NIHRDataInsights/HRCSData huggingface dataset:
Title: A detailed network of transcriptome regulation associated with life-span extension in model organisms
Funder: Medical Research Council

Abstract: Recent work has shown the remarkable conservation of mechanisms that can extend life-span in model organisms Work in worms, flies and mice has shown that single mutations in the insulin/insulin-like growth factor signalling pathways can result in long-lived animals. Similarly, long standing work has shown that dietary restriction also increases life-span in a range of species. I propose the following related projects to understand the mechanisms that extend life-span: 1. Use tiling array and sequencing technology to give a complete view of the transcriptome in model organisms 2. Use DAM-ID technology to understand the DNA-protein and protein-protein interactions of transcription factors (TFs) that are known to be involved in life-span extension Most transcriptome data collected on long-lived animals has been limited to detecting changes at the 3‘ end of genes. Whole genome tiling arrays would report the expression of different exons and non-coding RNAs. To understand the role of these elements in longevity, total RNA hybridization to tiling arrays from long-lived worms and flies would be compared to hybridizations using wildtype worms and flies. In addition, little is known about the tissue specificity of changes to exon or non-coding expression, and tissue specific samples in flies would be taken for comparison. It is hoped that given such a detailed view of the transcriptome, we will be able to build a network showing the possible interactions between coding and non-coding transcripts that lead to transcriptional and post-transcriptional changes. Current knowledge of transcription factor binding is also very limited and methods that report interactions between TFs and DNA do not distinguish between regulation that exists because of DNA-protein or protein-protein interactions. Chimeric proteins containing TFs essential for longevity fused to the Escherichia coli DNA adenine methyltransferase (Dam) domain would be used to identify regions where TFs associate with DNA. These regions are methylated by the Dam domain and can be isolated from unmethylated DNA by restriction enzymes. Chimeric proteins using wildtype TFs would show all interactions, and comparison of DNA methylation profiles of wildtype TFs and mutant TFs that lack DNA binding capability or deletions of domains essential for protein-protein interaction would allow one to distinguish between regulation that exists because of direct DNA-protein interactions or because the TF interacts with another protein that is bound to the DNA. The TF interactions would then be integrated into the regulatory network created for the tiling arrays.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: North West HTMR
Funder: Medical Research Council

Abstract: The gold standard study design for determining efficacy of a treatment is the randomised controlled trial (RCT) but trials are not without their difficulties (Prescott et al, 1999). This proposal is to create a world-class centre where methodological issues facing the clinical trials community can be investigated, the overall aim being to improve patient care by improving the validity and relevance of the healthcare evidence base. This will include provision of a training programme that will deliver individuals with the capacity to be leading clinical trialists and methodologists. The Hub will focus on selected methodological research themes, initially developing and translating the methods for application across four clinical areas. The methodological areas include the promotion, modification and implementation of recently devised methods for improving the efficiency of a wide variety of early phase trials, the enhancement of the link between the findings of systematic reviews and the design of later phase trials particularly in relation to outcome selection (Clarke 2007, Sinha 2008), the development and application of methods of adjustment for non-compliance in both clinical and cost effectiveness analyses, and ensuring that the design and conduct of trials over their entire lifecourse is informed by evidence on the perspectives of patients. This will enable the design, interpretation, and dissemination of the results of RCTs that are of greater relevance to stakeholders.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: The ConDuCT Hub: Collaboration and Innovation for Difficult or Complex Randomised Controlled Trials
Funder: Medical Research Council

Abstract: The overall aim of the MRC ConDuCT Hub is to provide the environment and infrastructure for the conduct of collaborative methodological research that will lead to marked improvements in the successful design and completion of randomised controlled trials (RCTs). The Hub will focus particularly on developing nationally and internationally leading methodological research for RCTs considered ?difficult? because of methodological complexity, clinical controversy, or recruitment challenges. This will be achieved by bringing together a critical mass of experienced multi-disciplinary researchers to develop novel applications of research methods. The Hub will be directed by a clinician with an established record of collaborative work within RCTs. The Hub will work nationally with other MRC Hubs to support the conduct of challenging or complex RCTs, and regionally, the Hub will support RCTs in general in collaboration with UKCRC-registered Clinical Trials Units (CTUs) and the NIHR Research Design Service The ConDuCT Hub comprises six major research themes: developing and integrating qualitative research methods to improve design and conduct, evidence synthesis and expected value of information for design and prioritisation, improving RCT monitoring and conduct, integrating patient reported outcomes and clinical data, and statistical and economic methods for design and analysis. Each theme will work individually and collaboratively to support the wider UK RCT network. Close links with CTUs will hasten translation of methodological findings into developing and ongoing RCTs. The ConDuCT Hub will provide a training programme comprising short courses and workshops based on the methodological research themes to provide basic and advanced learning opportunities in RCT methodology and application for researchers and clinicians designing and conducting RCTs. Courses to be provided in the design and analysis of RCTs will include existing introductory courses for qualitative research methods, statistics and health economics; questionnaire design and analysis; and new courses including: integrating qualitative methods in RCTs, incorporating patient reported outcomes with clinical outcomes in RCTs and introduction to expected value of information for decision-modelling. There will also be one-day workshops for specific issues relevant to complex RCTs. PhD studentships will provide advanced training in RCT methodology. In conclusion, the ConDuCT Hub will permit the rapid development of research methods for RCTs by enabling experienced and developing researchers to dedicate substantial time to each methodological theme, and, through existing and new inter-theme collaboration, enable the design, conduct and analysis of ?difficult? RCTs at the cutting edge of health improvement.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Midland Hub for Trials Methodology Research at University of Birmingham
Funder: Medical Research Council

Abstract: The aim of the Midland Hub at University of Birmingham is to be a centre of excellence for trials methodology research, providing local and national researchers undertaking trials with innovative methodology for design, conduct and analysis, thereby improving the quality of trials. The Hub will develop existing expertise in trials methodology at Birmingham to deliver a high-quality Research Programme that will be of practical use to the trials community. There is a culture of collaborative working at Birmingham and the Hub will continue to cultivate regional, national and international collaborations to facilitate the successful delivery of research. A comprehensive training programme in trials methodology will train the potential experts of the future and educate trial practitioners in methodology. By providing a mechanism for advice, support and dissemination the Hub will benefit the trials community and ultimately patient care. Our proposed research programme centres around the current specialist methodological areas but the wealth of expertise will enable us to develop new research themes identified as important by the clinical trials community. There are seven key research themes at Birmingham: (1) Quality of life evaluation for clinical and health economic assessment; (2) Discovery and evaluation of diagnostic, prognostic and predictive biomarkers; (3) Methods to obtain reliable conclusions and involve users; (4) Bayesian methods in design and analysis of trials; (5) E-trials; (6) Systematic review for clinical and health economic assessment; (7) Education in trial methodology. Methodological expertise within the Research Programme feeds into all major areas within the trial process i.e. pre-trial development, trial design and set-up, trial conduct, trial analysis and evidence synthesis. In summary, Birmingham is at the heart of the trials community, providing academic expertise based on real-life trial experience, ready access to a wealth of datasets that can be used for methodology research, real situations in which to implement new methodology and direct support to many members of the clinical trial community. As one of the leading centres in the UK for clinical trials, the University of Birmingham is the ideal location for the Midland Hub for Trials Methodology Research.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: The physiological importance of phospholipase D signalling
Funder: Medical Research Council

Abstract: Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine generating phosphatidic acid (PtdOH) as its lipid product. This reaction is stimulated by ligation of receptors for a variety of hormones, neurotransmitter, cytokines and growth factors. PtdOH binds to and activates a number of intracellular targets including phosphatidylinositol-4-phosphate-5-kinase, mTOR, S6kinase, sphingosine kinase1 and the NADPH oxidase. Activation of PLD signalling has been implicated in the regulation of membrane trafficking events, e.g. exocytosis and cytoskeletal events such as adhesion and migration; other reports have suggested roles in regulating glucose transport, superoxide generation, apoptosis, proliferation and differentiation. The two mammalian PLD genes are expressed in all tissues, but their regulation and physiological functions appear to differ. The lack of isoform-specific inhibitors and the limitations of cell line studies have prevented a clear definition of the physiological roles of this ubiquitous signalling pathway. This has pointed to the need to generate genetic models to examine PLD regulation and function. This application builds upon MRC-funded preliminary work that generated a PLD2 knock out mouse that demonstrated effects upon neutrophil responsiveness and brain lipids, in addition defects in ras signaling were detected in derived MEFs . In this programme we will determine the physiological importance of PLD2 by studying the mouse, isolated cells and derived MEFS. The importance of PLD signalling in adhesion, migration and superoxide generation will be examined in isolated neutrophils, whilst mast cells will be used to examine the regulated secretion of inflammatory mediators. By making use of knockouts in other signalling enzymes, particularly PI-3-kinases and PIP-5-kinases to generate double knockouts, we will investigate the regulation and importance of signalling cross talk in physiological regulation. These studies will define the importance of PLD signalling pathways in physiological systems and may point to potential therapeutic targets in inflammatory disorders and other diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: DPFS resource request (University of Oxford) development pathway director
Funder: Medical Research Council

Abstract: To accelerate the translation of our biomedical research outputs, we request support to recruit an experienced director from industry to establish and lead an Oxford development pathway, capable of managing a portfolio of eight to ten parallel development projects.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Assembly of fibrillin microfibrils and elastic fibres
Funder: Medical Research Council

Abstract: Elastic fibres of the extracellular matrix endow dynamic tissues such as blood vessels, lungs, skin and ligaments with the essential properties of resilience and elastic recoil. Their critical importance to life is emphasised by elastic fibre defects that cause common life-threatening diseases such as aortic aneurysms and emphysema, and several severe heritable disorders such as Marfan syndrome and cutis laxa. Elastic fibres comprise a crosslinked elastin core and an outer mantle of fibrillin microfibrils. Our research has highlighted the essential contribution of the cell-matrix interface to microfibril formation, and sets the scene now to deliver a step-change in understanding the hierarchical process of elastic fibre assembly. The hypothesis to be tested is that the cell?matrix interface orchestrates the cell surface assembly of microfibrils, the formation of elastin microassemblies, and their convergence to form elastic fibres. This timely study will provide new insights that will advance therapeutic strategies to restore elastic fibre function, and inform genotype-phenotype relationships in heritable disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of microtubule motor proteins in cargo sorting
Funder: Medical Research Council

Abstract: The organization of all metazoan cells depends on the fidelity of membrane trafficking processes. Movement of vesicles and tubules between compartments is responsible for the correct sorting of proteins and lipids in to discrete compartments, the maintenance of compartment identity, and the secretion of newly synthesized proteins. All organelles are linked to the microtubule cytoskeleton and increasing evidence indicates that this membrane-microtubule coupling is responsible for the morphology and positioning of organelles within cells as well as the movement of both organelles and vesicles during membrane trafficking. Recent work from us and others has provided mechanistic insight in to the mechanisms by which motor proteins that drive vesicles along the microtubules couple to the membranes. This work also demonstrates that the force imparted by motors on membranes can drive formation of trafficking intermediates as well as dictating cargo selection in to these carriers. Motor proteins drive cargo in one direction along microtubules, dynein family motors to the minus end and most kinesin family members to the plus end. This proposal is built on the hypothesis the opposing forces imparted by these motors direct the sorting of cargo within organelles. During the transport of biosynthetic cargo from its site of synthesis in the ER to the Golgi apparatus, secretory cargo is sorted away from recycling cargo that is to be returned to the ER. Anterograde (secretory) cargo is driven by dynein towards the Golgi while recycling cargo is directed by kinesin back to the ER in the cell periphery. Similarly, in the endocytic pathway, cargo molecules destined for different destinations (e.g. the plasma membrane, lysosomes, or the TGN) are sorted from one another to maintain compartment identity and correct intracellular routing of receptors. Microtubules direct the organization and motility of transport carriers between these compartments and provide a highly related system to study the role of motors of opposing force in the biogenesis and maturation of transport intermediates. Our hypothesis is that opposing motors (dyneins and kinesins) drive bidirectional motility of these carriers in both the biosynthetic and endocytic systems, and that this motility is inherently linked to cargo sorting within these structures. Here, we propose to test this hypothesis applying high resolution light and electron microscopy to the study of cargo sorting within motile carriers. This work should establish fundamental principles for the way in which motor proteins direct membrane trafficking.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Inference using calibration samples
Funder: Medical Research Council

Abstract: It is commonplace for researchers to want to undertake analysis of several studies combined together but are prevented from doing so by the differences in measurement protocols used. We examine various methods (structural equation modelling, multiple imputation and meta-regression) for overcoming this problem by the use of internal or external cross-measure calibration samples. We will highlight differences among the methods and designs in the assumptions made, and in the power and robustness of the conclusions reached. The methods are developed and compared in a study of general population cohorts, a clinical cohort, and two randomised trials.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing methodologies for use in observational studies of drug effects using computerised clinical data.
Funder: Medical Research Council

Abstract: The efficacy of a medicine is established by the time it becomes marketed. However, the possible harms associated with a drug are usually less well understood. Randomised controlled trials to assess side effects are often impractical as they may need to be unfeasibly large or could be unethical. Observational studies therefore offer an ideal practical method for investigating drug safety issues, and in recent years the number of such studies has increased. Much research in this area is done using anonymised patient information from large primary care databases such as the General Practice Research Database (GPRD). Over the last three years I have gained substantial experience in using the GPRD to answer questions about the safety of medicines. Recent advances in data quality and linkage offer even greater opportunities for research, but better methodologies are needed to take full advantage. I propose the following programme of research in order to improve approaches to using primary care data for drug safety studies: AIMS: Further develop strategies for using primary care data. In particular focusing on diagnostic validity, the impact of consultation frequency and distinguishing prevalent from incident diagnoses. Explore the utility and limitations of the self-controlled case series method. Specifically I will investigate the impact of time varying confounders, situations where the occurrence of an outcome of interest affects the length of the observation period and instances where the likelihood of exposure is dependent on the presence or absence of the outcome of interest. OBJECTIVES: To improve on existing methods and establish optimal methodologies for conducting drug safety studies. METHODOLOGY I plan to achieve these aims by conducting four drug safety studies examining the associations between: SSRI antidepressants and cerebral haemorrhage; ezetimibe and cancer; tiotropium and stroke; and glitazones and myocardial infarction. I will use the self controlled case series method, comparing results with other study designs, such as case control and cohort methods and using external validatory data from randomised clinical trials. Collaborative input will be provided by the Medical Statistics Unit of LSHTM and the Department of Statistics at the Open University SCIENTIFIC/MEDICAL OPPORTUNITIES The current regulatory environment demands more observational studies of drug effects. Patients and prescribers rightly expect investigators to produce reliable answers to questions about the safety of a drug and robust methodologies are therefore needed to ensure confidence in the outcome of drug safety studies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Expected Value of Information and Synthesis Methods for Research Prioritisation and Study Design
Funder: Medical Research Council

Abstract: The National Institute for Health and Clinical Excellence (NICE) and similar bodies worldwide use formal modelling techniques to answer policy questions about whether to adopt a new technology for routine use. But a series of further policy issues then arise that are relevant to research commissioning bodies such as the National Institute for Health Research (NIHR) Health Technology Assessment Programme (NCCHTA) and the MRC: (a) is more evidence required to support the adoption of this technology (b) which model inputs in particular should we collect evidence on? (c) what research designs deliver the best societal pay-off from research? (d) what is the optimal sequence of multiple new studies? These questions can be addressed using Expected Value of Information (EVI) methods. While the principles of EVI methods are well understood, applications in health and medicine face technical challenges before they can be routinely implemented. These include: correlated model inputs; non-linear decision models; complex relationships between evidence and model inputs; heterogeneity in baseline characteristics, subgroups, and model uncertainty; biomarkers and biased evidence; optimisation over large design-spaces and optimal sequences of research. Changes in the policy environment, leading to coverage with evidence and risk-sharing schemes raise further technical challenges. The aim of this proposal is to develop methods that address these technical challenges for EVI computation that are practical within the time constraints faced by NICE, NIHR NCCHTA, and those designing trials, and sensitive to the developing policy context. To achieve this, a series of carefully chosen worked illustrations will be assembled, covering the most important and commonly encountered evidence structures and cost-effectiveness models. The examples will include the design of randomised controlled trials, epidemiological studies, drug-development studies, use of biomarkers, and design of research portfolios. EVI analysis depends on the validity of underlying systematic review, evidence synthesis, and cost-effectiveness analysis, and has implications for all of these disciplines. The training element is designed to broaden my knowledge of these disciplines, and will expose me to policy considerations at National level surrounding the use of these methods in Health Technology Assessment. Thus ensuring the policy-relevance of the research, and facilitating future research across the whole EVI agenda. Research findings will be disseminated through publications and presentations at international conferences. Wherever possible generic methods to prioritise and design new trials/studies will be made available for use in standard software. The worked exemplars and methods will form the basis of short courses and a book. 400 words


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