NIHRDataInsights/HRCSData huggingface dataset:
Title: Upgrade of the Wellcome Trust Protein NMR Facility at Kent.
Funder: Wellcome Trust

Abstract: Nuclear magnetic resonance spectroscopy (NMR) allows us to model the 3-dimensional shape of biomolecules as well as providing information on the interactions these molecules make within the cell. This is important, not only to enrich our understanding, but also because many of these molecular processes are linked to diseases and/or genetic defects. At Kent, we have a 13-year-old NMR spectrometer to gather our data to study biomolecules and the instrument is used by several research groups to l ook at protein folding catalysts, vitamin biosynthesis, muscle proteins and drug stability that all have biological and medical relevance. Our NMR spectrometer is becoming out-of-date and our equipment does not allow us to work as efficiently as we would like in terms of the time need to collect data and the ability to study samples only available in very small amounts. We are asking for funds to help us upgrade our NMR spectrometer to enable us to obtain data more quickly and to detect very s mall amounts of these new and sometimes unstable molecules. This will bring our equipment up-to-date and provide more answers to how biomolecules function that can be of use in medicine and bioscience in general.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: The molecular mechanism of active nucleoside transport across biological membranes.
Funder: Wellcome Trust

Abstract: Nucleoside transporters are essential for the salvage synthesis of nucleotides by many cell types, and for the efficient uptake of hydrophilic nucleoside drugs. By regulating the extracellular concentrations of adenosine and other nucleosides, they also modulate numerous physiological processes, ranging from cardiovascular activity to lipolysis. Elucidating their molecular mechanisms is therefore not only crucial for a fuller understanding of nucleoside biology, but should also underpin the deve lopment of novel therapeutic strategies for human disease. Towards this end, the key goals of the proposed research are: [1] To elucidate the structures of bacterial representatives of the ubiquitous concentrative nucleoside transporter (CNT) family, in particular NupC from Escherichia coli. 2-D and 3-D crystallography of NupC will exploit the availability of large amounts of wild-type and conformationally locked mutant proteins. [2] In parallel to investigate helix arrangements and dynamics in NupC by non-crystallographic approaches, including Forster resonance energy transfer (FRET) and thiol cross-linking. [3] To perform complementary investigations on homologous sodium- and proton-linked CNTs from humans to elucidate the mechanisms underlying nucleoside selectivity, cation-coupling, and conformational changes. [4] To attempt the production of human CNTs in amounts sufficient for structural investigations, exploiting recent advances in high-throughput methods for screening euk aryote membrane protein expression.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Can mass media campaigns reduce child mortality?
Funder: Wellcome Trust

Abstract: Millenium Development Goal 4 seeks to reduce under-5 child mortality by 2/3 between 1990 and 2015. Many low income countries, especially in Africa, face challenges in scaling up interventions to achieve this goal. Mass media campaigns have the potential to change knowledge and behaviour, and hence to affect health outcomes. If effective, they can be taken to scale relatively easily. The proposed research is designed to test the hypothesis that comprehensive mass media campaigns, targeting a rang e of family behaviours, can change those behaviours to a sufficient extent to result in a measurable reduction in child mortality. The research will be conducted in Burkina Faso, West Africa, a country with high child mortality and where mass media are sufficiently localised that a rigorous, cluster-randomised research design is possible. The trial has been designed to be able to detect a reduction in post-neonatal under-5 child mortality of 19-20%.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Analysis of the mesothelium as a source of adult progenitor cells for tissue homeostasis. .
Funder: Wellcome Trust

Abstract: Tissues and organs in the body need to be maintained after birth and throughout adulthood to enable the organism to function properly. Stem and progenitor cells have been shown to contribute to renewal of cells in some tissues like the skin and the intestine, thus providing a constant source of cells for tissue maintenance. However, for many tissues and organs it is not known how they are maintained. We propose to determine whether the mesothelium, an epithelial layer encasing many organs, serve s as a source of progenitor cells to these organs. In our analysis we will trace the lineage of mesothelial cells in the adult organism to show that mesothelial-derived cells give rise to non-mesothelial tissues, and thus contribute to their maintenance. Further, we will determine the role of the Wilms tumour protein 1 (Wt1) during this process by inactivating the Wt1 gene in mesothelial cells; Wt1 is thought to regulate epithelial characteristics in mesothelia. Finally, by ablating mesothelial cells in adult animals we will reveal whether mesothelia are necessary for tissue and organ maintenance.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The Road from Pluripotency to Lineage Determination.
Funder: Wellcome Trust

Abstract: In the early embryo a small group of cells form with the ability to make all cell types of the organism. This property is called pluripotency. It is possible to keep cells in a pluripotent state in the laboratory. These are called embryonic stem cells. Research with embryonic stem cells over the past 10 years has identified the master genes that control pluripotency. This lead to the discovery that adult cells could be reprogrammed into a pluripotent state using these master genes. There are now great hopes that this technique can be used to produce different cell types in the laboratory for studying disease, testing drugs, and perhaps one day even for transplantation. However, there is still an important part of pluripotency that we do not understand well. That is how the pluripotent cells choose to become different types of cell. Without understanding this it is difficult to control them and use them for biomedical purposes. We propose to investigate this question in mouse embryonic stem cells and mouse embryos. We have developed a method to isolate cells that are in the process of choosing to differentiate. We will study these cells to identify the mechanisms that control their decision.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The interaction of RAMPs with GPCRs; understanding structure-function relationships.
Funder: Wellcome Trust

Abstract: Natural ligands such as hormones and neurotransmitters largely produce their effects by acting at proteins on the surface of cells known as receptors; drugs work by binding to these receptors to either mimic the natural transmitter or reduce its action. It is important to know the structure of receptors, to understand basic biological processes and to design new drugs. Receptor activity modifying proteins (RAMPs) are a family of three proteins that interact with many important receptors, frequen tly receptors for which it has been difficult to discover drugs. A new class of antimigraine drug works by binding, in part, to RAMP1. RAMP 2 and 3 form parts of receptors involved in control of blood pressure, blood vessel growth and also appetite. If we knew more about RAMPs, this would help drug discovery as well as increasing our fundamental knowledge of physiology. This project will investigate the structure of RAMPs by biophysical techniques. It will investigate how they can bind to recept ors and how, in turn, natural ligands can bind to them once they are part of a receptor complex. This will help the design of new drugs to treat diverse conditions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating and validating MRI-based markers of white matter microstructure.
Funder: Wellcome Trust

Abstract: Magnetic resonance imaging (MRI) uses strong magnets to take pictures of water in the brain. Since water exists throughout the brain, these pictures show its overall structure. However, neuroscientists often want to study brain cells (neurons), which can t currently be depicted with MRI. My research will develop two new MRI technologies that may allow scientists to study neurons more directly than is currently possible. The first method measures disturbances in the magnetic field caused by tissu e components like iron or myelin. These components are important to brain function, and have different purposes. My research will allow scientists to tell them apart. In the second method, we track how far water can move to determine whether it s inside a small or large neuron. If we compare these MRI measurements with mathematical predictions, we can estimate the size of neurons. This method could detect if the neurons are shrinking or swelling, which changes their ability to transmit signals. My research will provide neuroscientists with an MRI microscope that can study neurons directly in living people without risk or discomfort, enabling neuroscientists to investigate how neurons change when we learn and grow, and helping doctors to develop more effective treatment for brain disease.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Probing the dynamics of ribosome assembly in yeast.
Funder: Wellcome Trust

Abstract: Ribosomes are complexes of proteins and ribonucleic acids (RNA) that are found in all kingdoms of life and is responsible for translating the genetic code stored in DNA into proteins. To translate information encoded in thousands of mRNAs, cells devote vast amounts of energy and resources to produce a large number of ribosomes; about 4 million in a typical human cell. Ribosome synthesis is tightly coupled to rates of cell growth and its deregulation is linked to initiation or progression of canc er. The step-wise assembly of ribosomes is tightly regulated and requires the activity of hundreds of assembly factors. Among these factors are a group of enzymes that utilize the energy stored in nucleotide tri-phosphates (NTPs) to exert their function. I hypothesize that these proteins play a key role in the ribosome assembly process by the directing structural changes necessary to produce functional ribosomes. The aim of the proposed research is to determine the function of several remodeling proteins using state-of-the-art biochemical techniques to gain detailed insights into the dynamics of ribosome assembly.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Community resource centres to improve the health of women and children in Mumbai slums: a cluster randomized controlled trial of a complex intervention.
Funder: Wellcome Trust

Abstract: Background: Urban health is a critical but under-researched requirement for India s development. The Government of India plans a National Urban Health Mission which recommends decentralization and partnerships between the public, private and non-government sectors. Goal: To improve the health of women and children in Mumbai. Objectives: The research programme aims to develop and test a model strategy to improve women s and children s health in Mumbai. The strategy turns on community resour ce centres at satellite locations in urban slums Each centre will be developed in partnership with its surrounding community and health care providers, and staffed by two community mobilizers. With backing and support from a non-government organization hub, they will collect and disseminate health information, identify families at risk, make referrals to appropriate services and follow them up, coordinate community health promotion events, communicate with service providers, and promote interac tion between communities and providers. Design: Community resource centres will be set up in 20 randomly selected urban slum areas. Measures of maternal health and infant feeding, women s reproductive health, childhood nutrition and domestic violence will be made in these areas, and compared with similar measures in 20 areas that do not have resource centres.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: CpG as a genomic signalling module.
Funder: Wellcome Trust

Abstract: In the human genome, the sequence of DNA bases within genes encodes the structure of every protein. In addition to the genes themselves, however, genomes also contain instructions about when and where these genes are to be expressed. For example, short DNA sequences near the beginning of genes trap factors that drive synthesis of that particular protein product. Among the coded instructions in the genome, there is evidence that one very short sequence only two nucleotides long CG plays a sign aling role that depends on its local density and it degree of chemical alteration. Proteins that bind to different forms of CG appear to read the signal so as to adapt that genomic address for a specific function (e.g. gene activation or silencing). We will test this idea further by studying the function of CG clusters and of the proteins that bind to them.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigation of the PTB-dependent RNA operon that regulates cytoskeletal organisation and cell migration.
Funder: Wellcome Trust

Abstract: Protein synthesis is the process by which the information in genetic material, DNA, is converted via an intermediary substrate, mRNA, into functional proteins. Protein synthesis requires the interaction of mRNA with a large complex, the ribosome, which contains both RNAs and proteins. Ribosomes and their associated factors are able to decode the genetic information held in mRNAs and carry out the synthesis of the corresponding proteins. The coding portion of mRNAs is flanked by non-coding reg ions at the front (5'-end) and tail (3'-end). Several distinct mechanisms are used to regulate the process of protein synthesis. Interestingly, sequences present in the 5' and 3' non-coding ends of the mRNA (untranslated regions) often contain information that controls how efficiently corresponding proteins are made and where they are made in the cell. In this proposal we aim to study how mRNAs encoding proteins involved in cell migration are co-regulated.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Studies in Theophanes Chrysobalantes de curatione.
Funder: Wellcome Trust

Abstract: The main part of the project is an edition and translation of de curatione, a Byzantine medical text commonly attributed to Theophanes Chrysobalantes. It is a therapeutic handbook of around 400 pages in length that was central to the development of Byzantine medicine. The text is only accessible in an edition from 1794 which is based on a fraction of the manuscript copies known today. This text is also of particular interest because it was revised several times. The introduction to the monograph will examine why these revisions were carried out, and what the underlying medical theory was. It will also analyze whether these were linked to the revisions of other works. Moreover, it will provide an introduction to the therapeutical measures encountered in the text and to the way diseases were described. The emphasis will be on topics which cannot be found in Classical medicine. As a by-product, the project will yield a sizeable amount of new lexicographical material on Byzantine medical t erminology. Parallel to this, a website on Simon Ianuensis' clavis sanationis will be set up. It will contain a transcription of the text according to an early modern edition. Users can add commentary entries or ask questions.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanism and biological function of transcriptional termination.
Funder: Wellcome Trust

Abstract: The start of a process is often considered more significant than its end. However the end of one process may lead to beginning another or lead back to the start of the same process. Therefore ending can be seen to be of equal status to beginning. Such abstract considerations directly apply to the readout (expression) of genes along a chromosome that result in formation of all biological products that make up living organisms This initial gene readout is performed by a complex molecular machine called RNA polymerase which copies (transcribes) the gene into an RNA transcript that is in turn converted (translated) into the final protein product. We study the basic mechanism of gene transcription and how this gene reading process is stopped at the end of a gene, so called transcription termination. This mechanism is intricately controlled, as it has profound influence on both the expression of the particular gene as well as its gene neighbours along the chromosome. We address recent dev elopments in Genetics that show virtually all parts of the chromosome are transcribed, not only the protein encoding genes. The need to regulate and restrict these intergenic transcripts is again critically regulated by transcription termination.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Prioritization of sensory resources for action in the healthy and lesioned brain.
Funder: Wellcome Trust

Abstract: The dexterity of our physical interactions with our surroundings relies on our ability to extract accurate information from our senses, particularly vision. Although this process seems effortless, research has shown that the brain is very limited in how much sensory information it can deal with at one time. The aim of this project is to understand how these sensory limitations affect the accuracy of our movements, what the healthy brain does to compensate for them, and how this process can go wrong following a stroke. My key goals are to: Test a new description of how sensory information is stored in the brain for controlling movement, based on sharing out a limited memory resource Determine where the brain chooses to look, what it chooses to pay attention to, and what it stores in memory during movement, and develop a mathematical description of how these choices affect the accuracy of movement Examine the basis of these choices within the brain by studying the e ye and hand movements of patients with spatial neglect , a condition in which interactions with the left-hand side of space are impaired after damage to the right parietal lobe of the brain


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Multifunctional molecular machines acting on DNA: the XPD and XPB helicases.
Funder: Wellcome Trust

Abstract: All living things use DNA to store the information essential to make all the working parts of a cell and to reproduce. Complex molecular machines composed of proteins have evolved to copy DNA, transcribe it into RNA messages and repair damage. The mechanisms of these machines are not always well understood and they are often the targets for mutation leading to human disease. We wish to take advantage of a simple model system (a type of microbe known as archaea ) where these molecular machines a re related to the human version but are easier to study. In particular we are interested in two DNA helicases, XPD and XPB, which unwind DNA during transcription and repair and are essential for human health. We will determine how these proteins work at a molecular level, how they interact both with DNA and with other proteins to carry out their functions. We aim to gain an understanding of fundamental aspects of molecular biology and processes relevant to human health and disease. We will also learn about the biological processes used by the archaea, which are an important and very poorly understood component of the biosphere with key roles in global processes such as methane production.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Cross-species analysis of the function of a novel ribosomal prolyl hydroxylase.
Funder: Wellcome Trust

Abstract: For the body to function properly oxygen demands and supply must be accuratelymatched. Insufficiency of oxygen in cells and tissues (hypoxia) is a major component ofmany diseases including strokes, heart attacks, lung disease, anaemia, inflammationand cancer. Our laboratories aim to understand how cells "sense" and respond to hypoxia, how these pathways are altered in disease and whether it would be possible to design drugs that would alter these pathways to alleviate the effects of hypoxia. In previous work we have discovered enzymes (biological catalysts) that use oxygen to control gene expression pathways that regulate a wide range of adaptations to hypoxia. In this program we are aiming to understand how their chemical properties in the test-tube relate to their function in the cells of the body. We want to find out key properties such as the range and function of the proteins they target. This is necessary to plan how best to design drugs that would enhance protective as opposed to harmful responses to hypoxia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of zinc transporters in cellular zinc signalling.
Funder: Wellcome Trust

Abstract: Zinc is essential to support life, too little causes death and too much can be toxic. Molecules called zinc transporters move zinc across cell membranes to guarantee the correct amount of zinc in cells. Increasingly, aberrant levels of zinc, and the relevant zinc transporters, have been linked to a number of disease states including diabetes, neurodegeneration and a variety of cancers. This has generated a need to discover more detail of how they function in order to prevent their aberrant level s in disease states. These zinc transporters are complex molecules embedded in cell membranes which can be difficult to target in cells. However, I have just discovered that one key zinc transporter, ZIP7, is turned on and off by the association of another molecule, a kinase, in order to transport zinc. This is an exciting result which provides a means of inhibiting zinc transport as this particular kinase is easily inhibited by small molecule inhibitors which can move into cells and, important ly, have been well tolerated by patients in clinical tests. This project will investigate how kinases activate zinc transporters for ZIP7, other transporters and extending the investigation to encompass other cell types.


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