NIHRDataInsights/HRCSData huggingface dataset:
Title: Plant name information services in support of medicinal and pharmaceutical research.
Funder: Wellcome Trust

Abstract: Information about plants, their chemistry and toxicology is published in hundreds of books, journals and databases citing research articles or patient records. Plants of pharmaceutical significance have dozens of alternative Latin names and vernacular or trade names used inconsistently. All these names prevent scientists from finding all data published about a plant without spending hours trawling libraries and reference collections at research institutions like Kew Gardens. Online res earch resources e.g. US National Center for Biotechnology (NCBI) record published gene sequence, protein, nucleotide and chemistry data. NCBI only includes 8% of scientific names and rarely records synonymy, however, so to find all NCBI records relating to a widely studied plant (e.g. Costus ) you must know all 23 synonyms of that plant and then search NCBI 23 times. Scores of equivalent resources and thousands of institutional databases face identical limitations. We request Wellcome T rust funds to: a build an index of plant names relevant to health and pharmaceutical research; b create a website offering intelligent google-like facilities for medicinal plants; c develop technical information services designed for professionals and their database systems; d establish an advisory group of clients to ensure that our services meet the needs of the research community.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: The telomere cap in budding yeast.
Funder: Wellcome Trust

Abstract: The genetic material DNA contains the instructions to make cells and organisms Genetic stability is important to pass on this information from one generation to the next. In humans and many simpler organisms such as yeast, DNA is found in chromosomes that contain extremely long, linear, double stranded DNA molecules. Just as with shoelaces, it is very important that the end of each chromosome is capped. The caps at the ends of chromosomes are called telomeres. If telomere caps fail, then genetic material near the telomeres can be damaged, or lost and cells with uncapped telomeres may not divide because cells can recognise the telomere failure. This project examines telomere capping in yeast cells (yeast is important for making bread, wine and beer) because these cells are easy to grow and study, and because the telomere structure of yeast cells is similar to that of human telomeres. In this project we make use of traditional genetic methods and more modern robotic geneti c methods to understand the budding yeast telomere cap. Such experiments are not possible or are too expensive to perform in mammalian cells. We expect that many of our discoveries will also be relevant to human telomere function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Conformational, dynamic and ligand-binding properties or protein disulphide-isomerase: studies with site-specific NMR and fluorescent probes
Funder: Wellcome Trust

Abstract: We will use state-of-the-art spectroscopic methods to probe the structure and dynamics of full-length PDI (abb xa c domains) and various domain combinations. We will determine relative domain orientations within the full-length protein, measuring residual dipolar couplings of PDI biosynthetically labelled with 15N-Leu. The Leu residues will be assigned using our existing full backbone assignments of domains and domain pairs and will also act as probes within each domain to reveal dynamics by NOE , relaxation and exchange studies. We will use FRET to measure distances between sites and single-molecule FRET to determine the distribution of distances and resolve multiple conformers; we will place FRET pairs on the redox-active sites in a and a domains of PDI, subsequently introducing Cys residues at other defined sites, to obtain several distances and so triangulate conformations and understand domain motions. We will repeat these studies in presence of unfolded and part-folded protein li gands to determine effects on PDI conformation and dynamics, and also study mutants which constrain the relative orientations of b and x regions. We will provide novel structural, kinetic and thermodynamic information on the interaction between PDI and ligands by introducing site-specific fluorescence and NMR probes into peptide and protein ligands.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Development of light and electron microscopy facilities at University of Sheffield.
Funder: Wellcome Trust

Abstract: A key to understanding biological processes is the ability to visualize individual components in their cellular, tissue or organismal environment. Confocal microscopy is widely used to visualize where particular proteins are in cells and how they interact with each other. We can look at events in living cells, which allows the dynamics of the process to be followed or in fixed cells which provides the equivalent of a snapshot. The size of the objects that can be seen by confocal microscopy is ho wever limited by the diffraction of light. Electron microscopy allows us to visualize the detailed architecture of the cell at a much higher resolution. By freezing samples rapidly and preventing the formation of ice crystals, it is possible to preserve many intracellular proteins so that they can still bind to specific antibodies that recognize them. These antibodies can be complexed with gold and the protein/antibody/gold complexes appear as black dots by EM. This allows us to precisely locali ze proteins in cells and provides an enormous amount of biological information. In this proposal we are requesting funds to buy a confocal microscope and the equipment necessary to rapidly freeze biological samples for EM.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing confocal imaging capabilities in IMPACT imaging facility, Centre for Integrative Physiology
Funder: Wellcome Trust

Abstract: Seeing is believing is a commonly used adage and no better illustration of this has been demonstrated in the last decade through the use of powerful imaging techniques, such as confocal microscopy, to allow us to understand how cells are controlled and how they interact with their neighbours. Such fundamental insights have transformed our thinking and led to significant breakthroughs in understanding the complex mechanisms controlling cell and tissue function in health and disease. In this a pplication we seek to replace one of our existing confocal microscopes, that is now > 13 years old, to allow us to exploit the very significant advances in imaging technology (including improvements in speed, sensitivity, quantification and flexibility) that have occurred in the last few years, to allow us to quantify the dynamics and spatial organisation of molecules and cells in real time. Not only will this allow us to progress our understanding of molecular, cellular and tissue physiological processes the images we generate are an excellent way to communicate the fascination and beauty of science to the general public. Indeed, one of our images of a cell adorned the fa ade of the Wellcome Trust building in London during its construction and refurbishment.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: The mechanism of Hsmar1 transposition and its epigenetic interactions with the host.
Funder: Wellcome Trust

Abstract: DNA is the hereditary material that carries the genetic information passed down from parents to offspring. We are investigating the mechanism of DNA recombination, whereby the strands of DNA are broken and rejoined in different configurations. This process is required for many important aspects of life, such as sex, growth and development. We are focused on one aspect of DNA recombination known as transposition. Transposons are sections of 'mobile DNA' that jump from one location to another. The y are of special interest because they account for a significant fraction of the DNA in the genomes of most higher plants and animals, including our own. We are investigating the mechanisms of DNA recombination used by transposons. There are many thousands of different transposons, but we are working on one particular group known as mariner. This is probably the most successful and widespread family of transposons in nature. Our experiments will provide fundamental insights into the ever-changi ng structure of the genetic information that programs the behavior of each cell. Since their discovery transposons have also been adapted to provide a set of powerful tools for medical research. For example, a recent transposon-based method has been used to discover numerous cancer genes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of microRNAs in body plan evolution
Funder: Wellcome Trust

Abstract: This project aims to investigate the role of microRNAs in the evolution of pattern formation and morphological diversity at genome-wide level. To do this, I will perform comparative analysis of the temporal patterns of microRNA expression during the ontogenesis of species following different modes of development. The work will involve various computational and comparative genomics techniques and algorithms, mining of existing datasets and RNA sequencing, to meet the following objectives: Objective 1: Assess the acquisition of microRNA genes during the evolution of short and long germ-band insects Objective 2: Analyse the temporal patterns of expression of microRNAs from different evolutionary origins during Drosophila melanogaster ontogenesis Objective 3: Compare the microRNA expression patterns of D.melanogaster with these of another long germ-band (D.virilis) and short-germ band (T.castaneum) species Objective 4: Test whether the microRNA expression divergence at the different developmental stages follows the hourglass model Accurate reconstruction of the evolutionary history of the microRNA repertoire of the examined species and determining microRNA orthologs (objective 1) is an essential prerequisite of the subsequent analysis. Analysis of pre-existing data on D.melanogaster microRNA expression (objective 2) will allow us to establish a relationship between microRNA evolution and function, and help determine the most appropriate time points for data acquisition. Comparison of the microRNA expression patterns between short and long germ-band arhtopods (objective 3) will allow us to assess the conservation of microRNA expression in species of different developmental modes at two different time scales, and test if novel microRNAs are associated with the segmental patterning evolution. It will also be used to identify any constraints on microRNA expression, test whether the microRNA expression is maximally conserved at the phylotypic stage, and overall, whether microRNA expression timing is essential for development (objective 4). The unbiased large-scale data generated in this project can benefit further studies addressing various evolutionary and developmental questions, both in vivo and in silico.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural Biology of DNA Repair: Spatial Organisation of the Multicomponent Complexes of Non-Homologous End Joining.
Funder: Wellcome Trust

Abstract: Chromosomes can be catastrophically damaged by reactive species inside cells and by ionizing radiation from outside, often resulting in cell death or cancer. Particularly serious are DNA double-strand breaks, which can at certain times in the cell cycle be repaired using homologous recombination, exploiting sister chromatids, but otherwise by Non-Homologous End Joining (NHEJ). The NHEJ pathway involves many components. Ku first forms a ring around broken DNA ends, maintaining them in proximit y. Subsequently DNA-dependent protein kinase catalytic subunit, a huge protein of 4128 amino acids, is recruited, causing Ku to move inwards from DNA ends and allowing access of other proteins. Rejoining of DNA ends is mediated by DNA ligase IV, which is associated with key proteins XRCC4 and XLF/Cernunnos, identified in NHEJ deficiency patients. We have used biochemical and X-ray techniques to define structures of individual components DNA-PKcs, XRCC4 and XLF and have extensive biophysical and crystallographic data of intermediate complexes. We are now in a strong position to define architectures of these transient multicomponent complexes. This is a necessary prerequisite for understanding the molecular mechanism of NHEJ and providing clues as to how to intervene therapeutically in cancers, perhaps in combination therapies with radiotherapy and chemotherapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Interplay of the Dpp and microRNA pathways in Drosophila germline stem cell regulation
Funder: Wellcome Trust

Abstract: The Drosophila melanogaster germarium serves as a paradigm for studying the regulation of stem cell maintenance and differentiation [1]. The Decapentaplegic (Dpp) and the microRNA (miRNA) pathway are both important for germline stem cell (GSC) maintenance [2,3]. The broad aim of the project is to understand how the interplay between the Dpp and miRNA pathways controls stem cell fate in the Drosophila germarium. This will be achieved as follows: 1) Determine the influence of Dpp signalling on arm usage of miRNAs. 2) Determine how altered arm usage of miRNAs in response to Dpp signalling impacts upon target mRNA selection. 3) Determine how Dpp-dependent miRNA arm switching and the selection of miRNA targets influences GSC fate in vivo. Results from these aims will give new insights into miRNA maturation and the basis of stem cell maintenance and differentiation. Furthermore, it will provide a mechanistic model of how Dpp influences post-transcriptional processes and underline the importance of miRNA arm usage as a means of higher order regulation of developmental processes. The BMP signalling pathway has a conserved role in stem cell fate regulation [4,5]. Therefore, results from this work will also be relevant to human stem cell research.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The nuclear function of the mitochondrial hydroxlase Clk-1
Funder: Wellcome Trust

Abstract: The lab has good evidence that nuclear Clk-1 is a regulator of ROS levels, but it is important to uncover the in vivo role of nuclear Clk-1 and to understand the molecular mechanisms that determine the balance between its nuclear and mitochondrial localisation. The specific aims of the project are: i) to determine how Clk-1 is targeted to the nucleus ii) to generate a novel mouse model to investigate the in vivo function of nuclear Clk-1.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining the links between tail-anchored protein biogenesis and the cytosolic quality control of mis-localised proteins.
Funder: Wellcome Trust

Abstract: Tail-anchored (TA) membrane proteins are a functionally diverse group of proteins that share a unique topology. Given their physiological importance in many functions at the cytosolic face of various sub-cellular organelles, recent studies have focused on investigating the delivery of TA proteins to their target membranes. There has been substantial recent progress in identifying factors and pathways involved in their biogenesis. Furthermore, in addition to unraveling the processes of membrane targeting and integration, the importance of a third process i.e. the recognition and degradation of mislocalised TA protein has also been highlighted. My project aims at identifying novel components involved in TA protein biogenesis and refining our understanding of the roles of all key cytosolic binding factors. In order to do so, I will establish a strategy to discriminate TA protein interacting partners that are involved in membrane delivery versus those that mediate degradation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Control of cell growth and division in fission yeast
Funder: Wellcome Trust

Abstract: In eukaryotes, cell growth and division are highly controlled to allow the maintenance of appropriate cell size during continuous proliferation. The Target of Rapamycin (TOR) pathway is responsible for this coordination in response to environmental changes (Fingar and Blenis, 2004). However, many aspects of TOR signalling are poorly understood, in particular processes upstream of TOR which are responsible for sensing nutrients. Overall objective: To extend current knowledge regarding the environmental control of cell growth and division. Specific aims: 1. To further investigate Plo1 kinase regulation, the mechanism for environmental controlled Plo1 localization to control cell growth and division and explore the role of post-translational modifications including protein cleavage. 2. Further analysis of the mechanisms of nutrient sensing, through the isolation and characterisation of mutants unable to response to nutrient stress to control cell growth and division. This work will aim to provide a better understanding of how cell division is controlled in response to environmental pressures. All of the experiments described will use the fission yeast Schizosaccharomyces pombe (S. pombe) as a model system. S. pombe has a simple life cycle and is a genetically tractable system with a control of mitotic entry and cell division that is more typical of that found in mammalian cells (a long G2 phase). Furthermore, most key signalling pathway components in fission yeast have homologues in mammalian cells (Nurse, 1990) so the findings will relate to higher organisms.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Purchase of electron microscopic infrastructure to establish a multi-user facility for cryo electron microscopy, in particular cryo electron tomography.
Funder: Wellcome Trust

Abstract: The requested resources will primarily enable us to bring the cryo electron microscopy facility in the Oxford Particle Imaging Centre (OPIC, the facility for the characterisation of infectious particles) at the Wellcome Trust Centre for Human Genetics to a state of the art level for this emerging scientific technique. This open access multi-user facility will allow for the determination of 3 dimensional structures of macromolecules and macromolecular complexes and in particular will underpin ena bling cryo electron tomography drawing upon the Gruenewald group's expertise in this emerging field. The latter method can interface to the comparably lower resolution light-microscopic imaging techniques existing locally; ultimately spanning from cellular to atomic resolution. The facility aims to integrate structural information resulting from different imaging techniques thus providing different levels of resolution and biological complexity. The improved capability of the facility and the n ew interactions will promote primarily collaborations between the Division of Structural Biology (STRUBI) at the Wellcome Trust Centre for Human Genetics, the Department of Biochemistry and The Dunn School of Pathology, but will be also be open to interested groups from other science departments in Oxford.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Characterisation of lipid oxidation by high accuracy mass spectrometry.
Funder: Wellcome Trust

Abstract: The body is normally well protected against attack by oxygen on the specialised fats (lipids) that form the membranes that surround cells. Uncontrolled generation of activated oxygen (oxygen free radicals) causes lipid oxidation, and is thought to be a fundamental pathological processs in many serious diseases, including heart, respiratory, diabetic and neurodegenerative conditions. Recent advances in a specialised analytical technique called mass spectrometry have enabled detection and measur ement of the low concentrations of oxidised lipid that contribute to these diseases. This application is for a novel mass spectrometer with an enhanced ability to dedect such oxidised lipids separately from all the other un-modified lipids in cell membranes. Analytical techniques established using this instrument will then be applied to study the role of lipid oxidation in a range of diseases.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: A High-throughput NMR Facility for translational and chemical biology at the University of Edinburgh .
Funder: Wellcome Trust

Abstract: We investigate the roles that protein molecules play in health and disease. Tens-of-thousands of different proteins are encoded by genes within the human genome and by the genomes of viruses, parasites and bacteria. We have therefore established a factory to manufacture numerous interesting individual proteins and to analyze their three-dimensional structures. Such knowledge facilitates discovery of small chemical compounds that selectively bind to specific proteins. These small compounds may subsequently be utilized as tools to manipulate the biological properties of the proteins to which they bind. This helps elucidate how proteins interact with other proteins in tissues; it also underpins design of drugs that work by binding to disease-causing proteins and tweaking their activities. We now require better equipment to handle the increased number of proteins being made in our factory and to exploit the libraries of chemicals we screen for their ability to interact with our protei ns. NMR is a powerful technique for analyzing proteins and the complexes formed between protein molecules and small chemicals. We request an upgrade to allow 10-15 times faster NMR analyses; also a robot to prepare and submit samples to the NMR machine so it can work 24-7 .


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Towards an integrated mechanistic and functional analysis of endosomal sortingin the establishment and maintenance of planar cell polarity
Funder: Wellcome Trust

Abstract: By combining work in a cell-free system, cultured cells and a model organism, this project aims to elucidate the molecular mechanisms that facilitate intracellular trafficking of the core PCP components. It is hoped that use of a scale of techniques, from in vitro reconstitution to consideration of the whole animal, will thoroughly test the veracity of data obtained, thereby convincingly expanding our knowledge of the process of tissue polarisation that is fundamental to animal development and function.


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