NIHRDataInsights/HRCSData huggingface dataset:
Title: The human body: its scope, limits and future.
Funder: Wellcome Trust

Abstract: We will develop research around the theme of The Human Body: Its Scope, Limitsand Future. Since the beginning of history, the human body has been the point of departure for understanding both ourselves and our relationship to nature and the wider universe. It provides a perspective, a unit of measurement, a reminder of our vulnerability and mortality, an ideal of beauty and of possibility, an image of success and of failure, of hope and of despair. It isthe central part of our understanding and our experience of who we are, in terms of our own identities, our relationships with others and our choices andconstraints. It has been the subject of traditions and taboos, art and science, of medical research and legal disputes, and today is subject to extensive external and self regulation. Our bodies are increasingly the focusof technological advances in medicine and science that challenge our ideas of what is natural and what can or should be subject to intervention. Building on established, dynamic research groups with diverse expertise, we will pursuenew research directions and, with the aid of a Wellcome Trust Strategic Award,we will make significant additional contributions to knowledge in bioethics, medical law and social science, as well as increase capacity for research and training, working towards a long-term strategy to consolidate and enhance the Institute's position as a major international, interdisciplinary centre of excellence in biomedical ethics with excellent collaborative networks.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: A new class of genes containing small Open Reading Frames: cellular and molecular function of the encoded peptides.
Funder: Wellcome Trust

Abstract: We have discovered a new type of gene, which we called tarsal-less. Its main novelty is that it gives raise to several small peptides with important function in development (including the development of the tarsus of flies, hence the name). These small peptides work as signals between cells. I propose to investigate the mechanism of action of these peptides: How they cross from cell to cell, and how, once inside the cell, convey a signal. I also propose to find out how many hidden genes like thi s one exists, and characterise several more. The interest of our research is that on the one hand, the type of signalling employed by tarsal-less might be conserved in humans; on the other, computer predictions suggest that hundreds of new genes like tarsal-less await characterisation in humans. They may also play important roles in development and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Southern Africa Consortium for Research Excellence (SACORE)
Funder: Wellcome Trust

Abstract: The key goals of SACORE are to develop and sustain a critical mass of local research scientists to be independent investigators and leaders capable of attracting competitive research grants. To achieve this we plan to improve research management and support capacity, introduce undergraduates to research, and stimulate research outputs at all levels of the research career pathway. This will be achieved through a number of interventions within the southern Africa region: 1. Developing south-south and strengthening existing north-south networks, through annual scientific meetings, mentorship, and joint PhD supervision. 2. Developing research leadership through mentorship of mid-level and senior scientists and by conducting relevant leadership and training courses. 3. Building a critical mass of research scientists, and research career pathways for them, through: a. competitive WT-SACORE PhD scholarships. b. competitive WT-SACORE post-doctoral fellowships. c. competitive WT-SACORE MSc scholarships d. providing competitive small research grants e. providing focus workshops to enhance research skills. 4. Consolidating career progression using professional development planning for all staff. 5. Establishing and strengthening Research Support Centres in the three low-income institutions including the provision of appropriate staff, equipment and skills and developing appropriate research governance and support frameworks. Importantly, the RSCs will pro-actively encourage and support scientists in their grant applications.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Factors that affect the regulation of splicing in Saccharomyces cerevisiae.
Funder: Wellcome Trust

Abstract: In most human genes the information (or code) in the DNA sequence is interrupted by non-coding regions called introns . An RNA copy of the gene has to be cut and then spliced back together to remove the introns and produce a continuous message with the correct information to produce a protein. In many cases, the message can be cut and put back together in different combinations giving rise to proteins with different functions. This means that the number of different proteins in a human cell c an be much greater than the number of different genes. Mistakes in the splicing of the RNA cause serious problems as defective proteins are produced, and this sometimes happens as a consequence of genetic defects or disease. The splicing machinery is highly complex and must be tightly regulated. We aim to understand how the many components assemble to form a functional machine and how its activity is controlled and monitored for accuracy. The RNA splicing machinery is highly conserved between ye ast and humans. We use yeast as a model organism as many powerful experimental techniques are available and it can provide important insights into splicing in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Sex, genomes, history: molecular, evolutionary and cultural effects on human genetic diversity.
Funder: Wellcome Trust

Abstract: We will use new sequence-capture technology and next-generation sequencing methods to analyse targeted segments of the X and Y chromosomes, and also a set of autosomal sequences, totalling ~4Mb in each of eight male great apes and ~20 humans. Key goals: Using these data we will infer signals of functional constraints and selection on gametologous (XY-homologous) and Y-specific genes, identify and understand the history of X-Y and Y-Y gene conversion events and conversion biases, and provide n ovel markers and variants to be analysed in population samples. In larger samples from specific human populations we will use custom SNP/PSV (paralogous sequence variant) and microsatellite typing to analyse the diversity of the sex chromosomes and autosomes. Key goals: Using population data we will illuminate the effects of social organisation and kinship rules on genetic structure; the roles of males and females in major demographic events, in particular the effects of Neolithic demic diff usion in Europe; and the demographic and sex-specific influence of cultural transitions in the British Isles and the Iberian peninsula. We will further understand gene conversion processes and the selective forces that act upon specific variants within and around gametologous and Y-specific genes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Centre of Excellence in Public Health Research.
Funder: Wellcome Trust

Abstract: Tackling the complex and inter-related root causes of public health problems requires systems approaches which recognize that the whole is often greater than the sum of the parts. More dynamic and effective relationships are needed between public health scientists, policy makers, practitioners and local communities, and a move away from an outdated linear model of passive knowledge transfer to one that recognizes that knowledge is both explicit and tacit, and generated by multiple stakeholders. Thus, the Queen's University Belfast (QUB) and the Institute of Public (Health in Ireland (IPH), in partnership with the Regional Health and Social Care Authority and the Community Development and Health Network, intend to establish a CoE for Public Health Science Research as part of a networked cluster of Centres across the country that will strengthen capacity for research and practice to improve the health of the UK population. The Centre will foster a multidisciplinary approach to research and training and the translation of research into policy and public health practice. The priority will be to use the unique opportunities that exist in Northern Ireland, with its distinctive approach to integrated health and social services and well connected civic and public sector structures, to research the social and biological causes of chronic disease and the main causes of inequalities in health experienced in the UK.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Establishing high-resolution electron cryo-microscopy in Edinburgh.
Funder: Wellcome Trust

Abstract: Edinburgh scientists are researching into fundamental processes such as how genes are switched on or off, the cell cycle, the molecular basis of diseases and how the body responds to infection. The multi-step mechanisms underlying each of these processes require a network of interacting molecules (proteins and nucleic acids), which often organize into larger complexes. These complexes act like molecular machines. To understand how these machines work, we need to know their blueprints. This infor mation is difficult to obtain by conventional methods, because often different copies of these machines vary in small details either because they are in motion or because they have extra modules that adapt their functionality to certain needs in the cell. Therefore, we want to use electron cryo-microscopy to image many thousand copies of these machines to reconstruct their common building principles. This requires a specially adapted electron microscope with a bright electron source and a large high-resolution detector, for which we seek support from the Welcome Trust. If successful, the detailed structural information obtained will reveal how these machines function and how structural changes can lead to defects in their functionality that lead to disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Bioimaging from single cells to organisms
Funder: Wellcome Trust

Abstract: We wish to understand the physiological mechanisms that control how the body works normally and also how it responds to disease conditions. Our research grouping has a particular expertise in processes associated with inflammatory stress (e.g., liver and kidney disease), cell plasticity (e.g., neuronal differentiation) and parturition (e.g., uterine activation with preterm labour). To really understand these situations we must be able to track the function of molecules that are crucial to thes e functions. And to do this we must be able to follow how they change in function with time, and where they move to in order to act in that time. We can do this with state-of-the-art bioimaging facilities that are requested in this application. This equipment will enable us to do several things: (i) To monitor incredibly fast (millisecond) molecular events that occur in isolated cells This will help us build up a picture of how normal or disease processes originate in particular cells of the body. (ii) to follow the movement of molecules or cells within and between the organs of whole animals. This will help us find out how processes starting in one part of the body can affect the wellbeing of the whole organism.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulating the redox conditions withn the mammalian endoplasmic reticulum
Funder: Wellcome Trust

Abstract: The proposed research will address three specific areas. Firstly we will determine how oxidative stress within the endoplasmic reticulum (ER) is regulated. Here we will focus on how the activity of the ER oxidases that are potentially responsible for the production of reactive oxygen species in the ER are regulated. Our goal will be to fully understand their mechanism of action so that we can predict how they contribute to oxidative stress. Secondly we will characterise the role of ER enzyme s in protecting the cell from alterations in redox status and ER-generated ROS. Our goal will be to identify and characterise key components that prevent excessive oxidative stress. Finally we aim to identify novel components that are involved in regulating the levels of the redox buffer within the ER and in sensing ER generated oxidative stress. Here our goal will be to develop methodologies to monitor cellular redox status and to use these tools to identify cellular proteins whose function is to maintain redox homeostasis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Single molecule tools for the analysis of biological reactions.
Funder: Wellcome Trust

Abstract: The purpose of this research is to study single molecules of RNA or protein as they participate in the very complicated cellular reactions involved in gene expression. Since these reactions cannot be reproduced with pure components, this is the only way to work out the order in which these components assemble together, the numbers of each involved in each complex and the changes in 3D arrangements during the reactions. Currently, single molecule methods are limited by the design of equipment or by the sensitivity or resolution of detection. I propose to collaborate with physical scientists to use new detection methods to follow assembly and conformational changes in real time, and to test the mechanical properties of the complexes formed. These methods will be applied initially to the study of RNA splicing, a key cellular process that ensures accurate maturation of messenger RNA and allows a surprisingly small number of genes to produce much larger numbers of proteins and to regulate t heir expression. This pioneering work will be followed by collaborations with biochemists following other complex reactions, such as regulated transcription.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Population genomics of the mouse.
Funder: Wellcome Trust

Abstract: The mouse is the leading model mammal in genetics and biomedical research, yet little is known about how variation in its genome translates to variation in reproductive fitness. This is important because the fitness effects of nucleotide variants are closely related to the nature of quantitative genetic variation, such as susceptibility to genetic disease in humans. We propose to study the population genetics of Mus m. castaneus, a highly variable subspecies from the ancestral range of the house mouse subspecies complex. We shall generate accurate, whole genome nucleotide polymorphism data for the genomes of a sample of wild-caught individuals. Using this data in conjunction with the mouse genome annotation and the rat genome, we shall apply new methods developed by the PI and others that analyse within population polymorphism and between species divergence to infer the fitness consequences of nucleotide variation. We propose to estimate the frequency distributions of effects of new mu tations for both coding and noncoding DNA, and the frequency of adaptive substitutions in the genome. We shall analyse the spatial correspondence between selected-site divergence and neutral diversity to estimate both the rate and strength of selection associated with selective sweeps.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Dynamic multiprotein complexes - insights from mass spectrometry.
Funder: Wellcome Trust

Abstract: Using state-of-the-art mass spectrometry approaches we will study two assemblies that are critical for the survival of cells: (i) the eukaryotic translation initiation factors complex that coordinate the sequential assembly of ribosomes, mRNA and tRNAi, and (ii) ATP synthases, the membrane complexes responsible for supplying energy for all cellular processes. The multifactor complex has been subjected to extensive study but due to its anticipated dynamics and heterogeneity structural information at the molecular level has not been forthcoming. By contrast ATP synthases have been studied at length, with some parts of the complex having been revealed in atomic detail. Using our combined approaches of disruption to form subcomplexes and so generate interaction maps, and ion mobility to assess the conformation of the resulting building blocks, we will produce detailed architectural models of both complexes. In the case of the multifactor complex, we anticipate that we will achieve this in advance of detailed structural information. For ATP synthases we will deduce the stoichiometry and interactions within the overall assembly from different species. Due to a recent, dramatic breakthrough we will assess interactions between membrane and soluble parts of intact ATP synthases under the same experimental conditions enabling study of their synergy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Genetics of the people of the british isles and their faces.
Funder: Wellcome Trust

Abstract: Who are the British people? Where did they come from? How does the genetics match up to the history? These are the questions we intend to answer. We are adding to our 3,500 samples (from rural areas, all four grandparents from the same area) by collecting another 1,000 samples from the Ancient British western fringe, and from the eastern areas that reflect the Anglo-Saxon influx. We will also collect 1,500 samples from countries surrounding the British Isles. All samples will be extensively ch aracterised for genetic markers chosen because they vary most in frequency between different parts of the UK. The extraordinary similarity between the faces of identical twins tells us that facial features are mostly inherited. Genetic markers for the face are expected to be amongst the most variable in frequency. We will find them by looking for associations between genetic markers and facial features identified from photographs. From a detailed statistical analysis of the genetic marker fre quencies we will be able to sort out the contributions, for example, of Ancient British and Anglo Saxon origins to different parts of the UK population. This detailed information also makes a valuable contribution to the study of disease susceptibility.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A 500 MHz NMR spectrometer to underpin biological and medicinal chemistry research in the Department of Pharmacy and Pharmacology.
Funder: Wellcome Trust

Abstract: The Medicinal Chemistry section of the 5* graded Department of Pharmacy and Pharmacology is comprised of ten research groups, with over 50 PhD students and Post Doctoral research officers. The research in the section is diverse, with interests in, but not limited to, novel treatments for HIV, influenza (Avian Flu), tuberculosis, Alzheimer s disease and cancer, in addition to projects in cell signalling, new methods of drug delivery, anti-inflammatory drugs, and opioid receptor blockers (designed as treatments for drug abuse). NMR spectroscopy is the primary tool for the elucidation of chemical structure, allowing the characterisation of new substances. The NMR service operates with an ageing Jeol 270 MHz spectrometer and a more modern Varian 400 MHz spectrometer, and is heavily over-subscribed, with long delays for sample turn-around despite day and night usage. The equipment requested will allow a much more rapid analysis of chemical samples and the opportunity to characterise sampl es where only a small quantity is available, as is typically the case. The new instrument will also give access to new experimental methods which will allow novel approaches to be used to investigate the properties of the chemical substances prepared in the department, enhancing our discovery of new drug molecules.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanism of exosome activation by the RNA-binding protein Rrp47.
Funder: Wellcome Trust

Abstract: A major objective is to catalogue the RNAs processed or degraded by Rrp6/Rrp47. We will develop a cross-linking and sequencing technique, involving RNP affinity purification, cross-linking, limited nuclease degradation, RT-PCR and massive parallel signature sequencing. Substrate RNPs in lysates will be stabilised by using catalytically inactive rrp6-1 strains. After validation by RT-qPCR, the steady state levels and 3 ends of identified transcripts will be analysed in total RNA from rrp47 and rrp6 mutants. The second key objective addresses how Rrp47 binds RNA. Identified RNAs will be screened for common contextual or structural features and the latter will be validated using binding assays. Rrp47 mutagenesis studies will map regions required for RNA binding in vitro and assess their impact on protein function in vivo. The third key objective will be to determine how Rrp47 promotes Rrp6 activity in vitro, using both recombinant proteins and purified exosomes. Mapping studies will define the regions/residues within Rrp47 and Rrp6 required for stimulation and these will be correlated with characterised biological activities. Photoactive cross-linking studies will be used to test for Rrp47-mediated substrate presentation. We will also address how Rrp6 stimulation by Rrp47 is affected in the presence of the TRAMP complex.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The influence of non-coding RNAs on chromatin structure in budding yeast.
Funder: Wellcome Trust

Abstract: The last fifty years of biological research has focused on genes that encode proteins that perform biological functions. RNA, the primary product of a gene, was thought of as an intermediary, but recent studies show the majority of genes produce RNA which does not code for proteins (non-coding RNA or ncRNA). The aim of this research is to understand what this RNA does. Enzymes that modify DNA must be recruited to precise sites, for example to copy, cut and paste segments of the genome. This process, recombination, is required to maintain and repair the genome, but must obviously be tightly controlled. Recombination is also vital during the production of sperm and eggs to mix parental genetic traits. Data I have obtained suggest RNA quality control proteins link ncRNAs to recombination. I suggest that ncRNA controls recombination by directing recombination enzymes to particular regions of DNA, a hypothesis I will test in this research. Other ncRNAs can influence protein codin g genes, but few have been studied. I will analyse a class of these ncRNAs to find general principles for their action, which is important as gene therapy to target ncRNAs would increase the range of disorders that such therapies can tackle.


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