NIHRDataInsights/HRCSData huggingface dataset:
Title: BMP-integrin signalling synergy
Funder: Wellcome Trust

Abstract: During development cells receive chemical signals, or signalling molecules, which instruct them to form a specific cell type, eg skin, nail. The signalling molecules which exist in the fruitfly, Drosophila melanogaster, are the same as those which control development in humans. As Drosophila has many advantages as an experimental organism, it is commonly used to study the action of signalling molecules. Signalling molecules work by activating proteins called transcription factors which contro l gene expression. The experiments in this proposal are aimed at identifying all the regions of DNA to which the transcription factors activated by a particular type of signal bind. We will investigate how this programme of gene expression ultimately directs cells to become a specific cell type, as this represents a basic aspect of development which is currently poorly understood. We will also investigate how the activity of the transcription factors is regulated, to ensure only the required genes are activated. Findings from this work will provide basic information as to how gene expression is regulated by chemical signals during development. Results from this study will also be relevant to how the studied signalling pathway functions in humans, where it has important roles in development and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of microenvironmental sensing by adhesion receptors.
Funder: Wellcome Trust

Abstract: Sticking, or adhesion, of cells, either to other cells or to the tissue proteins that surround them in the body, is a vital part of multicellular life. Adhesion is needed for holding the body together and for keeping cells in the right place. During the course of many diseases, adhesion is used by cells to move abnormally throughout the body. Consequently, drugs that control adhesion might be useful for treating cardiovascular diseases, asthma, cancer, bacterial infections and ulcers. The work p roposed in this application uses a new technique to study the ways in which adhesion controls cell behaviour. If successful, the work will help us to understand more about how the molecules involved in adhesion work. It might also suggest ways to design drugs to control adhesion.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: k-turn structure in the architecture of functional RNA molecules.
Funder: Wellcome Trust

Abstract: RNA is the working substance of genetics, involved in every stage of gene expression. For example, the ribosome decodes the information of the gene (as messenger RNA) and turns it into a protein sequence. The ribosome is a large RNA-protein apparatus to do this, that must be folded and assembled from its components in a precisely ordered way. Within the RNA are tightly-kinked elements called k-turns, that organize the architecture of the RNA. They can exist in two conformations, an extended o ne, and the kinked form. Most k-turns bind specific proteins, and these can induce the folding of the element. We hypothesize that the ordered binding of these proteins helps control the correct assembly of the ribosome. Other k-turns are involved in RNA-protein apparatus used to modify RNA molecules, to splice together RNA during processing, and in the control of gene expression. The basis of this work is to understand these RNA folding processes, and the role and function of the proteins in th ese events.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Profiling chromatin dynamics by site-specific proteomic analysis of ADP-ribosylation
Funder: Wellcome Trust

Abstract: All animals are made from cells and the study of how cells function is known as Cell Biology . Our goal is to develop and apply the most powerful approaches in Cell Biology - including genetic, biochemical, structural and computational methods - with the aim of understanding how cells work and how this knowledge can ultimately be used to improve human health. The cells of many organisms, ranging from yeasts to humans, use remarkably similar strategies to grow, divide and handle information. Thu s, insights gained from studies in simpler organisms or cultured cells are frequently directly relevant to understanding human cells - and the defects that give rise to disease. In 2001, the Wellcome Trust identified an internationally recognized group of scientists based within the Michael Swann Building in Edinburgh and awarded them Wellcome Trust Centre status. We now seek to renew the Centre core grant, which pays for communal equipment and staff positions and greatly facilitates the work of the 16 research groups in the Centre. These groups also have individual funding from the Wellcome Trust, but the core grant increases the yield of high quality science generated by this investment by promoting synergy between Centre members.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Zebrafish
Funder: Wellcome Trust

Abstract: It may seem a peculiarity to use zebrafish for human disease duties, however fundamental processes of human biology are shared at cellular and genetic levels. Zebrafish therefore have become an important medical research tool. Zebrafish have some unique capabilities, including the ability to regenerate certain organs. Indeed current studies examine spinal cord and heart regeneration, which may have significant impact on human health. The ability to maintain many genetically distinct lines, witho ut undue expense, is another major attraction of this model organism. This importance of a zebrafish facility to research at the University of Edinburgh is also reflected in the financial contribution made by the College of Medicine and Veterinary Medicine ( 1.45M). The capacity of the current zebrafish facility has now been exceeded by the requirement for fish tank space, borne out by the need to maintain numerous genetically distinct lines of fish. This grant application seeks funds to i nstall a large 2700 tank aquarium system, with support equipment, to facilitate medical-associated research in Edinburgh. This proposal outlines the current projects that require expanded capacity to maintain research momentum and requests funds to finalise the establishment of a world-class aquarium that will serve our research community for years to come.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: The structural basis of the interactions of the NuRD co-repressor complex.
Funder: Wellcome Trust

Abstract: The length of human DNA is approximately 2 meters, exceeding that of the compartment in which it is packaged by 40,000 fold. In eukaryotic cells, compaction of this genetic material is achieved by winding DNA around small, basic scaffold proteins called histones. However, this packaging of DNA (to give a structure called chromatin), renders genes inaccessible to proteins required for copying genetic material from DNA into RNA, and subsequently into proteins (essential for processes including cel l development and cancer progression). Therefore, chromatin structure is tightly controlled both by remodelling/rearrangement of histone subunits and the addition/removal of different tags to these proteins, which controls the recruitment of particular complexes to specific genes. These activities are coupled by the nucleosome remodelling and deacetylase (NuRD) complex. Discovering the three-dimensional structure of this assembly and its functionally diverse components will provide important clu es about how it performs its multifaceted role, and should also provide a template for the rational design of targeted therapeutic drugs. I will map the interacting regions of its components by examining the ability of truncated/mutated subunits to bind and recognise their partner proteins, and will use various structural tools to propose a viable and accurate model of the whole system.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Expression and function of human variant U1 snRNAs.
Funder: Wellcome Trust

Abstract: The collection of genes referred to as the genome contains all the information required for our growth and development. The DNA that makes up the genes is copied into RNA for the information to be decoded, for example into proteins, which can be structural or catalytic. In many genes, the RNA copies contain protein-coding regions (exons) interspersed with non-protein coding segments (introns) and the RNA is processed to remove introns and join exons together in a process known as splicing, direc ted by standard signals within exons and introns. In many cases, exons can also be excised or introns retained, altering the RNA such that different proteins are generated from the same gene. This process in known as alternative splicing and is fundamental to generating protein diversity in different cells. Failure to correctly regulate alternative splicing can result in disease due to the appearance of the wrong product in the wrong place and/or at the wrong time. The aim of the proposed resear ch is to determine the role of a novel group of small RNAs in alternative splicing, which will 1) elucidate how misregulation of their expression could lead to disease and 2) allow their development as drugs to combat disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining protein-protein interaction networks in cytochrome c assembly.
Funder: Wellcome Trust

Abstract: Proteins are complex biomolecules essential to the structure and function of living cells. In order to diversify their functions, proteins use additional molecules called cofactors. C-type cytochromes, essential proteins in respiration and electron transfer, contain a cofactor called heme which is attached via chemical bonds. Heme attachment does not occur spontaneously and different systems exist in bacteria and humans. In bacteria a set of proteins, the Ccm proteins, is required to catalyse th e covalent attachment of heme to protein to give a cytochrome c. We seek to understand how some of the key components of the Ccm system function. In particular, we will study DsbD, CcmG and CcmH and how they interact with a cytochrome protein which does not yet have a heme attached. These interactions are thought to be essential in preparing the cytochrome for the subsequent attachment of heme. The main experimental approach in this study is nuclear magnetic resonance spectroscopy which is un iquely able to provide detailed information about the way that protein molecules interact with each other in solution. Understanding the molecular mechanisms by which DsbD, CcmG and CcmH function will have broader implications including the potential for developing novel drugs to selectively target disease-causing bacteria.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Application for a mass spectrometer for lipidomic research .
Funder: Wellcome Trust

Abstract: Lipids are important chemical messengers that participate in virtually all cellular processes in health and disease. In 2005, we established a specialized facility at Cardiff University for quantitative and structural analysis of lipids in biomedical research. This comprises a state-of-the-art technique termed liquid chromatography- tandem mass spectrometry (LC/MS/MS), and the facility is one of only a handful in the UK dedicated solely to lipid research. In our group, we focus on two subgroups of lipids, termed eicosanoids (centrally important in inflammation, cancer, organ development, kidney function and gastrointestinal tract) and phospholipids (the building blocks of all cell membranes). We also conduct work for several other researchers by analysing lipid mediators in their samples, which include both animal models of disease and human clinical tissue. Due to the success of our facility, we now have far more samples than we are able to analyze, and for structural studies require greater sensitivity. Thus, we request funding for a tandem mass spectrometer with more powerful and newer separation technology to concentrate on faster quantification of eicosanoids and phospholipids, as well to provide as greater sensitivity for structural analysis.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of mitochondrial protein dynamics and mitochondrial function by reversible ubiquitination.
Funder: Wellcome Trust

Abstract: (1) To identify and characterise deubiquitinases involved in mitochondrial dynamics and/or mitophagy using two sets of siRNA based screens. (2) To define and characterise the mitochondrial ubiquitin-proteome in human cells (3) To measure mitochondrial protein turnover at a global scale


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Open access research to promote drug discovery.
Funder: Wellcome Trust

Abstract: A comprehensive understanding of the roles of human proteins in normal and disease biology will be required to develop effective medicines, and this understanding will come only with a functional understanding of each protein. High-quality research tools will be necessary to achieve this understanding, however only a fraction of human proteins have been purified to homogeneity, only 6% of the human proteome is understood at the structural level and there are few potent and selective probes of function to human proteins (i.e. chemical inhibitors or antibodies). Over the past 5 years, we have developed and implemented a structural genomics pipeline to increase significantly the available structural knowledge for human proteins ? targeting proteins of relevance to drug discovery. Our laboratories now consistently produce over 20% of the global output of human protein structures - over 30 % in 2009 - and have purified over 2,000 human proteins in milligram quantities. In the next funding period, we propose to expand the capabilities of our pipeline to tackle more challenging structures, and to exploit the purified proteins and structures to generate a broader and more impactful range of research tools, including high-quality chemical probes and recombinant protein-capture agents. We will again target proteins of relevance to drug discovery, but place particular emphasis on proteins linked to the regulation of epigenetics, an exploding area of biomedical research and a frontier area of drug discovery. These new initiatives will involve novel models for collaboration, in which our industry partners will allocate internal resources (e.g. medicinal chemistry) to the projects, whose goals are to generate reagents that will go into the public domain without restriction on use.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: The dynamic mechanical properties of animal cells.
Funder: Wellcome Trust

Abstract: In studies of cell shape change, the gel in the cell interior is generally viewed as an innocuous backdrop. This view misses a major point: during gross shape change such as cell division or movement, the skeleton of the cell provides the force for shape change but the maximal speed at which shape change can occur is controlled by the gel in the cell interior. Our previous work suggested that this internal gel behaves similarly to a liquid-filled sponge. As the bathing liquid is incompressible, any deformation of the cell requires fluid movement out of the sponge and the ease with which this can occur depends on the size of pores in the sponge. One fundamental implication of this liquid-filled sponge description is that cells may be able to exploit pressure changes due to inhomogeneous ionic concentrations in their interior to change shape. This study aims to: -Validate the liquid-sponge model -Understand what biological structures set the pore size of the sponge -Examine the biolog ical and clinical implications of changes in sponge structure


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Studying the role of atypical chemokine receptors CCRL2 or CXCR7 for germinal centre differentiation
Funder: Wellcome Trust

Abstract: Studying the role of atypical chemokine receptors CCRL2 or CXCR7 for germinal centre differentiation (a) Aims of the project: To understand how B cells are instructed to move between different compartments in germinal centre. In particular: to test the hypothesis that the atypical chemokine receptors CCRL2 and CXCR7 are involved in these processes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of alternative pre-mRNA splicing.
Funder: Wellcome Trust

Abstract: In order for genes to exert their effects the sequence of bases in the DNA must first copied into a related molecule called pre-mRNA. A process called splicing then joins together the parts of the RNA sequence that are used to direct the production of specific proteins. The human genome has approximately 20,00-25,000 genes, but the process of alternative splicing , in which the RNA can be joined together in different ways, allows most genes to be switched on in different ways. In this way th e same gene can produce different proteins at different times or in different tissues. The importance of this process is demonstrated by human diseases that are caused when alternative splicing is misregulated. This proposal is aimed at understanding how alternative splicing is controlled. In one approach we will study a small number of alternative splicing events and analyze how particular RNA sequences interact with regulator proteins to affect alternative splicing, either as activators or re pressors. The second approach involves looking at all of the alternative splicing events that occur in smooth muscle cells. This will allow us to learn the general properties of a programme of co-regulated alternative splicing events.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Equipment for Structural Biology in the School of Life Sciences at the University of Sussex.
Funder: Wellcome Trust

Abstract: Knowledge of the atomic structure of the protein molecules that control living cells allows us to understand many genetic or infectious diseases, including cancer, and can assist the development of new drugs to treat those diseases. The most effective way of defining the atomic structures of proteins molecules involves shining X-rays through crystals of the protein, and measuring the pattern of X-rays that emerge. In this application we are requesting support for the establishment of laboratory facilities and specialist equipment to allow us to make the pure proteins from which the crystals can be grown, and to perform the X-ray experiments and mathematical analysis of the X-ray patterns, to determine the atomic structures


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Multiscale simulations of signalling at membranes: embracing T cell receptors.
Funder: Wellcome Trust

Abstract: The overall aim is to develop predictive models of signalling across, within, and at the cytoplasmic surface of cell membranes. In particular the plan is to develop a dynamic structural model of signalling clusters at cell membranes. To achieve this overall aim, the following objectives will be addressed: 1. To develop an integrated computational framework for multi-scale molecular modelling of membrane signalling systems; 2. To test and evaluate this computational framework on well documen ted systems for which there are good biophysical and cell biological data; 3. To develop dynamic models of signalling involving (i) receptor tyrosine kinases; and (ii) phosphoinositide lipid recognizing proteins; 4. To exploit the predictive capability of the framework to study more complex systems of key biomedical relevance, especially in the context of e.g. structural genomics advances which are shifting our focus from model systems towards biomedically critical signalling proteins. The br oader context of this work is that membrane/protein interactions are an attractive potential drug targets, especially as current simulations allow us to describe quantitatively the interactions of drugs with membranes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Multi-Scale Integrative Modelling of Signalling at Membranes.
Funder: Wellcome Trust

Abstract: Signalling at cell membranes controls many processes in mammalian cells, ranging from development of tissues to immune responses. Many diseases (from e.g. diabetes to cancer to autoimmune disorders and embryonic malformations) are associated with errors in membrane signalling. Improved understanding of how the three dimensional structures of membrane signalling proteins determine cellular function is the key to developing new therapies. In order to relate protein structures (at the level of indi vidual molecules) to complex events of systems of molecules within a cell we will develop computational methods which allow one to predict how perturbation of proteins (by mutations or by binding of drug molecules) results in changes in cellular function. A major aim of the study is to develop such computational models using systems for which good experimental data are available, and then to exploit the predictive capability of the models to study more complex systems of key biomedical relevance . The broader context of this work is that membrane/protein interactions are an attractive potential drug targets, especially as current simulations allow us to describe quantitatively the interactions of drugs with membranes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Control of gene expression by the MAP kinase and SUMO pathways.
Funder: Wellcome Trust

Abstract: The identity of the cell is determined by the proteins it contains. This protein content is itself determined by the range of RNA transcripts present (the transcriptome). To change its function the cell responds to physiological signals involved in body homeostasis and development or signals generated in response to tissue damage or disease. These signals are transmitted from the cell periphery to the nucleus by signalling pathways, where they cause activation of gene transcription (the process whereby RNA is produced). The signals are interpreted by a range of regulatory proteins called transcription factors and coactivators/corepressors which turn on gene expression. The aim of this proposal is to further our understanding of how different types of signals lead to specific patterns of gene expression through studying transcription factor-coactivator/corepressor complexes and their regulation by signalling pathways and other pathways in the cell. Stem cells represent potential buildin g blocks for the regeneration of diseased, damaged or old organs and tissues, and therefore represent potential therapeutic targets. We aim to pursue these studies in stem cells and thereby contribute to our understanding of how these cells function and can potentially be manipulated to form new tissues.


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