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Earliest award date
22 Feb 2017
Latest award date
28 Nov 2017
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Principles of human development and germ cell program
<p>Specification of human primordial germ cells (hPGCs)&nbsp;occurs around gastrulation, a critical juncture when the specification of the primary somatic lineages&nbsp;also occurs. In combination with human preimplantation embryos, in<em> vitro</em> models and hPGCs from aborted fetuses, our objective is to elucidate the origin and properties of the early human germline.</p> <p>For&nbsp;the mechanism of the hPGC fate, we will use experimental models that simulate early human development. We aim to investigate how cells gain competence for&nbsp;germ cell fate, and then respond to combinatorial effects of the critical transcription factors, which induce hPGC specification.&nbsp;Altogether, this study will&nbsp;reveal the organisation of the very early human embryo, and mechanisms of hPGC and somatic outcomes, which is essential for advances in regenerative&nbsp;medicine.</p> <p>Following hPGC specification, epigenetic resetting of the early human germline leads to extensive erasure of DNA methylation and epimutations&nbsp;in response to the critical regulators&nbsp;of chromatin organisation and nuclear architecture&nbsp;towards the epigenetic ground state. &nbsp;Some conserved resistant loci ('escapees') evade reprogramming. &nbsp;We will explore if some escapees have been exapted&nbsp;to function as&nbsp;regulatory elements. &nbsp;If so, this&nbsp;may have a crucial influence on&nbsp;human development, including brain development and neuronal diseases.</p> <p>&nbsp;</p> <p>&nbsp;</p>
Amount: £2,750,000
The chemical biology and function of natural modified DNA bases in genomes
<p>I aim to elucidate the function of natural, chemically-modified DNA bases in the genomes of model organisms, using chemical&nbsp;biology and physical science approaches on genomic DNA. Modified bases are of fundamental importance to transcriptional programming and cell identity during and after development. The role of the cytosine derivative 5-formylcytosine and its influence on nucleosome formation, active enhancers, transcription and cell identity will be one area of focus to build mechanistic understanding, following on from hypotheses derived from our prior work. There will also be an investigation of 5-carboxycytosine&nbsp;and 5-hydroxymethyluridine and their potential links with transcription regulation.&nbsp; For other modified bases, such as N6-methyladenine, we will develop and use new chemical mapping/sequencing methods to elucidate their function in mammalian systems. The programme will include a systematic discovery of other&nbsp;natural DNA base modifications, building on and augmenting chemical methodologies I have developed to discover and profile modified bases in RNA.&nbsp; The function of newly identified base modifications will be investigated during the programme. The insights provided from these fundamental studies may have far-reaching consequences for normal biology and disease states.</p> <p>&nbsp;</p> <p>Keywords: chemical biology, nucleic acids, DNA, modified bases, epigenetics, sequencing</p>
Amount: £2,198,391
Development of likelihood-based methods in structural biology
<p>I propose to build on our development of new likelihood-based methods for structural biology, transposing approaches that have had great impact in macromolecular crystallography to the new area of cryo-EM.&nbsp; 1) In crystallography we will enable the solution of difficult structures (poor data or poor starting models) that still evade current methods.&nbsp; New statistical innovations will automate the clustering of alternative molecular replacement models into sensible ensembles representing different conformations. &nbsp;2) We will exploit a promising new approach to the determination of substructures for SAD phasing, based on our SAD likelihood function.&nbsp; 3) In cryo-EM we will investigate the propagation of errors in reconstructions, building on this understanding to devise improved likelihood-based methods to dock atomic models into cryo-EM maps, particularly those challenging cases determined at low resolution such as sub-tomogram averages.&nbsp; The implications of multi-variate cryo-EM likelihood targets will be explored, with potential applications in the angular deconvolution of cryo-EM maps.&nbsp; 4) Finally, we will develop a new approach to modelling macromolecular structures at low resolution, using interactive molecular dynamics flexible fitting to combine high-quality potential functions with likelihood targets.</p>
Amount: £1,916,285
Molecular mechanisms of alternative splicing regulation
<p>Alternative pre-mRNA splicing (AS) is a widespread regulatory mechanism enabling individual genes to generate multiple protein isoforms. We have investigated the mechanisms controlling AS events that are regulated during the transition of smooth muscle cells (SMCs) between contractile and proliferative phenotypes. We have shown how the widely-expressed RNA binding proteins (RBPs) PTBP1 and MBNL1 regulate SMC splicing events. Recently, we identified RBPMS as a potential &ldquo;master&rdquo; regulator of SMC AS. RBPMS is sufficient to switch AS events to the SMC pattern and its activity is strongly modulated by its own AS and by phosphorylation. Critically, RBPMS is sufficient to switch AS to the SMC pattern <em>in vitro</em>. This offers a unique opportunity to determine the molecular anatomy of regulated splicing complexes. We will carry out detailed mechanistic analyses of RBPMS-regulated splicing using a combination of biochemical, proteomic, single-molecule, and structural approaches including Cryo-EM. We will identify critical regulatory interactions between regulatory RBPs and core splicing factors, and test their importance by genome editing and mRNA-Seq. In a complementary aim, we will investigate how peptide-ligand interactions equip PTBP1 to regulate AS and a range of other post-transcriptional processes, and whether a family of such peptide-mediated interactions extends to related RBPs.</p>
Amount: £1,503,005
A multi-disciplinary approach to understanding and improving hearing by cochlear implant users
<p>Cochlear implants (CIs) restore hearing by electrically stimulating the auditory nerve. This allows many CI users to understand speech well in quiet, but even the most successful have poor pitch perception and struggle in noisy situations. We believe there are two main reasons for these limitations.(i) Although it is possible to elicit different pitches by stimulating different electrodes, the selectivity of this &quot;place-of-excitation&quot; cue is much worse than in normal hearing (NH). (ii) It is also possible to increase pitch by increasing the pulse rate applied to each electrode, but use of this temporal cue is also much worse than in NH.&nbsp; We will study both of these limitations by performing analogous experiments in cats and humans, using some of the same measures in the two species. This will allow us, for the first time, to link the limitations that occur perceptually to their underlying physiological bases, and to do so even for novel stimulation methods that are not possible with existing clinical CIs. The knowledge gained wiill allow us to propose and test modifications both to implant design and audiological practice.</p>
Amount: £1,727,476
Institutional Translation Partnership Award (iTP A): University of Cambridge
The University of Cambridge is committed to achieving excellence in research and scholarship and ensuring that our research contributes to the wellbeing of society. The Cambridge bioscience cluster is the largest outside of the US, and third largest in the world, which, together with our multidisciplinary research strengths indicates tremendous potential to further build on the translational biomedical research activity at the University. The aims in working with the Wellcome Trust iTPA are to stimulate the translatable ideas pipeline across the breadth of relevant research at the University of Cambridge, and enable the early collaborative partnerships (industry and/or clinical medicine) that are essential in successful delivery of translational biomedicine. There will be an initial focus on chemical biology and resource will be deployed to conduct translational workshops, provide Cambridge scientists with flexible support and access to medicinal chemistry experts and bring together cross disciplinary and cross sector groups via challenge-led workshops. This will be complemented by a proof of concept funding scheme which will focus on funding cross-disciplinary collaborative projects.
Amount: £1,000,000
21st Century Families: Parent-child relationships and children's psychological wellbeing
<p>New pathways to parenthood have recently emerged that did not exist, nor had even been imagined, at the turn of the 21<sup>st</sup> century. Individuals who were previously unknown to each other have begun to meet over the internet with the purpose of having children together; transgender men and women have begun to have children through medically assisted reproduction; single heterosexual men have begun to use surrogacy to become single fathers by choice; and women have begun to use identifiable egg donors to have children. These emerging family structures raise new ethical, social and psychological concerns, particularly regarding the potentially negative consequences for children. The proposed research will provide empirical evidence from a multidisciplinary perspective on the social and psychological consequences for children of growing up in family arrangements involving non-cohabiting co-parents, transgender parents, elective single fathers and identifiable egg donors. In this emotive area of family life on which people often hold strong opinions, our aim is to challenge prejudice and assumption with evidence on the actual consequences &ndash; good, bad or neutral &ndash; for children. The ultimate goal of the proposed research is to increase understanding of diversity in family life and improve the lives of 21<sup>st</sup> century children.</p>
Amount: £1,552,401
In vivo mechanisms of epithelial tissue morphogenesis
<p>Understanding how a tri-dimensional tissue is built from the genetic blueprint is a key frontier in biology. In addition to genes known to be important in specific aspects of morphogenesis, physical constraints and properties play a major role in building tissues. In this proposal, I aim to understand how the genetic inputs integrate with the mechanical properties of the cells and tissues to produce form. To investigate this, we study the early development of the <em>Drosophila</em> embryo. We have found previously that actomyosin-rich boundaries play an important role in two fundamental and conserved morphogenetic phenomena, axis extension and compartmental boundary formation. We have also found that an extrinsic force contributes to axis extension. We will build on these findings by first investigating how the actomyosin-rich boundaries form and how they might repair genetic patterns during axis extension. Second, we will ask how, during compartmentalisation, they control the planar orientation of cell division and also epithelial folding. Finally, we will examine the impact of actomyosin-rich boundaries and extrinsic forces on epithelial tissue mechanics. Our approaches will be interdisciplinary, combining genetic, quantitative and&nbsp;<em>in silico&nbsp;</em>analyses&nbsp;to find novel and universal morphogenetic rules.</p>
Amount: £1,440,082
Biomechanics of Ciliated Tissues
<p>Many of the paradigmatic events in embryonic development involve geometric or even topological rearrangements of tissues in response to mechanical forces generated within them. While these processes are familiar and much studied from genetic and biochemical perspectives, there is a striking contrast between the great depth of such biological detail and the glaring lack of quantitative <em>mechanical</em> understanding of the forces and responses involved. &nbsp; We propose to close the theory-experiment loop in specific, carefully chosen examples of these problems, to gain a quantitative understanding of the underlying biomechanics. &nbsp;We seek to solve three outstanding problems: (i) the link between cell shape changes and cell sheet morphology as found in gastrulation, neurulation, and related problems in embryogenesis; (ii) the mechanism of generation of cilia orientational polarity in tissues; (iii) the origin of metachronal wave formation in carpets of cilia.&nbsp; The research will combine state-of-the-art light-sheet microscopy, micromanipulation, high-speed imaging and microfluidics with emerging theoretical tools for understanding complex geometrical transformations of tissues and the stochastic nonlinear dynamics of eukaryotic flagella.</p>
Amount: £1,656,325
Entry, innate sensing and replication of enteropathogenic caliciviruses.
<p>Our overarching aim is to gain insights into the biology of enteropathogenic caliciviruses,&nbsp;focusing on the fundamental aspects that have remained elusive to date: &nbsp;viral entry into target cells, the interplay with the host innate response and the recruitment of host-cell co-factors that support replication.&nbsp;&nbsp;<strong>Having significantly improved the culture systems for human noroviruses and developed reverse genetics, we now have the first opportunity to study human norovirus replication in a physiologically relevant system.</strong> We will focus on three areas:</p> <p>&nbsp;</p> <p><strong>1.&nbsp;C-type lectin receptors (CLRs)</strong>: We have found that CLRs may work in concert with blood group antigens to allow norovirus infection.&nbsp;We will further dissect the role of CLRs in the norovirus life cycle.</p> <p>&nbsp;</p> <p><strong>2. Innate responses to infection</strong>: We have found that type I/III interferons&nbsp;restrict norovirus replication but&nbsp;that infection induces the COX-2/PGE pathway to promote replication. We will dissect the response to infection in the organoid system and characterise a novel virus-encoded regulator of the NF-kB system.</p> <p>&nbsp;</p> <p><strong>3. Trans-acting factors:</strong>&nbsp; We will examine their role of a number of host factors (VapA/B, Squle&nbsp;and PI4Kalpha) in norovirus replication and expand this study to an undertake an unbiased analysis of the human norovirus replication complex.&nbsp;</p>
Amount: £2,204,335
Mechanisms of epithelial polarity in flies and mammals
<p>Apical-basal polarity is essential for all aspects of epithelial cell function and loss of this polarity is a hallmark of cancer. We have recently found that the endodermal epithelium of the <em>Drosophila</em> adult midgut polarises by a different mechanism from other <em>Drosophila</em> epithelia and may provide a good model for endodermal epithelia in mammals. This proposal aims to understand how polarity is generated in both epithelial types. Firstly, we will examine how the canonical polarity complexes polarise the secretory epithelium of the <em>Drosophila</em> follicle cells. We will investigate how Cdc42 is activated to define the apical domain; we will use optogenetics and super-resolution microscopy to investigate the dynamics and composition of polarity complexes; and we will analyse how cortical polarity organises the microtubule cytoskeleton through the lateral polarity factor, Par-1. Secondly, we will perform clonal screens to identify essential epithelial polarity factors in the <em>Drosophila</em> midgut and characterise their functions. To test whether these factors play conserved roles in mammals, we will knock out their orthologues in mouse intestinal organoids. This research will reveal the fundamental mechanisms that polarise different epithelial types, which is an essential prerequisite for understanding epithelial function and how it is perturbed in diseases like cancer.</p>
Amount: £3,611,874
Whole genome sequence based analysis of genetic variation and genome evolution
<p>DNA sequencing is a core technology for modern biomedical science, and our ability to sequence genomes with ease and use that information efficiently is still unfolding. I propose first to build new bioinformatics data structures and software to map sequence data, call genetic variants, and integrate phasing and imputation, scaling to millions of samples with high accuracy and making best use of new long read sequencing technologies. These will be based on sequence variation graphs and haplotype panels over them, effectively exploiting already-discovered genetic variation in the population. Second I will develop new statistical methods to infer the evolutionary history of genome sequences to identify ancestral populations, model gene flow between them, and date and place mutations into them. I will apply these methods to modern and ancient samples to elucidate Eurasian and African human population history. Finally, I will apply these methods to new data I collect from the Lake Malawi adaptive radiation of over 500 species of cichlid fish, to infer the evolutionary relationships in the radiation, test models of speciation, and identify genes involved in cranio-facial adaptation. These studies will empower future use of sequencing data in biomedicine, and advance our understanding of genome structure and evolution.</p>
Amount: £3,027,662
Molecular characterisation of antibiotic tolerance in Mycobacterium tuberculosis
Tuberculosis, caused by Mycobacterium tuberculosis still causes 1.8 million deaths per year and takes months to years to treat. Long treatment times are due to subpopulation(s) of bacteria that, although genetically susceptible, are not killed effectively by antibiotics – termed antibiotic tolerance. Understanding mechanisms of antibiotic tolerance is the key to shortening treatment times for tuberculosis. We have recently shown that mycobacteria use the essential amidotransferase GatCAB to regulate rates of specific errors in gene translation and that mistranslation is both necessary and sufficient for tolerance to rifampicin – the most important anti-tuberculous drug. However, the precise molecular mechanisms by which GatCAB and the mycobacterial translation machinery control fidelity are not understood. We have also recently identified further mechanisms which contribute to rifampicin tolerance. We now propose to determine the mechanism by which GatCAB modulates mistranslation rates. We also propose three complementary forward genetic screens to a) comprehensively identify the pathways that regulate mycobacterial translational fidelity; b) employ bacterial genome-wide association studies to identify mutations that influence rifampicin tolerance in clinical isolates, and c) use saturating transposon insertion mutagenesis and deep sequencing to identify mycobacterial genes that cause differential rifampicin susceptibility in a murine model of antibiotic treatment.
Amount: £1,195,984
Fundamental mechanisms controlling human energy homeostasis
<p>Obesity and associated diseases such as type 2 diabetes, cardiovascular disease and some cancers represent a significant health burden. My overall aim is to identify new therapeutic strategies for severe obesity. Using extensive genetic and clinical data on unique cohorts of individuals at both extremes of the weight distribution (severe obesity and thinness), we will comprehensively map the molecular networks that maintain energy homeostasis and their disruption in disorders of weight regulation. Building on our previous work, we will focus on dissecting cellular mechanisms that converge on leptin-melanocortin signalling using human stem-cell derived hypothalamic neurons. In human studies, we will characterise the effects of specific pathways on eating behaviour, energy expenditure and substrate utilisation. By uncovering the fundamental mechanisms that control human energy homeostasis, our goal is to identify and validate control points that can be targeted to improve outcomes in obesity associated diseases.</p> <p>&nbsp;</p>
Amount: £3,582,289
Structural cell biology of transport vesicle and organelle biogenesis
<p>Integral membrane protein cargo are constantly moved in coated tubular/vesicluar carriers between the cell's organelles and its limiting membrane in order to maintain membrane identity and function. That these transport processes are of fundamental importance is reflected by the fact that ~30% of mammalian proteins are either components of the vesicle/tubule transport machinery or are its cargo.&nbsp; Coated vesicular/tubular carrier formation including cargo selection requires the interplay of a network of peripheral membrane proteins and membrane components including phospholipids, small GTPases, docking proteins and the cargo itself. The coat must also prepare and facilitate the carrier for fusion with its target. AP2, AP3, COPI and retromer/VARP based coats along with their accessory/regulatory factors are vital for producing a fully functional endosomal system. We will use a combination of X-ray crystallography, NMR and the fast developing techniques of single particle cryoEM and cryo electron tomography allied with biochemical/biophysical studies to formulate theories concerning the architecture, assembly routes and control/regulation of the formation of these four key tubular/vesicular transport carriers. Specific function abolishing mutations designed on the basis of these studies will allow us to test and further explore our theories in cells using a&nbsp; wide range of in vivo techniques.</p>
Amount: £3,445,099
Embryo architecture, potency and tissue interactions during mouse and human development
<p>Mammalian embryogenesis entails close partnership between embryonic and extra-embryonic tissues to regulate changes in embryo architecture and developmental potency. We aim for an integrated view of how these events progress hand in hand during key stages of mouse and human embryogenesis.</p> <p>The first architectural changes of the embryo are polarisation and compaction that trigger the separation of embryonic and extra-embryonic lineages. Yet their own trigger remains unknown. We will dissect potential triggering pathways and through genetic manipulations determine their importance for cell fate.</p> <p>Embryo remodelling at implantation is intimately associated with pluripotent-state transitions. We will harness our novel techniques for embryo culture throughout implantation to uncover mechanisms behind these events in relation to signalling partnerships between embryonic and extra-embryonic tissues.</p> <p>By arranging partnership between embryonic and extra-embryonic stem cells in 3D-culture we have recapitulated embryo-like morphogenesis and spatio-temporal gene-expression. We will characterise tissue interactions in such stem&nbsp;cell-derived&nbsp;embryos to understand principles of self-organisation.</p> <p>Our work established an unprecedented opportunity to study human early post-implantation embryogenesis <em>in-vitro</em>. We will build the first morphological and transcriptional atlas of human development beyond implantation.</p> <p>This will bring understanding of normal development and shed light upon why many pregnancies fail at early stages.</p>
Amount: £2,135,983
Behaviour Change by Design: Generating and Implementing Evidence to Improve Health for All
<p>Reducing food, alcohol and tobacco consumption would dramatically reduce non-communicable disease and, since these behaviours cluster by deprivation, would also reduce health inequalities.&nbsp; However, progress in achieving such behaviour change is slow.</p> <p>&nbsp;</p> <p>Traditional approaches to behaviour change involve providing information with, at best, modest population-level effects and sometimes increased inequalities.&nbsp;Conversely, <em>Choice Architecture</em>&nbsp;interventions (&ldquo;<em>Nudges&rdquo;</em>) have potentially larger, more equitable effects, involving re-designing environments&nbsp;<em>e.g.</em>&nbsp;reducing plate size to reduce food consumption. However, evidence of effectiveness in real-world settings and understanding of mechanisms are limited.</p> <p>&nbsp;</p> <p>We will bridge this knowledge gap through a novel collaboration between behavioural and cognitive sciences. In the most ambitious co-ordinated set of studies to date, we propose field studies to estimate effect sizes of promising <em>Choice Architecture</em> interventions to reduce food, alcohol and tobacco consumption. Enabled by unprecedented collaborations, these will be conducted in supermarkets, bars and cafeterias and interventions optimised through laboratory studies determining mechanisms.</p> <p>&nbsp;</p> <p>We will run international workshops, public engagement activities and a Behaviour Change Summit to facilitate implementing the evidence generated, overseen by an Implementation Advisory Panel. This will enable us to realise our vision of accelerating progress in changing behaviour by re-designing environments to improve health for all.</p>
Amount: £3,123,724
KRAB-ZFPs and the establishment of lineage- and species-specific gene regulatory networks
<p>KRAB-ZFPs constitute a large yet neglected family of proteins with around 350 members in human and mouse. Collectively, they target transposable elements and until recently were thought to be mostly involved in their transcriptional repression in embryonic stem cells. During my post-doctoral work, I unveiled the binding sites of most (222) human KRAB-ZFPs, but the role played by the majority of them could not be fully explained by current theorems. Instead, we found that many target ancient transposable elements which often contain regulatory platforms; we also obtained correlative evidence that these could affect the expression of nearby genes. We hypothesize that evolutionary conserved KRAB-ZFPs can use their heterochromatin-inducing capabilities to modify accessibility of these transposable element-derived regulatory elements. We propose to functionally demonstrate this potential by using large scale enhancer screens in multiple cell types. Furthermore, we want to follow-up on these findings by genetic manipulations aimed at characterizing the biological processes affected by a few KRAB-ZFPs, including the generation of mouse models. Finally, we want to better understand the evolution dynamics of KRAB-ZFP binding sites and verify if they can lead to lineage- and species-specific rewiring of gene regulatory networks.</p>
Amount: £1,393,506
Space distortions: Towards a general framework of the hippocampal cognitive map
<p>A fundamental question in system neuroscience is where spatial cognition is generated and how it is used for navigation. Strong evidence points at the hippocampus as a cognitive map. Hippocampal place cells are active in restricted fields and hippocampal lesion impairs navigation. Recent experiments showed that spatial representations are also found in the entorhinal cortex, an interface between the hippocampus and neocortex. Entorhinal grid cells are active in many fields arranged in equilateral triangles. How these cells interact to provide a cognitive space remains elusive. It has been suggested that grid cells represent a spatial metric system and provide major inputs to the place cells. A number of recent experiments indicate a greater role of place cells in constructing grid cell pattern. Here, we propose to investigate how these cells interact and what role they play in navigation. We will test whether grid cells act as a spatial metric of the brain. Alternatively, we suggested that they could act as a matrix system conveying the information about the proximity of locations. Furthermore, we will study how single-cell perturbations affect interconnected grid-place cell network as well as an animal&rsquo;s ability to navigate.</p>
Amount: £1,377,847
The role of Eros in Innate and Adaptive Immunity
<p>I will investigate the role of a novel protein, Eros, in immunity. I discovered the fundamental importance of this protein by demonstrating that Eros-deficient mice die from Salmonella infection because their phagocytes cannot make reactive oxygen species. This is because Eros is essential for expression of vital components of the phagocyte NADPH oxidase. My work represents&nbsp;the only paper on this protein. I&nbsp;have found that Eros-deficiency has effects that go far beyond the generation of reactive oxygen species. In particular:</p> <ul> <li>Eros regulates the expression of other key macrophage proteins including P2X7, a key activator of the NLRP3 inflammasome</li> <li>Eros regulates the expression of numerous cytokines from CD4+ T cells. Eros -/- T cells make 10-fold more IL-4 than control cells</li> </ul> <p>In mouse and human systems, I will investigate the molecular mechanisms by which Eros:</p> <ul> <li>controls the abundance of a subset of proteins working on the hypothesis that it is a novel component of the protein quality control pathway&nbsp;using structural, biochemical and cell biological techniques.</li> <li>controls T cell cytokine secretion. I will spend time working with John O'Shea, a world leader in this field.&nbsp;&nbsp;</li> </ul>
Amount: £1,319,075