains its scaffolding role and its function as a tumour suppressor. The main aim of this project is to establish the structural basis for specific recognition and selective recruitment of endosomal proteins by HD-PTP. We will use X-ray crystallography to directly reveal the details of the molecular interactions that underlie HD-PTP function. The structural work will be integrated with biochemical and functional analysis, to gain a full picture of the mechanism by which HD-PTP coordinates specific ESCRT binding with EGFR trafficking. The structural analysis proposed here, would provide important new insight into how HD-PTP controls EGFR turnover that could be used in future cancer therapies. Likewise, deciphering the mechanisms that control ESCRT trafficking could in the future be translated to design new strategies to fight neurodegenerative diseases and bacterial infections.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Unravelling the mechanism of complement activation via the lectin pathway
Funder: Medical Research Council

Abstract: The overall aim of this project is to elucidate the molecular mechanism of complement activation through the lectin pathway by employing a multidisciplinary structural strategy to determine the solution structures of (1) the MASP dimer, (2) MBL-MASP complexes and (3) mutant MBL multimers. A complete set of small crystal structures of MBL and MASP fragments are now known that define atomic-resolution structures for parts of MASP and MBL. However, these small crystal structures are not able to explain how the full-sized structures of MBL, MASP and MBL-MASP are formed, nor do they provide much mechanistic insights on activation. These full-sized structures are too flexible to be crystallised, and crystallography would not be informative on their important solution properties including the conformational changes that trigger activation. We have developed a new strategy based on scattering/ultracentrifugation/modelling to determine the solution structures of the MBL oligomers starting from small crystal structures. This revealed near-planar MBL structures in physiological buffers. We will now extend this method to determine solution structures for (1) the MASP dimer and the necessary conformational changes that take place on MASP self-activation, (2) the MBL-MASP complex to establish its assembly and explain how activation takes place, and (3) mutant forms of MBL that over-activate or do not activate the MASP dimer in order to explain the effect of the mutants on MBL function. We are ideally positioned to complete all three major aims within a single Project Grant. The results will resolve major currently-unanswered questions about the structure of the MBL-MASP complex, and how this activates the lectin pathway, and how abnormalities in MBL lead to disease. This knowledge in turn will reveal novel targets for therapeutics aimed at inhibiting/modulating MBL function in ischaemic diseases where activation of the lectin pathway causes damage to the host.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Pon3, a natural antioxidant protein: its role in development and disease.
Funder: Medical Research Council

Abstract: Oxidative stress increases with age and is a well-recognised feature of several common major diseases. The paraoxonase (Pon) family, consists of 3 closely related esterases which hydrolyze lactones in biologically important molecules, including lipid peroxides. Pon3 are anti-inflammatory antioxidants and transgenic expression of PON3 inhibited atherosclerotic lesion formation and adiposity. In addition to their presumed role as potent circulating antioxidants, these enzymes are capable of metabolising precursors or derivatives of regulatory hormones (arachidonic acid and estrogen esters); are anti-atherogenic; anti-inflammatory; can degrade xenobiotics and have the potential to alter host/microbe interaction. As such, they are implicated in diverse biological processes. Despite this, their physiological function remains unclear. We have identified a novel aspect of PON3 biology, showing it is markedly up-regulated in late gestation in the rat, sheep and human. This may be a systemic preparative process for birth which is (at least in the sheep) controlled by glucocorticoids. We have commenced studies on a Pon3 knock out. After het x het mating there were significantly fewer Pon3-/- animals than expected. We conclude that Pon3 has an essential non-redundant biological role in embryonic development. Preimplantation embryos are sensitive to oxidative stress and we hypothesise that loss of Pon3 leads to increased oxidative stress and embryonic lethality. We will determine when and where Pon3 is expressed in the developing mouse embryo and the cellular consequences of its ablation. Early lineage assignment will be followed. "Floxed" Pon3 ES cells are available from the EUCOMM consortium and we will use these to generate conditional animals. We will investigate whether ablated adult animals show increased sensitivity to age and high-fat diet induced oxidative stress and using metabolomics, determine which biochemical pathways Pon3 acts in.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing ROBIS - a new tool to assess the risk of bias in systematic reviews
Funder: Medical Research Council

Abstract: Systematic reviews synthesise evidence across primary studies and are generally considered to provide the most reliable form of evidence for informing decisions in health care. When assessing the reliability of the results of a systematic review the potential for bias in the results of the review should be considered. The aim of this project is to develop the "ROBIS tool", a new quality assessment tool to assess the risk of bias in systematic reviews. We will adopt the following four stage approach to develop ROBIS: Stage 1. Defining the scope: The steering group will discuss and agree key features of the desired scope of ROBIS. Stage 2. Reviewing the evidence base: We will conduct three reviews to inform the development of ROBIS. These include classification of MECIR (Methodological Expectations for Cochrane Reviews) items, review of existing quality assessment tools for systematic reviews, and a review of studies that have used the AMSTAR tool. Stage 3. Face-to-Face consensus meeting We will hold a one-day meeting of 25 methodological experts and systematic reviewers to develop a first draft of the ROBIS tool. Decisions on tool content will be made by informal consensus. Stage 4. Piloting and refinement of the ROBIS tool We will use multiple rounds of piloting to refine successively amended versions of the ROBIS tool. We will hold workshops at relevant conferences where we will present the ROBIS tool and give participants the opportunity to pilot the tool and provide feedback. Pairs of reviewers working will pilot a draft version of the tool on a number of reviews. Once sufficient agreement has been reached, a final version of the tool will be agreed. The ROBIS tool will be published in a peer reviewed journal and will be presented at relevant methodological conferences. We will also establish a website for the tool which will contain the tool itself and related documents providing further guidance and resources.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Time lags in the translation of medical research: Developing a case study approach to achieve a better understanding
Funder: Medical Research Council

Abstract: This project uses a case study approach to investigate time lags in the translation of medical research. Existing models of research translation typically refer to the concept of a translation 'gap', but how these gaps are defined differs between approaches and can lead to results not being comparable. We propose to use the process marker model proposed by Trochim et al (2011) as the basis for our case study approach. Here, specific research translation milestones are considered to be process markers and are clearly defined to enable comparability between the various examples of translation (and the diverse models currently used to describe them). Time lags can then be assessed relative to these markers. A key element of this project is to develop and trial this approach as a basis for case studies to investigate time lags. We plan to conduct six pilot case studies in the fields of cardiovascular and mental health research. We will conduct both backward and forward tracing case studies, and in particular intend to cover a range of types of intervention (e.g. new drug, surgical procedure, medical device, screening programme) as we believe the translation pathways, and hence both the markers and the primary sources of time lags, are likely to differ between types of intervention. This study will also provide an initial test of the applicability of the process marker model. If the method proves successful, we hope to conduct further case studies using the approach allowing us to produce a more in-depth analysis of the sources of time lags, which ones are desirable or undesirable (a delay in translation to ensure the safety of a new drug, for example, may well be desirable), and how they differ between types of intervention. This will allow us to develop policy-relevant recommendations; building on this we hope to produce on the basis of the findings of the pilot project.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: The Regression Discontinuity Design: a novel approach to evaluating the effect of drugs and treatments in primary care
Funder: Medical Research Council

Abstract: The regression discontinuity design (RDD) is an econometric quasi-experimental design aimed at estimating the causal effects of a treatment by exploiting treatment rules. It can be applied in any context where a particular treatment is administered according to a pre-defined rule linked to a continuous variable. Such thresholds exist in primary care in the context of drug prescription and we focus on the examples of statin and insulin prescription. The idea is that if we can assume that individuals on either side of a threshold belong to a common population with respect to the characteristics informing the assignment rule and determining the outcome, then the threshold can be seen as a random intervention assigning the treatment to those falling just above the threshold and no treatment to those just below it. Regressions are typically used to predict the value of the outcome on either side of the threshold. We will use regression methods developed in econometrics such as local linear regression as well as more sophisticated regression models if the relationships we observe are non-linear. One methodological issue is represented by the fact that in most clinical cases, it is likely that the threshold is not strictly adhered to. This is due to two levels of non-compliance: 1) whether GPs follow the prescription guidelines (GP decision making) and 2) whether patients who are prescribed a drug take it (patient prescription adherence). Since the RDD has several mathematical similarities with Instrumental Variables (IVs), we will exploit the econometric literature to produce our estimations of the treatment effects. However, since we will be concerned with binary outcomes, it will be necessary to expand standard IV methods. In particular, we will use a Bayesian approach; this will be beneficial, since methods to deal with weak instruments, which can be adapted to the RDD when the guidelines are loosely adhered to, are best handled within a Bayesian framework.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Integrated multi-dimensional molecular organ imaging
Funder: Medical Research Council

Abstract: The next wave of biomedical science requires 'next generation' LM imaging and new modes of translating it into clinical practice. Our new technology platforms will draw on existing collaborations with commercial partners and physical scientists (chemists, engineers, optical physicists and IT specialists) from UoE and elsewhere. A 'true' multi-functional two-laser intra-vital imaging platform will be developed in collaboration with La Vision BioTech. This will be enhanced to provide a platform that allows simultaneous photo-ablation, -uncaging, -activation, -conversion, -switching, fluorescence lifetime (FLIM) and non-linear optical measurements of relevant cells, proteins and small molecules. We will develop and integrate adaptive optics for tissue aberration correction and a CARS element to enable label-free high resolution imaging of lipid- and collagen-containing structures. We will also incorporate the 'spinning disk' technology and IT systems that have allowed 'beyond-state-of-the art' whole brain mapping and extend this to other organs. This unique facility will enable our campus, with 3 MRC Centres, not only to build 'information-dense' 3D gene expression maps of whole organs, but also provide complex biological data using multiple fluorescent probes and 'label-free' CARS simultaneously. Catalysed by the adjacency of the Edinburgh Royal Infirmary, our interdisciplinary Centres share the challenge of translating their work into the diagnosis and treatment of human disease. This will be facilitated by collaboration with Haslett/Bradley who are synthesising and validating bespoke fluorescent 'Smartprobes' against key inflammation/scarring targets and using a unique pCLE platform to translate into human lung disease in vivo. Molecular Imaging is a Core theme in Edinburgh which has identified the optimal site for the proposed facility, the costs of its fitting out and a major 'cash' contribution towards the equipment.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Bio-Continuum Microscopy: Seamless imaging from the micro- to the nano-scale
Funder: Medical Research Council

Abstract: We will develop new imaging methods: 1 Integrate standard SRM with our novel electron-excited SRM making this technology simple to use. We will use our novel probes (see 3 below), which can be excited with both light and electron beams Building on our expertise in standard SRM and CLEM, and our relationship with JEOL, we will improve the optical resolution of JEOL's novel ClairScope, a combined light/electron microscope. This will be achieved by adding a high performance PMT to the optical light path to enable ca 20 nm multicolour resolution. We will also build Bayesian Imaging onto the system for comparative imaging. 2 Develop integrated SRM-SEM for direct CLEM imaging. DELMIC will integrate PALM with the SECOM platform to study dual-label specimens in situ. Exploit our own recent advances in preserving fluorescent signals such that they can be used to give precise overlay of fluorescence and EM images. This will permit ca 2 nm resolution of samples. Finally we will integrate miniaturised fibre-optic laser microscopy into the automatic serial imaging workflow of the 3View platform to enable the analysis of complex networks in larger samples. 3 Further develop our novel probes. Optimise the probes for brightness and size distribution to be used in 1 and 2 (above) such that we will be able to image individual particles. We will also change the dopants so that the probes can also be used for live cell, MP imaging and then as fiducial markers for CLEM. These developments will address key biomedical questions, focussing on mammalian cell biology and molecular/cellular microbiology including -imaging of tissue, cellular and subcellular processes related to cancer. -visualizing activation of silent synapses related to learning and memory. -molecular/cellular microbiology questions related to bacterial and parasitic infections, the formation of bacterial communities and the mechanisms of bacterial chromosome segregation and plasmid partitioning.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE