NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding the role of the RNA-binding protein Mmi1 in coupling transcription and RNA processing by the exosome complex.
Funder: Wellcome Trust

Abstract: Regulation of gene expression in eukaryotes is integral to establishment of the cell identity and survival. Synthesis of pre-mRNA in eukaryotes is catalyzed by RNA polymerase II (Pol II). The level and quality of RNA is controlled by the RNA gsurveillance h machinery represented by the highly conserved exosome complex of 3'-5' exonucleases, which is therefore responsible for establishing the balance between RNA synthesis and degradation. Recent studies revealed that the exosome has a key role i n RNA metabolism by degrading defective RNAs in both nucleus and cytoplasm. It is also involved in precise trimming of the 3'ends of sn/snoRNA, tRNA and rRNA precursors. However, the mechanisms regulating and targeting exosome activity to its multiple RNA substrates are poorly understood. The proposed research will explore how RNA quality is monitored by investigating the molecular mechanisms involved in regulating the exosome activity in S. cerevisiae. Initially, genetic and biochemical approac hes will be applied to identify potential exosome co-factors. The functional contribution of each co-factor in determining specificity of the exosome complex will be further examined by monitoring RNA processing in vitro and in vivo. This study will be instumental for our understanding of how different expression programs are executed in cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Role of the exosome complex in RNA quality control .
Funder: Wellcome Trust

Abstract: Cells use DNA to store genetic information. One of the fundamental questions in biology is how do cells convert the information encoded in DNA into functional units (proteins)? An important means of regulating the level of a protein in all cells is by controlling the amount of messenger RNA (mRNA) produced from the corresponding gene since mRNAs are translated to yield protein. The exosome, a complex of 10 proteins, was recently described as a major regulator of RNA stability, quality and matura tion in yeasts and human cells. Yet, very little is known about the molecular mechanisms regulating the exosome activity and targeting it to the RNA substrates. I will investigate this interesting problem using yeast cells as a model since yeast gene expression is very similar to that in mammals, and is amenable to biochemical and genetic experiments that are impossible in other systems These studies are expected to advance our understanding of how cells execute different programs of gene expre ssion involved in development, differentiation and adaptation to stress conditions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: How is cell migration regulated by the extracellular matrix: role of syndecan-4 and integrin-alpha5beta1 receptors in the regulation of Rho family GTPases?.
Funder: Wellcome Trust

Abstract: In healthy adults, cell adhesion is tightly regulated so that proliferation and migration of most cell types is limited, unless stimulated by infection or wounding. Initiation of migration depends upon recognition of changes in the extracellular matrix environment by individual cells. Engagement of a single receptor type is not sufficient to distinguish new matrix engagement from the existing matrix contacts over the surface of a cell. Therefore, there is increasing recognition that understan ding the basis of cooperation between functionally related receptors is a research priority. I will examine the mechanisms of synergistic signalling by the matrix receptors; syndecan-4 and integrin-alpha5beta1. I will resolve the molecular pathways linking syndecan-4 and integrin-alpha5beta1 to signalling molecules that regulate membrane protrusion (Rac1) and cell body contraction (RhoA) in fibroblasts. I will determine how the balance between protrusive and contractile signals is maintained, with particular attention to the spatial and temporal relationship between the molecules involved. I will also examine mechanisms of direct crosstalk between syndecan-4 and integrin-alpha5beta1 that would facilitate synergy. By understanding the process of cell migration, we gain insight into the cellular mechanism of tissue repair that should contribute to the development of techniques for the treatment of wounds in future projects.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: An Upgrade of the Protein Crystallography Facility at University of Bath.
Funder: Wellcome Trust

Abstract: X-ray crystallography is a powerful technique, which helps us determine the precise position of each atom in a molecule. When an X-ray beam strikes a crystal phenomenon of diffraction takes place (i.e., scattering as in a light microscope). The scatter produced can be captured onto a film or in recent years onto an electronic detector system such as is used to capture images in a digital camera. The diffraction pattern obtained from X-ray scattering off the periodic assembly of molecules or atom s in the crystal is unique to each protein or DNA molecule. Using advanced mathematical calculations one can convert this diffraction pattern into the 3D digital picture (called electron density) of the molecule. A model is then progressively built into the experimental electron density, refined against the X-ray diffraction data and the result is a quite accurate 3D molecular structure. These structures provide details of the catalytic machinery (the active site), protein-ligand and protein-pro tein interactions. Such details can be exploited to correlate with the functional knowledge using protein engineering, computational and biophysical techniques. In this application support is requested to upgrade our structural biology facility (a multi-user facility) at Bath to pursue new ambitious projects.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Transcription-coupled mechanisms of nuclear mRNA surveillance and their global role in human gene expression.
Funder: Wellcome Trust

Abstract: Most cells in the human body have the same DNA content, yet not all cells are the same because not all genes are active all the time. Thus, the active genes, and the extent to which they are active, can determine the properties of the cell (its phenotype) and whether it is healthy or not. By current estimates, the most diverse class of genes are those that code for proteins. In the human genome there are tens of thousands of protein-coding genes and a major challenge is to understand how thei r activity is regulated. During protein-coding gene expression, the DNA is copied into a related molecule called RNA, which is then matured before being transported from the nucleus to the cytoplasm where it is used as a template for protein synthesis. Each of these processes is monitored by enzymes (called exonucleases) that destroy errant RNAs. With these facts in mind, it can be stated that the extent to which a gene is active depends on balancing RNA synthesis and degradation and, on a broad level, so does the phenotype of a cell. I aim to discover the mechanisms that maintain this balance and their relative contribution to gene expression.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Public health and health services in postwar Britain: constructing the history, connecting with policy.
Funder: Wellcome Trust

Abstract: The application proposes a range of interlinked activities which will be conducted by a team of contemporary historians, a policy analyst and an archivist. Our institutional base is a school of public health, and we will exploit this unique location to facilitate collaborative working which will inform our research and provide access to contemporary policy makers. Our overarching goals are: 1. To develop research questions and themes in public health, health services and health consumerism which contribute towards a synoptic view of postwar health history in Britain. The application details several specific projects which build upon the achievements of the research team during the period of our Enhancement Award (2004-9). 2. To develop our existing informal collaborations with public health scientists to establish more formal research and advisory links. 3. To utilize the archival resources of the school to develop our own research and to advance public understanding. 4. To reflect critically on the policy significance of our work and that of other medical and health historians, and to bring such research into the policy arena.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Establishment of a biophotonic animal imaging system for in vivo biology.
Funder: Wellcome Trust

Abstract: The genes and proteins that have been implicated in disease and homeostasis do not function in isolation, but interact in a dynamic manner in the physiological environment of whole organisms The equipment requested will facilitate our existing research focusing on understanding these interactions in infection and immunity as well as other applications in drug delivery and neurosciences. The infection-based projects are concerned with understanding how infections cause disease and developing new strategies for vaccination and treatment. The immunobiology component of the application will allow observation of cells of the immune system particularly in studies where immune dysfunction has been implicated in diseases, such as arthritis, asthma and cardiovascular disease. The system allows multiple images of the same intact live animal over time, reducing animal usage and maximising the information obtained from each animal. Importantly, the macroscopic imaging provided by the equipment wi ll complement current microscopical in vivo imaging projects in the Centre for Biophotonics in collaboration with a number of groups in the UK. These facilities will therefore not only provide added value to the applicants but also to in vivo biology researchers in SIPBS, across the city of Glasgow and the many groups we collaborate with throughout the UK.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Protein Data Bank in Europe.
Funder: Wellcome Trust

Abstract: The molecular-biology revolution (studying life and disease processes at the molecular level) yields vast amounts of data, the systematic capture and study of which has become a new area of scientific enterprise: bioinformatics. This has resulted in many high-quality databases and services that are used in structural, molecular, cell and systems biology, medicinal and computational chemistry, bioinformatics, biotechnology, biochemistry and biophysics, and agricultural and pharmaceutical scienc es. The European Bioinformatics Institute (EBI) is responsible for providing such databases and services, which is critical to the competitiveness of European life-science research. EBI hosts five core databases including the Protein Data Bank in Europe (PDBe). PDBe holds the 3D structures of proteins and other important biological macromolecules. Knowledge of such structures often provides detailed understanding of the molecular basis of life and disease processes, and sometimes facilitates t herapeutic intervention. For instance, determination of the structure of a protein of the AIDS virus (HIV-protease) enabled the development of the drugs on the market today. The structural archive is managed by a worldwide organisation in which PDBe is a major partner representing Europe. This proposal is for funds to maintain the core operations of PDBe (data-deposition and running the databases).


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: A proposed structural biology resource in the Department of Biochemistry.
Funder: Wellcome Trust

Abstract: An essential aim of our work is to determine the three dimensional structures of proteins and protein assemblies at atomic resolution using X-ray crystallography. In brief, we prepare highly ordered crystals from purified materials and illuminate them with an exceptionally bright monochromatic X-ray beam and record the intensities of the diffracted X-rays. From these diffraction data, we can solve the three dimensional structure of the molecules in the crystal. We also prepare specific complex es with cognate small molecules to understand how these are recognised by the proteins, and we study binding of synthetic compounds that can be re-designed by chemical synthesis to bind more avidly to the target protein. In this way, we can rapidly evolve small compounds that block functionally important surfaces of the biological molecules and thus have potential as therapeutic agents to treat disease, or as chemical switches to change the function of specific proteins in the context of a livin g cell or whole organism.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Systems biology profiling of SUMO substrate proteome in signaling pathway.
Funder: Wellcome Trust

Abstract: SUMO is a small protein that attaches to other proteins as a flag recognized by different components of the cell. Depending on the identity of the linked protein the SUMO flag can bring different messages, some of which are involved in fundamental cellular processes and disease states. Traditional biological methods have studied separately each protein modified by SUMO. Mass spectrometry is a powerful tool for detecting and quantifying proteins. Recent advances in this field allow us to study al most all the proteins made by a cell. A goal of the proposed project is to improve mass spectrometric methods to allow an easier study of proteins attached to SUMO. A second goal of the project is the investigation of how the attachment of SUMO to proteins is regulated in many different processes that occur in cells. This will help us to understand the potential role of SUMO in various diseases. The large amount of data obtained will be analyzed with specialized computer software to explain the behavior of the cell from a SUMO perspective.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Signalling to chromatin: Balancing growth versus longevity.
Funder: Wellcome Trust

Abstract: The effect of restricting calorie intake on life span extension has been recognised for over 70 years. Although many hypotheses to explain how calorie restriction (CR) modulates ageing have been proposed, the underlying mechanism is still elusive. The effect of CR on ageing is conserved in a wide range of organisms from yeast to man and point to a nutrient-sensing mechanism. Yeast is a very powerful genetic system in which to glean information on the ageing process that will be relevant to man. Enzymes of the sirtuin family are already implicated in the ageing process. They protect and control the genome and promote longevity in growing cells. Recently, we have discovered a new pathway, separate from the sirtuins, which controls the response of yeast cells to CR and stress. Simply, this pathway controls the choice between growth and longevity and is important to maintain the lifespan of replicating cells and cells that have stopped growth and division. The purpose of this study is to u nderstand how this new pathway acts to influence ageing, and the effects of stress on ageing. In the long term this will increase our understanding of some of the molecular mechanisms underlying growth and ageing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Time-resolved X-ray crystallography.
Funder: Wellcome Trust

Abstract: 1) Develop a statistical approach to distinguish coherent (functionally related) and incoherent (noise) structural changes in time-resolved crystallographic data. 2) Develop the use of single crystal spectroscopy to provide time-resolved ' spectroscopic data correlated with the diffraction experiment : 3) Combine QM/MM (quantum mechanics/molecular mechanics) simulations with the experimentally determined time-resolved structures to yield a full, experimentally restrained, structural and dynamic description of macromolecular function.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: GPCR-G Protein Interactions Investigated Using Electron Microscopy and Surface Plasmon Resonance.
Funder: Wellcome Trust

Abstract: G Protein Coupled Receptors (GPCRs} are pharmacologically important membrane receptors comprising, at over BOO proteins, the largest superfamily (1%) of the human genome. They are the first link in a chain of signal transduction events that passes messages from the exterior of the cell to the nucleus, ultimately resulting in transcription and translation of proteins in a response pathway. Initial signals occur via interactions with heterotrimeric guanine nucleotide binding proteins (G proteins} (Figure 1) [1]. G protein activation by the receptor initiates signalling via changes in the levels of intracellular messengers such as cyclic-3',5'-monophosphate (cAMP), Ca2+ or signalling lipids. Classical GPCR signalling theory suggests that the activated ligand-receptor complex is required for G protein binding [2], but more recent evidence has shown that a pre-coupled receptor-G protein complex [3; 4], and even a liganded receptor dimer-G protein complex is able to form [5]. All GPCRs have a canonical structure of seven transmembrane ?-helices. The N-terminus in extracellular, the C-terminus is intracellular, and there are three interhelical loops on either side of the membrane. The GPCR family has proved particularly intractable to most high-resolution structural techniques such as X-ray crystallography or nuclear magnetic resonance (NMR), due to the intrinsic conformal flexibility of these proteins, their relatively low expression levels and the fact that they are membrane-bound. While 30-40 % of current drugs target GPCRs [6], less than 2 % of the Protein Database (PDB) comprises membrane protein structures [7]. GPCR structures make up fewer than 30 of the known membrane protein structures, and of those, approximately two thirds are rhodopsin structures (see Table 1 in [8] and references cited therein}. Many functional and structural aspects of the receptor-G protein complex remain to be elucidated, and mechanistic information about the complex is essential for rapid, targeted drug research to proceed apace.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Fat and Dachsous and the hierarchy of planar polarity gene function in Drosophila.
Funder: Wellcome Trust

Abstract: We are interested in understanding how the human body develops to form complex tissues and organ systems This involves the regulation and coordination of three processes: first, the multiplication of cells; second, the differentiation of the right types of cells in the right positions; third, the correct orientation (or polarity ) of cells relative to each other. It is this final process in which we are primarily interested. As the orientation of cells relative to each other is a fundamenta l conserved process in animal development, we are able to study it using a model experimental system, of which the one of the most suitable is the fruitfly Drosophila melanogaster. The simplicity of manipulation of Drosophila, particularly for studying the function of genes, has allowed the identification of many genes involved in the coordination of cell polarity. The aims of this project are to understand how some of these many genes work together and how they are organised into hierarchies . Ultimately, by understanding how the genes act, we hope to be able to intervene to correct developmental diseases caused by dysfunction of the genes, and also gain insights into conditions such as cancer metastasis which involve coordinated changes in cell polarity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Adoption of rapid ethical appraisal as a practical method of assessing ethical issues relating to biomedical research projects in Ethiopia.
Funder: Wellcome Trust

Abstract: The proposed research will test whether Rapid Ethical Assessment can be introduced as a mainstream tool to enhance biomedical research ethics appraisal in Ethiopia. Review of literature will shape a quantitative study to assess the most important issues to have affected research ethics review todate. A qualitative study will then explore deeper sociological, anthropological and ethical dimensions to the issues surrounding ethical appraisal. From the information gathered, tools based on the Rapid Ethical Assessment used in the Gambia will be developed and presented at a one-day stakeholder workshop. After feedback from participants, the tools will be piloted in at least three community-based epidemiologic research projects in Ethiopia. Basedon evaluations made, the tools will be further refined, and presented to a wider audience through a second 3-5 day workshop. A database made up of Rapid Ethical Assessments preceding a range of studies will be compiled, and will beavailable to interested researchers, on application.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Towards a thorough mechanistic understanding of phosphoinositide-mediated endosomal sorting.
Funder: Wellcome Trust

Abstract: Mammalian cells are composed of a variety of interconnected membrane compartments each composed of a unique combination of proteins and lipids. For cells to function correctly, proteins and lipids are required to be transported to specific compartments within this maze of membranes. Understanding how cells achieve this is a major challenge in modern cell biology. Our research focuses on the role of two lipids, PI3P and PI3,5P2 in the regulation of transport within a specific membrane maze cal led the endocytic network. Altered levels of these lipids, and resulting defects within the network can lead to various diseases including cancer and neurodegenerative diseases. In the current proposal, we outline a multidisciplinary programme of research that aims to describe how one family of PI3P-binding proteins - the sorting nexins - regulate transport within the endocytic network. We also initiate a new line of research that aims to identify specific PI3,5P2-binding proteins and elucid ate their role within this network. In doing so, we hope to gain new insight into the mechanism by which defects in endocytic transport can lead to human disease, and identify new targets for drug intervention.


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