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Recipients:
University of Cambridge
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GBP

Results

Embryo architecture, potency and tissue interactions during mouse and human development 11 Jul 2017

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. 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. 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. 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 cell-derived embryos to understand principles of self-organisation. Our work established an unprecedented opportunity to study human early post-implantation embryogenesis in-vitro. We will build the first morphological and transcriptional atlas of human development beyond implantation. This will bring understanding of normal development and shed light upon why many pregnancies fail at early stages.

Amount: £2,135,983
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulation of nuclear envelope function and links with disease 22 Feb 2017

The nuclear envelope (NE) lies at the interface between the nucleus and the cytoskeleton. It forms a complex structure controlling cell compartmentalization and regulates many processes including nucleo-cytoplasmic transport of proteins and RNA, chromatin organization, DNA replication and DNA repair. Hence, defects in NE integrity and nuclear architecture cause drastic changes in cell homeostasis and are associated with a broad range of diseases including cancer, premature ageing syndromes, neurodegenerative diseases or muscular dystrophies, but also with physiological ageing. One of the main challenges is to understand how NE defects lead to so many types of diseases. Previous theories include changes in gene expression and mechanical weakness. My previous work has shown that subcellular processes including microtubule or chromatin organization can modulate NE function, and has identified the acetyltransferase NAT10 as a key regulatory node for control of nuclear architecture. My goal is to now investigate how NAT10 and other factors regulate the NE. I will thereby gain new understanding of how of nuclear architecture is orchestrated and how this is disrupted in age-related diseases including HGPS. This research will not only contribute to our fundamental understanding of nuclear architecture but will also potentially identify new therapeutic strategies for NE-associated syndromes.

Amount: £1,084,517
Funder: The Wellcome Trust
Recipient: University of Cambridge

Liquid droplets and hydrogels: protein phase transition in health and disease 05 Jul 2016

We have shown that local control of RNA and protein metabolism by ribonucleoprotein granules plays a vital role in synaptic function. Recently, we discovered that the RNA binding protein, FUS, physiologically transitions between dispersed, liquid droplet and hydrogel states. These transitions, driven by its LC domain, underpin reversible assembly of FUS granules and regulate protein synthesis in nerve terminals. Crucially, pathogenic FUS mutations induce irreversible assembly and RNP granule dysfunction. Our results raise questions about how FUS assembly is regulated, how it affects synaptic activity, and causes disease. To address these questions, we will use bioinformatics, proteomics, and iCLIP to identify key modulators (posttranslational modifications, interacting proteins) (Aim 1). We will use soft matter physics to investigate their impact on FUS assembly (Aim 2). We will apply advanced single molecule imaging tools to assess how modulators affect granule function (Aim 3). We will explore the reciprocal relationships between FUS assembly and synaptic activity in neurons under optogenetic control (Aim 4). We will use novel imaging methods to determine whether FUS assemblies are secreted and can be detected in CSF (Aim 5). This work has major implications for neurobiology and medicine.

Amount: £2,568,786
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the fitness landscape of influenza evolution in immunosuppressed patients 07 Dec 2015

Time-resolved genetic data offers a new and exciting opportunity to study pathogen evolution. Sequencing a population at multiple time points reveals genetic changes as they occur. Mathematical models based upon the dynamics of evolutionary systems allow for more accurate identification of alleles under selection, and better measurements of the magnitude of selection, than have previously been achieved. I will develop models to interpret time-resolved genetic data, so as to better understand the evolution of pathogens. Unified by the theme of modelling rapid evolutionary dynamics, this work will make progress in understanding multiple pathogenic organisms. Specifically, this project will use high-coverage sequence data to quantify the role of selection in the intra-patient evolution of influenza, relevant to the emergence of new pandemics. It will examine how immune and drug pressure, acting upon the HIV virus, affect viral diversity in the early stages of an infection. The project will develop methods to better interpret genetic data from drug resistance experiments, in order to identify genomic factors leading to drug resistance in malaria parasite, helminthes, and leishmania. Finally, I will investigate the potential of multi-locus genetic models of evolution to understand, and to predict, the evolution of seasonal influenza.

Amount: £270,445
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding how herpes simplex virus proteins UL51 and UL7 modulate focal adhesions 07 Dec 2015

I will address two related questions: 1. How is mammalian intracellular membrane fusion regulated? 2. How do enveloped viruses fuse with the plasma membrane to escape infected cells? To address the first question I will study the multiprotein HOPS complex, which regulates the fusion of late endosomes and lysosomes. I will map interactions within HOPS and with partner proteins, characterising these interactions structurally and biophysically. This will illuminate molecular mechanisms by which HOPS is recruited to late endosomes and lysosomes, uncoats and physically tethers compartments destined to fuse, and modulates the SNARE activity that governs their fusion. For the second question I will concentrate initially on how hepatitis delta virus binds the coat protein clathrin. Structural and biophysical analysis of this interaction will reveal whether clathrin recruitment to viruses competes with its binding to cellular partners. During the fellowship I will develop a research programme identifying the mechanisms large DNA viruses like poxviruses or herpesviruses use to exit infected cells. I will study how they hijack cellular membrane trafficking components like SNAREs, small GTPases and exocyst complex components. I will characterise interactions between these viral and cellular proteins structurally and biophysically to elucidate the molecular determinants of enveloped virus egress.

Amount: £146,614
Funder: The Wellcome Trust
Recipient: University of Cambridge

Diagnostically cross-cutting intermediate phenotypes of impulsivity and compulsivity. 19 Nov 2015

The proposed research will deconstruct impulsivity and compulsivity using cutting-edge neurocognitive tests, structural and functional neuroimaging, pharmacological challenge of the brain dopamine/adenosine systems, and quantification of peripheral dopamine status. In this way I aim to link cognitive and brain systems phenotypes of impulsivity/compulsivity to more mechanistically specific markers of abnormal neurotransmission and to demonstrate how these intermediate phenotypes are expressed dim ensionally in the population, and cut across two major diagnostic categories of psychiatric disorder. The key goals will be to address three core hypotheses: 1. That underlying intermediate phenotypes of impulsivity/compulsivity (measured using neurocognitive tests and psychopathology questionnaires) manifest as extremes of the normal population distribution (in the absence of overt psychiatric disorders) and, similarly, in classical psychiatric disorders of impulsivity and compulsivity (atte ntion-deficit hyperactivity disorder and obsessive-compulsive disorder). 2. That these intermediate phenotypes of impulsivity/compulsivity emerge as a consequence of altered fronto-striatal activity, and are under the modulatory influence of brain dopaminergic and adenosine neurochemical systems. 3. That these intermediate phenotypes of impulsivity/compulsivity, and their tractability to dopaminergic and adenosine drug manipulations, are correlated with peripheral blood-based biomarkers o f dopamine function.

Amount: £989,383
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulatory potential of repeat elements in the evolution of tissue-specific transcription 05 Jul 2016

The human genome, like all mammalian genomes, is in large part composed of decayed--but once active--repeat elements, many of which carry tissue-specific regulatory information. We hypothesise that repurposing of repeats has been critical for creating tissue-specific transcriptional regulation. Our research plan is an integrated experimental and computational strategy to systematically explore how these repeat elements have shaped the regulatory genome across the recent placental mammalian radiation.

Amount: £1,715,976
Funder: The Wellcome Trust
Recipient: University of Cambridge

Use of 68Ga-DOTATATE PET to identify the “inflammatory phenotype” in cardiovascular disease: a clinical translational programme 23 May 2018

Inflammation drives atherosclerotic plaque rupture underlying most coronary events. While vascular inflammation can be visualised using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), as a glucose analogue this method lacks cell specificity and is unreliable for coronary imaging owing to myocardial signal overspill. My research has shown that 68Ga-DOTATATE, a somatostatin receptor-2 PET ligand, provides a more accurate readout of macrophage-related atherosclerotic inflammation than 18F-FDG, with superior ability to distinguish high-risk versus lower-risk coronary lesions. In three parallel studies, I will test the clinical utility of 68Ga-DOTATATE PET to: i) quantify treatment response to high-intensity lipid-lowering with statins and proprotein convertase subtilisin/kexin type 9 inhibitors in patients with stable cardiovascular disease and familial hypercholesterolaemia; ii) predict disease progression post-myocardial infarction by identifying individuals with "residual" on-treatment coronary arterial inflammation; and iii) diagnose large-vessel vasculitis and monitor treatment response. 68Ga-DOTATATE imaging will also be compared to established MRI, CT, and intravascular imaging markers of atherosclerotic disease severity; and validated in vasculitis using autoradiography, histology and gene expression analyses. Moreover, transcriptomic and epigenetic profiling of monocyte-derived macrophages will be performed to better understand mechanisms underlying residual inflammatory risk defined by 68Ga-DOTATATE. This research will accelerate translation of 68Ga-DOTATATE inflammation imaging to the clinic.

Amount: £716,938
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neural circuits underlying fertility 17 Jul 2018

This programme aims to establish in detail the characteristics and in vivo significance of the arcuate (ARNKISS) and rostral periventricular area of the third ventricle (RP3VKISS) kisspeptin neurons in driving the pulsatile and surge patterns of luteinising hormone (LH), respectively. Genetic cFOS-dependent activation and rabies trans-synaptic strategies will enable permanent GFP/mCherry tagging of RP3VKISS neurons activated at the time of the surge, or projecting directly to GnRH neurons, for subsequent electrophysiological and RNAseq analyses. GCaMP-based fiber photometry and GRIN lens miniscopes will be used to evaluate RP3VKISS neuron and population activity. This will be combined with microfluidics delivering pharmacological agents or adeno-associated viruses bearing CRISPR components to interrogate the key factors regulating the activity of RP3VKISS neurons in vivo. Studies aimed at understanding how the ARNKISS neurons synchronise to generate LH pulses will use the same strategies in addition to expansion microscopy and brain slice dual calcium and electrophysiological recordings. Novel strategies for slowing LH pulses in an animal model of polycystic ovary syndrome will be explored. It is expected that the in-depth understanding of these two kisspeptin populations will provide opportunities for developing new therapeutics aimed at the beneficial regulation of fertility in the clinic.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

The Genetic Basis of Congenital Hypothyroidism 30 Sep 2018

I have already identified 2 novel genetic causal variants for congenital hypothyroidism (CH) by whole exome sequencing (WES); IGSF1 defects in central hypothyroidism and SLC26A7 in dyshormonogenetic CH. I will therefore continue this strategy to identify further genetic causes of CH. I will expand my CH cohort, enriched for probability of genetic mutations. After excluding candidate gene defects, cases will undergo WES. I will then undertake functional characterization of specific novel variant s using in vitro techniques and a zebrafish model of thyroid development. Human SLC26A7 mutations are a novel cause of dyshormonogenetic CH and the disorder or its pathogenesis has not been characterized; I will phenotype cases to define this syndrome in more detail. I will characterize the biological function of SLC26A7 (a key transport protein), by performing electrophysiological studies to define its role as a putative anion transporter in the thyroid. Structure-function relationships in S LC26A7 are poorly understood. I will therefore characterize the properties of naturally-occurring and artificial SLC26A7 mutants to define functional domains in this protein.

Amount: £214,297
Funder: The Wellcome Trust
Recipient: University of Cambridge

Complete humanisation of adaptive cellular immunity in the mouse: Vaccine and therapeutic TCR discovery 30 Sep 2018

Adaptive cell mediated immunity is one of the central components of immunological homeostasis. While the basic mechanisms are conserved the components that encounter antigen are subject to rapid evolutionary change driven by species specific pathogens co-evolving with the host and divergence of the host genome against which antigen receptors are negatively selected. Thus, epitopes that direct protective immunological responses differ between species. Consequently, translation of results obtained from immunisations conducted in model organisms to humans remains a pernicious issue. The long term goals of this proposal are to identify and validate vaccine candidates and discover therapeutic T cell receptors To achieve these goals we will build mice in which all components of adaptive cellular immunity have been humanised, building on the technical success, biological insights and health-care benefits accrued from the construction of a mouse with a complete human immunoglobulin repertoire. We will use this humanised mouse as platform to isolate therapeutic T cell receptors for acute myeloid leukaemia in which the nucleophosmin gene has been mutated. In an independent and parallel work stream we will systematically explore the Plasmodium falciparum genome to identify vaccine candidates protective against the liver stage of the pathogen.

Amount: £5,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterisation of protein networks driving haematopoietic stem cell fate choice 30 Sep 2018

Haematopoietic stem cells (HSCs) are situated at the top of a hierarchy of blood forming cells and are ultimately responsible for the production of all mature blood cell types. HSCs must therefore execute a balance of self-renewal and differentiation divisions to maintain the stem cell population throughout adult life while providing enough cells to meet daily needs. Over the past decades, several HSC subtypes have been described, differing in mature cell type production and self-renewal durability. De-regulation of these cell fate choices in HSCs has been implicated in ageing and tumorigenesis and recent advances in single cell technologies have allowed greater insight into transcriptional changes driving these decisions. However, little is known about how well these profiles correspond to the proteome of HSCs and we therefore aim to construct a comprehensive protein network for HSC subtypes in order to identify key proteins involved in HSC self-renewal. The importance of candidate self-renewal regulators will be assessed by both in vitro and in vivo methods. A more complete understanding of HSC self-renewal would lead the way for more effective in vitro expansion of HSCs for research and future clinical applications such as gene therapy and bone marrow cell transplantation.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Resolving mesodermal diversification with single cell transcriptomics 30 Sep 2018

During the course of development, cells divide, migrate, and specialize to form major organ systems. Furthemore, among most mammals and birds, mouse cells differentiation follows a unique morphology. Understanding the molecular mechanisms underlying such process is a core issue in Biology and a curiosity in mouse, which despite differences still share fundamental properties during the process. The challenge has been addressed by leveraging current high-throughput technologies such as single cell transcriptomics. The amount and complexity of this data requires innovative mathematical frameworks that take advantage of current computational capacities. I am intersted on resolving mesodermal diversification during mouse gastrulation. Based on the premise that single cell profiles represent snapshot measurements of expression as cells traverse a differentiation process, I will use probabilistic modeling among other statistical and mathematical methodologies to reconstruct a measure of a cell’s progression through some biological process, and to model how cells undergo some fate decision and branch into two or more distinct cell types. In particular, Bayesian Inference has shown to be a useful approach to take advantage of computational resources, and to include prior knowledge into models, by providing a formal probabilistic framework that allows learning from the data in order to make predictions.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Development of likelihood-based methods in structural biology 28 Nov 2017

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. 1) In crystallography we will enable the solution of difficult structures (poor data or poor starting models) that still evade current methods. New statistical innovations will automate the clustering of alternative molecular replacement models into sensible ensembles representing different conformations. 2) We will exploit a promising new approach to the determination of substructures for SAD phasing, based on our SAD likelihood function. 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. The implications of multi-variate cryo-EM likelihood targets will be explored, with potential applications in the angular deconvolution of cryo-EM maps. 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.

Amount: £1,916,285
Funder: The Wellcome Trust
Recipient: University of Cambridge

Infectious science engagement activities in post-Ebola Sierra Leone 30 Jan 2018

Having experienced the Ebola epidemic first-hand, we realised that the majority of the population did not know what a pathogen was, creating fear and misbeliefs that hampered outbreak control. There is a clear need for science engagement and an opportunity to provide it now. We have found school children to be highly tuned into discussions about Ebola and other pathogens. Now is the right time to broaden their awareness of infectious diseases beyond Ebola, and to engage their curiosity through science creating a positive legacy. We aim to: - Engage young people in Sierra Leone in the science of infectious diseases that are all around them, sparking their scientific curiosity and making conversations about pathogens commonplace. - Empower young people with the understanding that if they know how infectious diseases spread, they can prevent infections, improving their health and that of those around them. - Excite young people about science and encourage scientific studies and careers.

Amount: £144,350
Funder: The Wellcome Trust
Recipient: University of Cambridge

Changing In/Fertilities 30 Jan 2018

In contrast to the promotion of planned parenthood which dominated the early and mid 20th century, it is the spectre of unplanned infertility that has beome more prominent in the early 21st century.Changing In/Fertilities is designed to facilitate the urgent task of more explicitly characterising post-ART fertility transitions through a global collaborative project uniting 24 research projects in 16 different countries. Over a three year period this large team will explore changing perceptions of fertility, fertility imaginaries, fertility fears and fertility behaviours in the post-ART context. We will document in ‘thick’ qualitative detail the often surprising and unexpected ways in which fertility is being re-imagined and redefined, and also how new fertility trajectories intersect – for example in the effort simultaneously to encourage women to begin their reproductive lives earlier, whilst offering increasing options to extend fertility. We will identify key factors and drivers linking the expansion of ARTs to fertility change, and these will feed into policy as well as basic scinece. Our detailed studies of situted fertility transitions will support a sustained comparative exercise that will in turn yield a more general sociological theory of post-ART fertility change.

Amount: £1,419,802
Funder: The Wellcome Trust
Recipient: University of Cambridge

Schwann cell-axonal communication during axonal degeneration and regrowth 25 May 2017

Myelinating and non-myelinating Schwann cells are reprogrammed after nerve injury into repair Schwann cells, specialized for maintaining survival of injured neurons and supporting axonal regeneration. This process is regulated by Schwann cell-intrinsic signals, such as the transcription factor c-Jun, however few other candidates have been identified. It is, currently, unknown how Schwann cell reprogramming is initiated, but unidentified extrinsic signals from injured axons are likely candidates. I aim to delineate the spatial and temporal regulation of Schwann cell-intrinsic downstream signals in real-time and define their role in repair Schwann cell function and axonal regeneration. Secondly, I aim to test the hypothesis that axon-derived signals initiate Schwann cell reprogramming during nerve injury. I will use cell culture, in vivo mouse models and a live and dynamic zebrafish larval model of nerve injury. This study will be the first to investigate how axon-intrinsic mechanisms of nervous system injury interplay with glial cell molecular responses to nerve damage, in real-time. Using cutting edge techniques in two species, this project will significantly advance our understanding of Schwann cell-axonal biology and tissue repair. Excitingly, this research may identify new potential therapeutic targets to improve poorly regenerating human nerves and treat patients with neuropathies.

Amount: £426,876
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding mammalian interphase genome structure in mouse ES cells 05 Apr 2017

The folding of genomic DNA from the beads-on-a-string like structure of nucleosomes into higher order assemblies is critically linked to nuclear processes, but it is unclear to what degree it is a cause or consequence of function. We aim to understand whether the Nucleosome Remodeling and Deacetylation (NuRD) complex regulates chromatin structure to control transcription, or whether it is NuRD’s regulation of transcription that results in global changes in chromosome structure. We have calculated the first 3D structures of entire mammalian genomes using a new chromosome conformation capture procedure, which combines imaging with Hi-C processing of the same single cell. Our objectives are now: To study: 1) how interphase mammalian genome structure is established in G1; 2) the factors that drive this formation and; 3) how this organisation is regulated by chromatin remodellers (such as the NuRD complex) as mESC’s differentiate. To build a dedicated bespoke microscope for 3D double helix point spread function detection with light sheet activation, optimised for 3D single-molecule/super-resolution imaging of proteins such as the NuRD complex. To combine 3D super-resolution imaging and the biochemical processing steps of single cell Hi-C to directly correlate binding of protein complexes to regions of the structures.

Amount: £2,031,409
Funder: The Wellcome Trust
Recipient: University of Cambridge

Computational tools for analysing developmental morphogenesis at the tissue-scale 05 Dec 2016

Computational tools for analysing developmental morphogenesis at the tissue-scale

Amount: £47,159
Funder: The Wellcome Trust
Recipient: University of Cambridge