NIHRDataInsights/HRCSData huggingface dataset:
Title: TwinsUK (2012-2014) - an epidemiological and genomic resource.
Funder: Wellcome Trust

Abstract: We seek funding to maintain, open, and increase data and sample accessibility of the TwinsUK resource, a key UK asset for genetic epidemiological research. Our success within international GWAS consortia underlines the importance of data sharing, and the challenges of data storage, accessibility, and confidentiality. The key objectives are: - To maintain the unique TwinsUK resource, previously core-funded by the Wellcome Trust - To provide open access to almost 20 years of TwinsUK phenotypi c data, extending current Wellcome Trust-funded work within the UK10K Project towards even more QCd data available to the wider scientific community, continuing under the supervision of the WTACC access committee. - To transfer samples to a Biobank facility including 7,000 twin DNA samples. The DNA, blood and urine samples will be quantified and incorporated using a LIMS system with barcoding, enabling enhanced access. - To continue and widen our high rate of collaboration, dissemination, and increase public engagement in the TwinsUK resource. - To open the resource to the scientific community for new data, part-funding a new twin visit over the grant duration. - To improve population representativeness by recruitment of twins in 7 London boroughs - enhancing the resources ethnic representation.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Carbohydrate microarray facility for biomedical exploitation.
Funder: Wellcome Trust

Abstract: Carbohydrates are important as recognition elements in diverse molecular interactions in health and in disease processes including infections, inflammatory reactions, immune responses and cancer. Carbohydrate microarrays have emerged as essential tools to unravel these interactions. With a highly skilled research team, we have pioneered a carbohydrate microarray system unique in the number and diversity of sequence-defined oligosaccharide probes that it contains, and in its ability to detect pro tein-carbohydrate interactions with high sensitivity and specificity. We have attracted numerous collaborative initiatives with groups in this country and overseas. Some have come to fruition; others are blossoming and giving very promising results in, for example, microbe-host interactions and immunological and endogenous recognition processes. We propose to establish a Carbohydrate Microarray Resource to provide specialist carbohydrate microarray analyses to broad biomedical communities in the UK and beyond. Major objectives are: (i) maintaining and further expanding an irreplaceable carbohydrate collection; (ii) expansion of the repertoire of the microarray platform to include glycome microarrays; (iii) applying these in analyses of diverse carbohydrate-recognition systems of biomedical importance as requested by collaborators as well as for our core projects; (iv) continuing software development and collaborating with international glycomics centres for carbohydrate microarray d ata storage and exchange.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Illuminating the in vivo molecular mechanism of bacterial chromosome replication and segregation.
Funder: Wellcome Trust

Abstract: Life demands that the genetic material that resides in chromosomes be faithfully duplicated during each cell generation, and that the duplicated chromosomes be faithfully transmitted to daughter cells at cell division. Mistakes in chromosome duplication of transmission can lead to inviability and pathologies of many types. Understanding the molecular mechanisms that duplicate and segregate chromosomes is central to our understanding and manipulation of these processes in health and disease. The research is aimed at understanding how these processes occur at the single-molecule level in living bacterial cells. State-of-the-art live cell imaging allows single-molecule protein visualization of the assembly and action of the molecular machines that act in chromosome duplication and segregation. When used in combination with techniques that allow the rapid removal or addition of components of these machines, one can begin to undertake in vivo biochemistry. Finally, elegant in vitro techniqu es allow the reconstitution and manipulation of these processes in the test tube.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Transmission electron microscopy with tomography for studies of cellular ultrastructure.
Funder: Wellcome Trust

Abstract: We request funding to purchase a Transmission Electron Microscope (TEM) with tomography to allow high resolution study of cellular ultrastructure and perform 3-dimensional imaging of bone, fungal, bacterial and immune cells. The equipment will significantly develop our capabilities for ultrastructural research, which have recently benefitted from acquisition of a modern Scanning EM. Our EM facility is used extensively by Wellcome Trust funded research groups including those supported by four se parate Wellcome Trust Programme Grants, a Strategic Award and several project grants. The equipment will be housed in a purpose-built facility for TEM in the Institute of Medical Sciences, adjacent to facilities for confocal microscopy, live cell imaging and SEM. Facilities for tissue preparation and ultrathin sectioning are located nearby and are fully equipped with state-of-the art instrumentation. The equipment requested comprises a modern TEM, tomography equipment, appropriate software and 5 -years warranty. We have University funded technical staff with extensive TEM expertise in place to run the equipment and have established collaborations with experts in TEM tomography to provide advice and training. By enhancing and complementing our existing imaging equipment this equipment will bring substantial added value to Wellcome Trust and other funded programmes in basic and translational research at Aberdeen.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Centre for accelerating medical innovation
Funder: Wellcome Trust

Abstract: The traditional research/discovery and development/regulatory processes are no longer seen as 'fit for purpose' and are attracting diminishing levels of commercial investment R:The discovery models of internalp harma/biotech research have failed to deliver on the promise of bioscience and face increasing funding challenge, as companies cut back on longterm research Models involving greater/longer public and third sector engagement, and greater sharing of IP across companies, need to be pursued and evaluated. Companies like GSK are experimenting with these but there is no systematic study of what works and why. D:The conventional, complex and costly model of drug development and regulation has evolved to tackle a different 'problem statement' from that we face today - rather than preventing adverse events from widely prescribed, affordable 'blockbusters' our greatest need now is to bring better targeted specialist medicines to patients faster, more reliably and more affordably While there are many discussions and projects underway on the 'D' problem, especially in the US, practical progress is extremely slow. This is because the problem has been conceived as a technical one to be discussed between developers and regulators: in fact it is a political problem, with ethical, legal, economic and governance issues. The goal of CAMI to engage these perspectives in designing and implementing solutions is a genuine differentiator One of the missing ingredients is properly structured and focused patient input. HIV, Tysabri and other specific examples show that when politicians/regulators encounter informed and engaged patients then change is possible. So a multi-disciplinary process with cross-stakeholder input is essential. Creating a European centre is vital, to liaise on equal terms with the US and also to reach out to other jurisdictions (China, India, Brazil) that will be laying out their policies in the next few years. with the aim of leading not following Western markets Finally the problem is urgent. While public and third sector investment in basic bioscience is being maintained, significant shifts and cutbacks are occurring in commercial investment. So the 'leverage', in terms of patient benefit, from successful solutions to the problems would be substantial.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural studies of protein:nucleic acid complexes involved in regulatory pathways of cellular differentiation.
Funder: Wellcome Trust

Abstract: Differentiation is governed by intrinsic regulatory programs that combine sequence and epigenetic information, chromatin organization and miRNA regulation with the spatial/temporal distribution of cells to control developmental transitions tospecialized cell types. The present doctoral thesis project proposes structural studies of two important protein:nucleic acid complexes in distinctregulatory layers of cellular differentiation pathways. First, the crucial signalling hub of the let-7/Lin28 developmental axis will be studied by determining the 3D conformation, primarily through cryoEM studies, of a complex between Lin28, let-7 pre-miRNA and ZCCHC11, the TUTase responsible forlet-7 maturation via 3'-end poly-uridylylation. The catalytic miRNA extension will be evaluated to identify a model for protein:nucleic acid interactions modulating the process; this could then be exploited to develop therapeutic strategies for the treatment of human cancers. Second, the role of chromatin organization in the DDR pathway and its relevance to the balance between genomic stability and cellular differentiation will be evaluated by focusing on the chromatin remodeller SMARCAD1. A systematic deconstruction of the interdomain regulation of its remodelling activities and identifying interacting partners and their role in SMARCAD1 cellular localization will provide a means to understand molecular recognition and remodelling mechanismsassociated with genotoxic events such as DSBs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The Genetic Architecture of Complex Traits and their Prediction.
Funder: Wellcome Trust

Abstract: The prediction of risk for disease is an area that is expanding in both the commercial and academic worlds; however, most prediction methods do not incorporate all of the available information on risk. I plan to develop computationally efficient phenotype prediction methods utilising as much of the relevant genetic information as possible, which will be tested in simulation and then applied to data from the UK Biobank. The accurate prediction of phenotypes relies on an accurate understanding of genetic architecture, including the overall effect size distribution and the relation between allele frequency and effect size. The Bayesian approach I plan to takewill incorporate knowledge about genetic architecture and learn about genetic architecture in an adaptive way. I will test whether the inclusion of environmental effects and gene-environment interaction effects improves phenotype prediction. It is known that the inclusion of genotype-phenotype data on close relatives improves phenotype prediction, and I will test whetherdata of this sort will enable more clinically useful phenotype prediction. This investigation will reveal fundamental facts about the nature of variationin disease risk while at the same time giving practical methods for risk prediction.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular determinants of chromatin organisation and accessibility at CpG islands in the mammalian genome.
Funder: Wellcome Trust

Abstract: The majority of DNA in the mammalian genome is methylated and tightly compacted around nucleosomes. In contrast, CpG islands (CGIs) are conserved regulatory elements found at mammalian gene promoters which remain unmethylated and are proposed to contain DNA that has nucleosomes in a more ordered but less occupied state. The factors responsible for maintaining this chromatin architecture at CGIs are presently poorly understood. Unmethylated CpG dinucleotides within CGIs are capable of recruiting various chromatin modifying enzymes. Previous work has identified some of these pathways as capable of regulating CGI chromatin accessibility, although this has not been examined genome-wide. I propose to investigate chromatin architecture at CGIs using genome-wide approaches and define the factors responsible. To achieve this, a high resolution assay for nucleosome occupancy at CGIs will be developed, in conjunction with other established techniques. Cell culture knockout models will be used to investigate the impact of CGI-specific histonemodifications on the maintenance of CGI chromatin organisation. The proposed experiments will define how nucleosome dynamics and chromatin accessibility are specified at CGIs and further our understanding of chromatin based mechanisms at these important regulatory elements in the genome.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigation of the role of post-translational modifications of termination factor Pcf11 in the regulation of gene expression.
Funder: Wellcome Trust

Abstract: Transcription termination is not just a constitutive process happening in the end of genes. It is a dynamic process that can occur upstream, downstream or within ORFs. Where and when transcription termination occurs can affect gene expression through several different mechanisms. Premature termination can down-regulate the expression of a gene whereas Alternative poly-adenylation can change the properties of the transcript by modifying its 3'UTR or alteringits the coding sequence. The aim of my work is to elucidate mechanisms and factors that modulate the regulatory role of transcription termination by studying the core termination factor Pcf11. Previous work from our lab found that Pcf11 is post-translationally modified in specific amino acids. My hypothesis is that the post-translational modifications of Pcf11 in certain positions of its CID domain play a role in the regulation of transcription termination. I plan to use molecular biology and biochemical approaches to verify these modifications and investigate their role in transcription termination. Furthermore I plan to perform genome wide studies to investigate the biological significance and the global role of Pcf11 in the regulation of transcription termination and gene expression.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Principled extensions of GWAS to multivariate phenotypes: uncovering causal genetic structure in the presence of unobserved confounders.
Funder: Wellcome Trust

Abstract: Despite years of active method development, genome-wide association studies (GWAS) are still typically performed with linear mixed models (LMM) applied separately on each marker-phenotype pair. We propose to jointly model the structure between all markers and all phenotypes. Joint analyses are inherently more powerful, and by directly estimating confounders our proposed method can identify causal markers in the presence of population structure. Moreover, recent optimization techniques make this approach computationally feasible for GWAS data sets, even for high-dimensional molecular phenotypes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of Smchd1 in topological architecture of the inactive X chromosome.
Funder: Wellcome Trust

Abstract: Recent evidence suggests that strictly regulated positioning of specific genetic loci respect to each chromosome territory, could be linked to their transcriptional status. With this study we therefore aim to investigate the relationship between gene positioning and transcriptional activation or repression. In detail, we are interested in following the relative positioningof specific sequences within the X-chromosome during its inactivation. X- Chromosome Inactivation (XCI) is, indeed, the mechanism through which all mammals compensate the different gene dosage between male (XY) and female individuals (XX), and a well-studied model of large-scale time-regulated gene repression. In detail, we will specifically assess the involvement of some candidate genes into this mechanism, such as SmchD1, which is known to be essential for maintaining gene repression on the Inactive-X in a Xist-independent fashion, as well as for a more general maintenance of chromosome structure. Indeed, preliminary data we got in the lab, suggest thatSmchD1 might have a major role in positioning the inactivated genes as soon asthey are silenced during XCI. For this purpose, we intend to take advantage ofsome recently developed techniques, such as 3D DNA-FISH, 4C sequencing and super-resolution microscopy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Elucidating the function and requirement of insulator protein CTCF in transcriptional regulation in the mouse.
Funder: Wellcome Trust

Abstract: Regions of open chromatin referred to as DNaseI hypersensitive sites co-localise in mammals with putative cis-regulatory regions that include promoters, enhancers and CTCF binding sites. Of these, the function of CTCF binding sites is the least well understood, although roles in chromosome folding, partitioning and transcriptional regulation have been identified. Our aim is to identify the function of CTCF binding sites in the regulation ofgene transcription and the establishment of the local chromatin architecture. To achieve this, we will explore two methods to study the effects of differential CTCF binding on gene regulation; the disruption of CTCF binding by TALEN-mediated mutagenesis and the study of differential CTCF binding events between inbred mouse strains. The effects on local chromatin and transcription will be assessed by chromosome conformation capture techniques, chromatin immunoprecipitation and expression analysis of local genes. In support of these strategies, we will characterise the binding of several knownCTCF binding partners to sub-classify CTCF binding sites. Thus, we aim to use a combination of functional studies and genome-wide approaches to elucidate the role of CTCF binding sites in gene transcription and chromatin organisation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Design and synthesis of Histone Lysine Methyltransferases inhibitors as epigenetic modulators.
Funder: Wellcome Trust

Abstract: The goal of this proposal is the design, synthesis and testing of inhibitors of Histone Lysine Methyltransferases. We will design HKMTs focused libraries based on available crystal structure information. Initially we will target the S-adenosyl methionine (SAM) binding site, since it offers the opportunity to identify inhibitors of different HKMTs. The crystal structures reveal several interesting features of this site7. The adenine moiety of SAM binds to a well defined pocket engaging in hydrogen bonds. Importantly, the rest of the molecule adopts a conformation that has not been observed for other SAM utilising enzymes, suggesting that mimicking this conformation will lead to inhibitors specific for HMKTs. Moreover, a recently published analysis concludes that the co-factor binding sites of HKMTs are druggable and can be explored to give selective inhibitors. To identify HKMT inhibitors that can compete with SAM we will initially designand synthesise inhibitors that mimic the adenine moiety. Initially, we will keep the molecular weight of these compounds relatively low (<350). Again these compounds will be tested and the most promising representative will be co-crystallised. The co-crystal structure then serves as the starting point for more advanced and potent compounds. The testing against selected HKMTs will be done using commercially available assay kits9. In addition, LCMS or Caliper based detection of HKMT substrates have already been established at the Unit and can be explored. The internal testing will be complemented with external profiling at appropriate vendors e.g. to profile advanced compounds against a larger ranges of HKMTs. The crystallography will be conducted with an external collaborator.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating possible new roles for mRNA localisation to cytoplasmic granules in S.cerevisiae.
Funder: Wellcome Trust

Abstract: mRNA localisation is a widely studied mechanism with important implications inmany aspects of cell biology. Recently, some evidence suggested a possible role for mRNA localisation in cytoplasmic granules as a way to co-ordinately regulate the expression of genes at the translational level. This might be thecase for genes that encode proteins of the same multi-protein complex or that are involved in the same pathway or process. This project is aimed at addressing this hypothesis by investigating whether the granules represent a factory for synthesis of the translation machinery. Another aim will be to assess the involvement of these mRNA granules in P-bodies formation. Finally, identification of proteins that bind these localised mRNAs, followed by gene deletion experiments, will provide a deeper understanding of the nature of thegranules, the dynamics of their formation and their role in the cell.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding the role of protein dynamics in focal adhesions.
Funder: Wellcome Trust

Abstract: Focal adhesions (FA) are the main organelles involved in sensing of the extracextracellular matrix but the mechanisms of how precisely the individual atrix.component regulate sensing remains unclear. In FAs, integrins bind with their extracellular part the extracellular matrix.With their intracellular domains they associate with adhesion plaque proteins that form the link with the tensile actomyosin machinery. Many of the plaque proteins are surprisingly mobile within FAs and the mobility varies greatly dibetween different subsets of proteins. Pilot data suggest that adapter proteins that form a mechanical link between integrins and actin are cell's absubstantially less mobile than regulatory proteins (e.g. kinases). We therefore hypothesise that these less mobile proteins form force-transducing units that are key for sensing extracellular mechanical stimuli, which determine whether cells migrate or remain stationary and proliferate. To test this hypothesis we will: 1) Assemble a hypothetical kinetic model to test different hypothesis by whichmechanical stimuli can change FA protein turnover. 2) Determine the turnover of the components when cells encounter substrates ofdifferent stiffness resulting in modifications in computational models. 3) Determine how the knockdown of mechanosensitive proteins affects the cell'sability to exert actomyosin-generated force on its extracellular environment.


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