NIHRDataInsights/HRCSData huggingface dataset:
Title: Consent in (dis)array? Genome-wide testing in the paediatric setting: bioethical and clinical perspectives on informed consent in practice.
Funder: Wellcome Trust

Abstract: Until recently, genetic investigations involved either examining the chromosomes microscopically or analysing a particular section of DNA sequence. New methods involve looking across all genes and chromosomes simultaneously. This means not only finding the cause of the problem being investigated but also potentially detecting abnormalities that are unrelated to the reason the test is being carried out. These findings include things which might cause subsequent problems for that person or for the ir relatives. Doctors might find things which are unusual, but not know what it may mean. This work will examine how doctors and families of children undergoing these tests talk about these different possible outcomes. This will involve looking at conversations between doctors and families when permission to do these tests is being taken, and then afterwards, when the results are shared. By talking to doctors and parents separately, we can explore what they understand about the information generated when these tests are performed and how this information should be shared. The goal of the work is to define how health professionals and parents understand the results of investigations which look across the whole genome, producing guidance, a consent form and a patient information leaflet to support this process.


Research activity codes: 4.3 INFLUENCES AND IMPACT;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: REMI-seq: generation of a genome wide mutant resource for Dictyostelium functional genomics.
Funder: Wellcome Trust

Abstract: Dictyostelium offers a powerful model system for discovery genetics and biomedical research, with strength in areas including chemotaxis, cell signalling and developmental biology. Existing bio-resources include the complete genome sequence and transcriptional profiles. However, full exploitation of this data is hampered by lack of a systematic, genome-wide collection of Dictyostelium mutants. To remove this key bottleneck, we will employ a novel technique (REMI-seq) to rapidly create a geno me-wide collection of barcoded insertional mutants using next generation sequencing (NGS). Each mutant will be mapped to the Dictyostelium genomic sequence and be searchable via dictyBase, a pre-existing publically accessible genome resource. Individual mutants, collections and random mutant pools will be available to the research community via dictyBase through the Dicty Stock Center. Specific objectives: (1) combine Restriction Enzyme Mediated Integration (REMI) insertional mutagenesis wit h NGS technology to create a genome-wide set of single gene mutants with defined insertion sites; (2) create a resource of individual, sets and pools of mutants, and develop new genomic level screening strategies for population fitness and parallel phenotyping to probe sub-lethal sensitivity changes to developmental signals, toxins or drugs; (3) integrate the REMI-seq data to dictyBase to provide direct access to the resource.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of genotype-phenotype relationships through combination of designed perturbations and quantitative genetic interaction mapping.
Funder: Wellcome Trust

Abstract: Understanding how mutations influence functions of proteins inside cells, and finally how this affects the organism as a whole is the holy grail of molecular biology. If we would be able to predict the consequence of a genetic change, or the effects of a drug, we would ultimately be able to define an unambiguous strategy for treatment. However, achieving this goal is far from trivial, and here, we propose an approach that combines the best of two fundamentally different approaches to understa nding disease. The first looks at large-scale data, which provide us with biological contexts; the second characterizes the biochemical details of the proteins that perform essentially all the functions of a cell. Specifically, we aim to address two problems The first is to understand why some genes cause disease if we have inherited a mutation from only one of our parents, and for others, both copies of our gene need to be mutated in order to develop a disease. Our second goal is to model mu tations of proteins that perform multiple functions in an organism. This is especially complex, and we propose a technology to dissect which of the mutations affects which of the functions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Quantifying the molecular organisation of DNA repair pathways in live cells.
Funder: Wellcome Trust

Abstract: Optical microscopy brings to light the detailed workings of cells and organisms, but it does not provide sufficient resolution to directly visualise the molecular interactions that underlie cell function. Recent technological advances now allow observation of individual fluorescent labelled molecules performing their function inside living cells. I will apply this powerful method to elucidate how cells repair DNA to preserve their genetic information. DNA repair involves reaction cascades by seq uential action of different repair enzymes. The fundamental mechanisms that control coordination, efficiency, robustness, and overall organisation of such reaction networks in the cell remain unsolved. By combining novel experimental and theoretical approaches, I will generate a quantitative model of an entire DNA repair pathway to answer these questions and predict the cellular response and sensitivity to DNA damage. I will measure how repair enzymes manage to find damage sites within the vast excess of undamaged DNA. I will explore how compromised repair can lead to the catastrophe of a break in the chromosome and how cells manage to resolve this difficult situation. My findings will provide a new perspective on the effects of DNA damage and will help to understand the molecular causes of cancer and ageing diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Maximizing South West Biomedical Sequencing and Informatics Capability.
Funder: Wellcome Trust

Abstract: We request four pieces of laboratory equipment and computing infrastructure to make a step change in our next generation sequencing and informatics service. Our objectives are: To increase by >20 fold the capacity of the Exeter next generation sequencing service. We will install state of the art sample preparation laboratory equipment and double the size of our high performance computing cluster. To become the leading next generation sequencing centre in the South West and Wales, becoming t he main centre for the GW4 University consortium and providing a fast, flexible local service that complements the services provided by large genomics centres. To become a leading centre for training biomedical scientists in next generation sequencing methods, applications and informatics. The University of Exeter is one of only 6 UK universities with a next generation sequencing service based on the market leading technology the Illumina HiSeq2500 Whilst large genomic centres such as the Sa nger centre continue to support our research, we need to relieve the bottlenecks in our local service to provide afast, flexible user focussed operation. The new equipment will accelerate throughput, reduce costs for a disparate range of research projects and free up technical resources to support increasingly complex experiments.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Bridging the gap between patients and carers : The case of rare disease patient-advocacy actors.
Funder: Wellcome Trust

Abstract: This project investigates the relationship between advocacy action and the empowerment of patient communities. Empowerment is here understood as patients participatory action in decision-making on disease research and treatment. The study specifically focuses on rare disease patient-advocacy actors because according to the scientific literature they are among the most empowered groups in the health sector and may serve as a model for other patient groups that are still struggling to get particip atory power in policymaking and research implementation. The project will develop four lines of investigation focused on specific elements of mobilization: [LI1] processes of information sharing among patients, health care professionals, institutions and policymakers; [LI2] lobbying strategies aimed at bolstering awareness in the institutional polity; [LI3] campaigning strategies aimed at generating awareness in the general public; [LI4] fundraising strategies aimed at generating economic suppor t for the development of drugs, treatments, and services. The investigation will examine a sample of rare disease patient-advocacy groups from the E.U. and the U.S. Web Content Analysis techniques (qualitative textual analysis combined with Hyperlink Network Analysis) will be used to study processes of information sharing, while interviews with organisation representatives will provide insiders information on lobbying, campaigning, and fundraising.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Using a permeabilized cell system and cell physiology to understand cytokinetic actomyosin ring constriction
Funder: Wellcome Trust

Abstract: Cell division in many eukaryotes requires an actomyosin-based contractile ring, whose constriction bisects a mother cell into two. Although this F-actinand myosin II motor-containing ring has been described for >40 years, we know very little about how it constricts and generates force. Our goals are to understand the mechanism of actomyosin ring constriction and its regulation inthe cell cycle. We will use Schizosaccharomyces pombe for our studies, since it divides using an actomyosin-based co ntractile ring, and is amenable to themethods of genetics, biochemistry, and cytology. We have developed a permeabilized cell system in which addition of adenosine triphosphate leads tocomplete contraction of intact actomyosin rings. We will use this system to 1.estimate the force generated by the constricting ring and 2. perform contractility assays on permeabilized cells generated from mutants in actomyosin ring proteins, to identify ring components important for its constriction. We wil l use proteomic approaches to uncover the molecular differences between actomyosin rings before and during constriction and to understand the cell cycle regulation of ring constriction. We will use cross-linking amino acid mutagenesis of actin to identify changes in actin filaments during cytokinesis and employ a new approach to identify protein conformational changes during cytokinesis. Finally, we will investigate if overlapping mechanisms regulate ring constriction in vivo. The combination of in vitro contractility, in vivo studies, and screens based on emerging technologies should provide tremendous insight into actomyosin ring constriction mechanisms and can lead the field in new directions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Corporate health interventions and constructions of health in mining communities in Guerrero, Mexico. .
Funder: Wellcome Trust

Abstract: The proposed research examines community perceptions and experiences of the health impacts of the Los Filos mines, in Guerrero, Mexico, as well as community experiences of corporate health activities in the area surrounding the mines. This project extends the literature relating to community experiences of contamination, the governance of private actors within health services, the treatment of health within corporate social responsibility and the socio-economic impacts of mining, by adopting an anthropological lens on the processes and impacts of mining and mining-related corporate health interventions. This project will examine local peoples experiences and perceptions of environmental health impacts and risks and how local residents are producing and sharing knowledge about health risks. It will also examine the impacts of mining through the already existing community-led health monitoring system. Finally, it will explore how the relationship between corporation and communities a ffect corporate health interventions, taking into account the ways in which local community members and the corporation may be materially intertwined. It will ask how the subject of mining-related health is negotiated between community and corporation through the public participation in, and through corporate representation of, its health-related activities in the area.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Religion and resistance: Evaluating access and responses to child health messages for boys aged 0-10 in Gateshead's ultra-Orthodox Jewish community. .
Funder: Wellcome Trust

Abstract: The rapidly growing ultra-Orthodox Jewish community in Gateshead is unique; its exclusive reputation as a global centre for Jewish learning encourages continuous migration from world Jewry, but simultaneously resists external influences. This PhD will evaluate interpretations and responses to preventive health messages which are designed to optimise the health of ultra-Orthodox Jewish boys, whose lives are religiously circumscribed. I will advance previous research into the health behaviours of ultra-Orthodox Jewish communities and investigate whether low responses to the look after yourself message is an act of resistance to preventive health services and technologies that are not considered culturally-appropriate, rather than an issue of non-compliance. Moreover, it will explore whether low uptake of preventive health services is indicative of the community circulating health behaviours that defy biomedical authorities. Qualitative data informed by GPs, parents, and children will examine interpretations and responses to preventive health messages which focus on critical areas of child health, such as immunisations, nutrition and physical activity. Quantitative data will assess differences in health behaviours between ultra-Orthodox Jewish boys and boys from the general population. Overall results will provide a clearer understanding of inter- and intra-community health behaviours in a historically disadvantaged region of the UK.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: A Multi-Site Study of Socially Engaged Art in Public Health Research within Low Income Settings.
Funder: Wellcome Trust

Abstract: There is increasing pressure for those working in community-based biomedical research to engage more with outside communities. This is justified by statements around democratising science and supporting two-way dialogue. Still, the underlying beliefs and assumptions driving engagement in practice are rarely explored and are not always understood by those involved, and the impacts of these activities are not always captured. Socially engaged art (SEA) may provide a unique space in which genuine e ngagement can take place. The aim of this research is to identify the impact and potential of SEA as a tool for community engagement (CE), allowing for open dialogue and addressing power imbalances between researchers and communities. This aim will be addressed by using two/three in-depth studies of SEA practice within the context of biomedical community-based research across different social, cultural and political contexts. Ethnographic and participatory methods will be used to explore the behaviours and attitudes of researchers, artists and other participants in the process and how these interact. As well as exploring the creative process the research will investigate the reactions and interpretations of the outputs of these works on local audiences. Outputs will hold relevance to research governance, research programmes, funders, NGOs and engagement practitioners.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Functional characterisation of RNA-RNA interactions
Funder: Wellcome Trust

Abstract: Small nucleolar RNAs (snoRNAs) have long been known to function as the guide molecules for the enzymes modifying ribosomal RNAs. Box C/D snoRNAs specifically result in the 2-O-methylation of their substrates. However, some snoRNAs lack any known target, and are named orphan snoRNAs. Recently, mRNAs have been identified as potential targets of orphan snoRNAs, though the consequence of snoRNA binding to mRNAs has not yet been investigated. This proposal aims to expose the effect of snoRNA binding to target mRNAs, as well as the underlying mechanism. Initially, the consequence of deletion of orphan snoRNAs and mutation of essential snoRNAs in Saccharomyces cerevisiae on global mRNA levels will be investigated, to test the hypothesis that snoRNA knockdown decreases mRNA levels. Once an effect has been established, it will then be determined which stage in the mRNA processing pathway is being affected by snoRNA binding. Following this, the project aims to identify factors that mediate snoRNA binding. These investigations will provide information about novel mechanisms involved in regulating mRNA processing, andexpose a previously undescribed function for snoRNAs. This may then provide preliminary information about the role of snoRNAs in human cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: What is the nature and function of the Sgo1/condensin interaction in Saccharomyces cerevisiae?
Funder: Wellcome Trust

Abstract: Shugoshins comprise a conserved family of proteins which associate with the region surrounding the centromere (known as the pericentromere). Shugoshins play multiple roles in chromosome segregation during mitosis and meiosis through recruitment of several important regulators to the pericentromere. Oneconserved function of shugoshins is to ensure that kinetochores from sister chromatids attach to microtubules from opposite poles of the cell during mitosis, called sister kinetochore biorientation. In budding yeast, shugoshin recruits the chromosome-organising complex condensin, specifically to the pericentromere, and this is important for efficient biorientation. Shugoshins also regulate cohesion loss during meiosis and mammalian mitosis. The nature of the shugoshin-condensin interaction and the contribution of this interaction to shugoshin function during meiosis is not, however, known. I aim to fully characterise the interactions between Sgo1 and the multi-protein condensin complex in budding yeast. This will allow me to determine the functional significance of this interaction. I will characterisethe role of condensin in meiosis and faithful chromosome segregation, and determine whether the interaction between Sgo1 and condensin is also importantin meiosis. Overall the results from this study will increase understanding ofhow condensin may affect the geometry of the pericentromeric region


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating the influence of DNA sequence on chromatin state and chromosome structure
Funder: Wellcome Trust

Abstract: In order to contain many millions of base pairs within every nucleus of a eukaryotic cell, DNA must be extensively packaged (Woodcock and Gosh 2010). The most extreme form of this is the highly condensed mitotic chromosome, rm formation of which is crucial in proper distribution of DNA in cell division, and yet whose exact structure and mechanism of folding remain unclear (Belmont2006, Woodcock and Gosh 2010). The hybrid cell line F1.1 contains a stretch of Schizosaccharomyces pombe DNA inserted at a locus in the mouse genome (Allshire et al. 1987) which has been observed to adopt a highly constricted structure on the mitotic chromosome (McManus et al. 1994), suggesting that underlying DNA sequence may influence mitotic chromosome structure in a way not previously characterised. Our goal is to use this cell line to study mitotic chromosome folding. I will first a characterise the chromatin properties of the S. pombe insert to determine whatsignals set this region apart from endogenous mouse chromatin. I then wish to investigate how these marks were recruited to the insert, in the aim of linking DNA sequence to chromosome structure. Finally, I will study the structure of the constriction and what factors are influencing it.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular regulation and function of GATA2 in the programming of haemogenic endothelium.
Funder: Wellcome Trust

Abstract: Molecular mechanisms regulating the generation, long-term self-renewal and multipotency of haematopoietic stem cells (HSCs) remain to be fully understood. This project aims to elucidate the molecular events governing the programming of the early embryonic domain of HSC specification, the haemogenic endothelium. It focuses on the crucial transcription factor gata2, particularly its function via a conserved enhancer located in an intron of itslocus. It addresses three key questions: 1) What is the spatiotemporal activity of this enhancer of gata2? 2) What are the molecular regulators that activate or repress gata2 through this enhancer? 3) How important is this enhancer in establishing the precise levels of gata2


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Directionality and decision making during mitotic exit.
Funder: Wellcome Trust

Abstract: The events that occur during mitotic exit, including chromosome segregation and central spindle formation, are fundamentally different to those that take place at mitotic entry. This asymmetric behaviour ultimately results in cell division rather than simply reverting to the pre-mitotic G2 state. This project intends to define how this asymmetry is generated, initially by identifying the stage at which cells become committed to cytokinesis. From there the activity and degradation of Cdk1, Plk1 and AurA/B, will be analysed throughout mitosis to identify the change in state necessary for mitotic exit.Finally we will investigate the exact molecular nature of the signals generated by these kinases, and how they enable cells to exit mitosis in a controlled, timely manner.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE