NIHRDataInsights/HRCSData huggingface dataset:
Title: Early cell fate decisions and cell positioning in the mouse embryo.
Funder: Wellcome Trust

Abstract: I propose three complementary approaches to study how early events can help to specify polarity of the mouse embryo. I first propose to study developmental cues in the egg whose animal-vegetal polarity dictates one axis of the future blastocyst, and the position of sperm entry determines the second axis. The sperm entry position sets the first cleavage plane and conveys a division advantage upon the cell inheriting it. I will investigate the cytoplasmic events underlying these two consequences of sperm entry and test their relative importance in establishing the embryonic abembryonic polarity of the blastocyst. I also propose to study why, although the animal pole of the egg can be removed without affecting development, its duplication is inhibitory. Secondly I will combine lineage tracing and transplantation studies to ask how polarity of the blastocyst, set up by the above processes, is transformed to give organised signalling centres in the postimplantation embryo. My focus will be to discover the origins of visceral endoderm with potential to signal to the epiblast of the egg cylinder. To determine when such signalling centres become active, I will first concentrate on transplantation experiments that test the ability of anterior visceral endoderm precursors to repress posterior gene activity. The extent of such experiments could be broadened by better knowledge of the patterns of gene expression from the blastocyst onwards. The third part of my proposal aims to identify genes that are expressed asymmetrically along axes of the blastocyst and/or at the earliest times within postimplantation signalling centres or their progenitors. My attention will centre upon finding genes that are differentially expressed in the animal and vegetal halves of the blastocyst or become uniquely expressed in progenitors of anterior visceral endoderm. These will be identified through the construction of subtractive cDNA libraries and by screening microarrays. I will select genes with expression patterns likely to be meaningful in the development of signalling centres and examine the consequences of both their ectopic expression and loss of expression using dsRNAi. In the longer term I propose to analyse how the patterns of expression of these or other genes are rebuilt following perturbation of development. Thus not only do I hope my work wil contribute to a molecular understanding of how asymmetries are established and transmitted to later stages of the embryo in normal development, but also will provide insight into the remarkable regulative properties of the mammalian embryo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A Q-Exactive for high throughput proteomics
Funder: Wellcome Trust

Abstract: My research programme is aimed at understanding how the nucleus is organised in mammalian cells, how specific subnuclear bodies are assembled and regulated and how nuclear structure is related to biological function and to human molecular disease. A major theme of the programme is to use a combination of quantitative in vivo and in vitro techniques to measure dynamic processes in the cell nucleus. To achieve these aims we will focus primarily on studying the dynamic properties of the nucleolus and the nuclear organisation and function of the pre-mRNA splicing machinery. We will also study the role of reversible protein phosphorylation in regulating both nucleolar interactions and the splicing mechanism. We will compare data derived from biochemical experiments carried out using nuclear extracts prepared from cultured cell lines with data on the movement and interactions of proteins in vivo in the same cell lines. We will use proteomic methods to analyse and quantitate the protein composition of nucleoli under different growth and metabolic conditions and we will characterise dynamic interactions in live cells by imaging Fluorescence Protein-tagged fusion proteins. In parallel, we will analyse the organisation and structure of nuclear factors in both transformed and normal human tissue, derived from patient biopsies, to maximise the opportunities for our work on the cell biology of the nucleus to enhance clinical practice.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: WELLCOME TRUST CENTRE FOR STEM CELL RESEARCH
Funder: Wellcome Trust

Abstract: The new Institute for Stem Cell Biology in Cambridge will be an international centre of excellence in fundamental stem cell research. The Institute will focus on definition of the genetic and biochemical mechanisms that control stem cell fate, providing foundations for applications in disease modelling, drug discovery and regenerative medicine. This proposal is for provision of core resources for embryonic stem cell manipulation and transgenesis. A central resource of skilled personnel will maximise research productivity and continuity, promote cooperation and synergy, and accelerate technological innovation. Timely and efficient production of customised gene-modified stem cells and mice is essential underpinning. Specialised expertise will support advanced genetic engineering of mouse and human stem cells, and operation of robotic platforms to develop screening methodologies for isolating genetic, protein and chemical regulators. A dedicated PdD programme in stem cell biology will capitalise on the opportunity for high level research training provided by the intellectual environment and core facilities in the Institute. A Strategic Award will immediately establish the Institute for Stem Cell Biology amongst the best-resourced and most attractive environments for stem cell research world-wide, providing a magnet for recruitment, and a much-needed focus for UK and European stem cell biology.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of cell polarity and mRNA localisation in the Drosophila oocyte.
Funder: Wellcome Trust

Abstract: The anterior-posterior axis of Drosophila is determined by the localisation of bicoid and oskar mRNAs to opposite poles of the oocyte, and provides an excellent system to investigate the conserved mechanisms of cell polarity and mRNA localisation. 1) We plan to screen the whole genome for mutants that affect the localisation of fluorescently-labelled bicoid and oskar mRNAs in living oocytes, in order to identify genes required for oocyte polarity and the localisation of each mRNA 2) The recruitment of the PAR-1 kinase to the oocyte posterior is the first sign of anterior-posterior polarity. We will characterise a number of genes required for this localisation, and use a proteomics approach to identify proteins that interact with PAR-1 in vivo. 3) Since PAR-1 regulates the organisation of the microtubule cytoskeleton, we will perform biochemical screens for PAR-1 substrates that associate with microtubules, and analyse several candidate proteins identified by genetic screens and bioinformatics. 4) We will characterise the components of the oskar mRNA and bicoid mRNA localisation complexes using genetic and proteomics approaches, and will visualise their localisation in vivo. 6) We will develop an oskar mRNA in vitro motility assay to determine how the motors that move it are regulated.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Hospitals and the Development of Modern Medicine in Iran from the Early Nineteenth Century until the Beginning of the Second World War.
Funder: Wellcome Trust

Abstract: This project studies the development of modern medicine in Iran from the early nineteenth century until 1941. In the nineteenth century medical modernisation was part of military modernisation and the first modern hospital was for the troops. Throughout the nineteenth century, Western influence as well as internal socio-political dynamics led to the Constitutional Revolution (1906-11) that aimed to curtail the unlimited power of the authoritarian Qajar shah. Medical modernisation during this pe riod consisted of expanding medical provision for society at large, and the military was no longer the sole purpose of, or impetus for, developments in medicine. Consequently, while in the nineteenth century there were only a few hospitals mainly for the army, in the twentieth century the number of the civilian hospitals increased greatly. Even the charitable endowments that previously were mostly devoted to mosques and religious colleges became increasingly available for civilian hospitals.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining the role of primary cilia in development and disease.
Funder: Wellcome Trust

Abstract: Cilia are tiny appendages that sit atop most cells in our body. Dismissed as vestiges of a bygone function, cilia are undergoing a renaissance owing to recent discoveries ascribing a sensory role. They are like cellular antennae taking cues from the local environment. We discovered that the debilitating Bardet-Biedl syndrome (BBS) is caused by poorly functioning cilia and have recently demonstrated that many of the BBS genes have a role in fundamental processes that govern development of structu res such as the face, brain, genitalia, kidneys and limbs. One aim is to understand why deficiency of BBS proteins has such devastating consequences such as blindness, mental retardation, obesity and kidney failure. Through observation of patients and mice with BBS we have predicted other diseases arise from dysfunctional cilia.One of these is Jeune syndrome, where the majority of infants die from respiratory failure secondary to a poorly developed rib cage. Having now discovered the first ge ne for JS, we aim to investigate its role in disease by generating knockout mice with the same condition. Finally, we have discovered we can prevent kidney cysts forming in BBS and JS zebrafish using adrug, rapamycin, paving the way for potential treatments in humans.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigation of the functions of variant histone H2A.Z acetylation .
Funder: Wellcome Trust

Abstract: The human body is made up of a wide variety of cells that are highly specialised despite containing exactly the same DNA sequence. Now that the human genome has been sequenced, a major challenge is to understand how the same DNA instructs the building of different cell types. Cells become specialised by regulating gene expression and diverse cell types express different subsets of genes. - e.g. genes that code for neurotransmitter receptors are switched on in brain cells while genes coding for digestive enzymes are switched off. My proposed research focuses on how the packaging of DNA into chromosomes impacts gene expression through the study of one chromosomal component, a variant histone known as H2A.Z, using yeast as a model system. Important cellular processes are almost identical in humans and yeast, so that my findings in yeast will be applicable to humans. The goal of the project is to investigate how the functions of H2A.Z can be altered through adding small chemical group s to the protein. The research aims to discover whether H2A.Z modification is necessary for cell division and gene expression, processes that are essential for normal growth and development.


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

Abstract: The precise control of potassium ion movement across the plasma membrane of cells is essential for the regulation of body function and dysfunction of this process leads to major disease states such as high blood pressure, epilepsy and diabetes. Many different types of potassium selective protein pores (ion channels) are required to allow this precise control in different cell types. A major mechanisms for controlling the properties of these potassium channels is through alternative splicing a mechanism by which a single gene can express multiple variants of a protein with different properties. The aim of this work is to understand how splicing changes the properties of Big potassium (BK) channels and the role BK channels play in controlling the body s response to stress. To address these issues, we will examine the properties and regulation of single BK channels, examine how they control the excitability of cells and understand how they control the stress response using mice in w hich the expression of the BK channel has been manipulated. Understanding the properties and function of these important channels in the stress response will provide important new insights into human physiology and stress-related diseases such as depression and obesity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Delineation of the signalling pathways that direct cellular differentiation in Dictyostelium.
Funder: Wellcome Trust

Abstract: Dictyostelium cell-type differentiation is best understood for the pstO cells where at least four transcription factors, STATc, DimA, DimB and MybE, are involved. Three of these, STATc, DimA and DimB, are activated by DIF and my central goal is to understand how DIF functions. Our recent evidence suggests that DimB is directly activated by a ser-thr kinase while STATc is indirectly activated by the ser-thr phosphorylation and inactivation of PTP3: a protein tyrosine phosphatase. These "proximal" ser-thr kinase(s) will be identified and the mechanisms of nuclear translocation of DimB and inactivation of PTP3 elucidated. The proximal kinases will be genetically ablated and the phenotypic consequences determined. The program's major aim will be to delineate the upstream signalling pathways that regulate the proximal kinases; because tracing these pathways should reveal the mechanism of action of DIF. Delineation of the DIF signalling pathways is fundamental to understanding prestalk-prespore divergence but we also need to understand how prestalk cell heterogeneity is generated. Hence, at a lower priority, the pstA specific sub-region of the ecmA promoter and the ecmB promoter sub-regions that direct its expression will be dissected and the transcription factors that bind these regions will be identified.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Health care in public and private.
Funder: Wellcome Trust

Abstract: The research focuses on aspects of the interplay between public, private and philanthropic sectors in the development and patient and practitioner experiences of British, European, African and South American healthcare systems, 1650-2006. Specific projects address: The development of political, patient and professional perceptions and expectations of publicly versus privately funded healthcare. The role of philanthropy in the development and patient experience of the mixed economy of he althcare. The experience and negotiation (by patients and practitioners) of the porous boundaries between public, private and philanthropic sectors. Relationships between a particular configuring of healthcare resources and the mainstreaming or marginalisation of patients. Institutions and the public and private spheres. Eugenics and medical responsibility. The goals of the Strategic Award are to: Deliver published results that can advance our theoretical or empirical underst anding of the interplay of public and private in the mixed economy of healthcare. Establish the Centre for Health, Medicine and Society as a forum for discussion of the historic dimensions of public and private healthcare. Use the research generated by the projects to underpin a substantial programme of public engagement and to foster interaction with participants in modern policy discussions.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Chemical biology, inositol polyphosphates and cell signalling.
Funder: Wellcome Trust

Abstract: We aim to apply tailored synthetic small molecules in investigative biology. Different cells must communicate within an organism, often via chemical messengers such as hormones and neurotransmitters. These first messengers operate outside target cells, often interacting with a molecular antenna or receptor to transmit a message into the cell. Second messengers , released as small molecules inside cells, then carry the signal to internal target proteins. The three-dimensional structures of t hese proteins are increasingly known, allowing design of lock-and-key type interactions with novel synthetic molecules, unknown to Nature. There is intense interest in such cell-signalling pathways, because they are ubiquitous and their malfunction underlies many diseases. We are particularly concerned with a cellular second messenger, InsP3, produced in response to many external stimuli. We have devised methods to change the molecular structure of InsP3 and related molecules as well as to tag them with fluorescent labels to allow visualisation. Such analogues , unavailable to standard biology, can behave in novel ways and be useful tools to help understand how signalling molecules are recognised by their protein targets, and may even lead to future drugs. This programme will use chemistry to produce redesigned signalling molecules and explore the biological consequences of their application.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Assembly and disassembly ESCRTs on membranes.
Funder: Wellcome Trust

Abstract: Receptors on the surface of cells are central to how cells respond to signals such as growth factors, hormones and neurotransmitters. The cell can tone down these responses by removing the receptors from the cell surface and degrading them in lysosomes. This involves a remarkable molecular gymnastics of internal membranes, leading to inward membrane budding, which is controlled by four large complexes of proteins known as the ESCRT complexes. Some viruses such as HIV hijack this machinery to enable the virus particles to bud out of cells. Our goal is to determine how the ESCRT machinery assembles itself on membranes and how the ATPase machinery disassembles these complexes once they have served their purpose. Our central approach is to study the architecture and function of this molecular machinery in its simplest form by reconstituting it in laboratory in a cell-free form.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A randomised cluster controlled trial of community level interventions to address social and structural determinants of physical activity, diet and mental well being.
Funder: Wellcome Trust

Abstract: We are seeking funding to measure effect and cost effectiveness of Well London: a complex 3.5 year intervention to promote healthy physical activity (HPA), healthy eating (HE), and mental health/well being (MH) in 20 of London s most deprived communities, delivered with 9.42m funding from Big Lottery. Well London is Greater London Authority s flagship project on health, supported by NHS London and 20 PCTs and Boroughs across London. Communities will participate in designing, delivering and eva luating interventions to meet their needs. We have chosen intervention communities (where Well London will deliver the intervention) by asking each of 20 Boroughs/PCTs to select two deprived communities as candidates, and selecting one at random; unselected being the comparison or control community). We will compare measures of HE, HPA and MH between Well London and control communities before health promotion activities have started, and after four years. The evidence obtained will be import ant to guide policy because diseases associated with HPA, MH and HE account for almost 40% of disability adjusted life years lost (a measure of the burden of disease) and around 14 billion of direct costs to the NHS. They also account for much health inequality between London s communities


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechansim, control and diversity of molecular motors on DNA.
Funder: Wellcome Trust

Abstract: The genetic blueprint held in the DNA in your body is not dormant; it is constantly being processed and manipulated by microscopic machines comprised of protein molecules. A great many of these proteins consume chemical energy (in the form of a compound called ATP) and convert it into mechanical events. These activities can be viewed as being remarkably similar to the macroscopic machines with which we are all familiar for example, some proteins are motors that move along DNA much like trains along a track. How then do these motors work? How are the activities of the motor linked to the other activities that the machine must undertake? What are the different motor mechanisms that these proteins have evolved? And how are they controlled so that they don t become runaway trains? Even more surprisingly, many of these motors can act like molecular scissors that can cut through the very track they are moving on. Since breaks in the track are dangerous to cellular health, how is this activ ity controlled in relation to the motor activity? In this project we will answer these questions so that we can better understand these molecular machines that are fundamental to life on earth.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Chromatin proteomics: from method development to biological insight
Funder: Wellcome Trust

Abstract: In all organisms proteins are at the centre of most cellular processes. Proteins rarely act alone but form complexes of all sizes and properties. The function of each protein can only be understood as part of the complex. Currently, there is no general tool that makes these protein interactions accessible to our observation. High-resolution structures give this information and can be obtained as a result of intense work. However, few soluble protein complexes exhibit the requirements to be studi ed in this way. The large group of insoluble protein complexes is almost entirely excluded from structural investigations as a result of being located on solid structures like chromatin, membranes, and the cytoskeleton. We hypothesize that there is technology within our grasp that reveals the information about which proteins interact with each other and what parts of these proteins make contact. We would like to develop this technology and apply it to a large and insoluble protein complex that i s beyond even the most daring dreams using current technologies.


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