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Recipients:
University of Cambridge
Award Year:
2017
Currency:
GBP

Results

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

Investigating How Epithelial-Endothelial Interactions Regulate Epithelial Cell Fate And Morphogenesis in Human Lung Development 31 Jan 2017

The mammalian lung has a complex tree-like epithelial structure tightly intertwined with vascular vessels. Endothelial cells, which line vascular vessels, have been reported to play an instructive role in maintaining tissue-specific stem cells and regulating regeneration. However, how endothelial-epithelial crosstalk functions in lung development, especially in alveolar cell fate specification and lung morphogenesis remain unknown. I propose three specific aims to address these questions. Aim 1: I will investigate specific functions and molecular mechanisms of lung epithelial-endothelial crosstalk. These co-culture experiments will take advantage of a human embryonic lung organoid culture system set up in the Rawlins lab and commercially available, or freshly derived, human endothelial cells. Aim 2: I will test the hypothesis that endothelial cells have heterogeneous behavior during normal lung development. Using lineage tracing in mouse I plan to label endothelial cells to better understand structure of pulmonary vascular vessels and then use monoclonal labeling to investigate clonal heterogeneity. Aim 3: I will test the hypothesis that developing lung endothelial cells are transcriptionally heterogeneous. I will use the single cell RNA-Seq technique to generate transcriptome libraries for human endothelial cells in different regions of lung, investigating their heterogeneity and identifying any specific markers for them.

Amount: £37,985
Funder: The Wellcome Trust
Recipient: University of Cambridge

Development and leptin signalling in human stem cell-derived POMC neurons 31 Jan 2017

Energy homeostasis in mammals is tightly controlled by a distinct neural circuit in the hypothalamus and its dysfunction leads to obesity. Pro-opiomelanocortin (POMC) neurons are a central component of this circuit. While obesity research has been largely limited to studies in rodents in the past decades, recently published protocols now allow the in vitro generation of human POMC neurons from human pluripotent stem cells (hPSCs). This enables us to study disease-associated mechanisms directly in the human cell type relevant to obesity. In my PhD I will contribute to a thorough characterisation and optimisation of this in vitro system. I will study when human POMC neurons are born in culture, assess their responsiveness to metabolic cues that regulate their activity and test different means of enhancing this responsiveness. This in vitro characterisation of POMC neuronal activity will be complemented by transplantation studies, in which I will test whether hPSC-derived POMC neurons possess all the features of functional maturity required to reinstall energy homeostasis in obese mice. I will finally use this novel tool to study the molecular mechanisms of certain signalling pathways in human POMC neurons, which might lead to the identification of potential targets for therapeutic intervention in human obesity.

Amount: £46,168
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the Impact of Extrinsic Factors on Intestinal Stem Cell Dynamics 31 Jan 2017

The rapid turnover of the mammalian intestinal epithelium is fuelled by division of stem cells residing at the bottom of the crypts of Lieberkühn. Our understanding of how stem cells populate the intestine in humans lags behind that of the murine system. In the latter, stem cells populate the crypts by a process of neutral drift. Moreover the number of functional stem cells per crypt and their replacement rate has been quantified in the mouse intestinal epithelium. However, it is not known how extrinsic factors, such as regular drug use, influence these dynamics. In humans, randomised clinical trials have linked low-dose aspirin to a reduction in colorectal cancer incidence and mortality. However, the mechanism is unclear. Since tumours originate from stem cells, I plan to conduct an in vivo study to investigate the impact of aspirin on murine intestinal stem cell dynamics. In the human system, functional stem cell numbers and replacement rates are still not well characterised. Somatic mutations can be used as clonal marks to investigate these parameters in patient samples. I thus aim to find and validate novel human somatic clonal marks and collect data for mathematical modelling of human intestinal stem cell dynamics.

Amount: £46,765
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role and regulation of UHRF1 during epigenetic reprogramming 31 Jan 2017

During both mouse and human embryonic development there are two waves of global DNA demethylation associated with an increase in developmental potential: firstly during the development of the inner cell mass from the gametes, and secondly during the development of primordial germ cells. Although some of these changes in DNA methylation are correlated with gene expression, it is not understood why this epigenetic reprogramming is consistently so extensive. Until recently it was believed that most of this erasure of DNA methylation occurred actively. However, recent research has revealed that regulation of maintenance methylation accounts for the differing rates of demethylation in different reprogramming contexts. Across the majority of these different contexts, the activity of maintenance methylation is controlled by regulation of UHRF1 protein. This project aims to elucidate the mechanism by which UHRF1 protein is regulated during epigenetic reprogramming, then to use this knowledge to assess the importance of this regulation to the acquisition of pluripotency during mammalian embryonic development. This will improve our understanding of developmental and reproductive health and may even shed light on new or improved methods of reprogramming cells for therapeutic applications.

Amount: £26,820
Funder: The Wellcome Trust
Recipient: University of Cambridge

Systematic Identification of Lineage Specification in Murine Gastrulation 31 Jan 2017

Single-cell genomics is a fantastic tool for studying developmental biology: it allows unbiased and large-scale study of gene expression at the correct resolution for cell fate decision making. New fluidics systems provide the capability to study tens of thousands of cells simultaneously - as many as there are in the young embryo. For my PhD, I will analyse scRNA-seq data generated on this platform, studying mouse gastrulation between E6.5 and E8. I will be able to study this process at both an exceptional cell-level resolution (thanks to the fluidics) and at an unprecedented time resolution, at 0.1 day intervals. My focus will be on identification of lineage specification, and how cells make their fate choices. I will need to develop new methods to account for the large numbers of cells assayed, the numerous lineage decisions made, and heterogeneity of speeds of development across and between embryos. I hope to produce a map of lineage specification from epiblast (E6.5) cells through to every cell type present at E8. This work will provide a developmental atlas through gastrulation, and general inferences on cell fate decisions may provide insight for cellular reprogramming and regenerative medicine.

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

Integrating genomic, transcriptomic, metabolomic and behavioural data from 12 strains of C. elegans to understand gene/environment interactions under different dietary regimens 31 Jan 2017

C. elegans can grow on a range of different bacterial diets. It has already been shown that it changes its behaviour depending on the available food. Its lifespan also depends on its diet. Autophagy has been shown to mediate the increase in lifespan when the nematode is grown on certain foods. However, the mechanisms by which the environment leads to a change in beheviour and life history traits remain largely unknown. With this project, we would like to use high-throughput sequencing and metabolomics to build a quantitative and comprehensive map of the underlying molecular networks activated in a specific dietary environment. Furthermore, we would like to harness the genetic diversity of C. elegans to study the genetic basis of its phenotype as well as the interaction of its genome and environment in the determination of its behaviour and lifespan. For this purpose, we plan to extend the latest statistical techniques to integrate all layers of genomic and phenotypic data. Many of the genes involved in metabolism are conserved between humans and nematodes. Therefore, we expect that the findings will be relevant to human physiology.

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

Understanding the Pathogenesis of Inflammatory Bowel Disease via Whole-genome Sequencing 31 Jan 2017

We will use a new whole-genome deep-coverage IBD dataset (15x+ coverage, 20 000 cases, 50 000 controls) to conduct genetic association studies. Several analyses are currently planned. The first study will use the data from >1000 IBD patients, who are part of a deep clinical phenotyping experiment, on their response to treatment with anti-TNF medication. We are hoping to determine specific genetic variants associated with successful treatment, non-response, loss of response, and unfavourable drug reactions. Once more samples are sequenced, we will attempt to discover novel low-frequency, rare, and very rare genetic variants associated with IBD. A recent low-coverage sequencing study has identified a rare missense variant in ADCY7 that doubles the risk of ulcerative colitis. In addition, a burden of very rare, damaging missense variants in genes associated with Crohn's disease was detected. The increased coverage and the size of the dataset may confirm the significance of such variants. Discovery of novel rare variants brings important insights into IBD biology, and improves the overall understanding of the genetic landscape of complex diseases.

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

Attachment and the transgenerational effects of loss, abuse and trauma: Exploring and testing classic ideas through historical analysis and developmental science 02 May 2017

Since it was introduced by John Bowlby, attachment research has been among the most influential paradigms for understanding the social underpinnings of infant mental health and transgenerational mental health. However, an odd artefact of the way a major research instrument was constructed in the 1980s by Mary Main has meant that to date attachment research has largely treated loss, abuse, and trauma as essentially equivalent, despite their very different clinical implications. A multidisciplinary approach will be used to investigate these concepts and examine potential differences. Work Package 1 will comprise a critical re-examination of the concepts of loss, abuse and trauma in the published and unpublished works by John Bowlby and Mary Main, exploring their reflections on how these experiences might impact parenting. In Work Package 2, hypotheses elaborated in Work Package 1 will be tested using Individual Participant Data pooled from 59 attachment studies, representing 4,542 families. Work Package 3 tests explanations for differential effects of unresolved loss, abuse and trauma on parenting and child development using longitudinal data from 400 mothers and children. The study will shed new light on transgenerational mental health processes, and insights will be disseminated to professionals and families.

Amount: £97,935
Funder: The Wellcome Trust
Recipient: University of Cambridge

Marriage, Health and Compatibility in Early Modern England 24 Jan 2017

This project will produce a history of marriage and health in early modern England. Marriage is generally understood as an institution governed by legal and religious regulations and social norms that have taken different forms throughout history. In post-Reformation England marriage was increasingly regulated and interrogated. Performing gendered spousal roles was part of religious practice, something perpetuated by the growing culture of conduct manuals. A central obligation of marriage was to care for one another in sickness. This has underpinned histories of domestic medicine that reveal that the early modern family was active in diagnosis and cure. The two major goals of this project are (1) To assess how good health defined a successful marriage in early modern England and (2) To investigate how the social norms and expectations of marriage changed over the course of a union. As part of this inquiry, subsidiary goals will be (3) To interrogate how marital compatibility was measured, (4) How poor health of one spouse affected the other, and (5) How illness impacted on the household as a whole. Finally, this project aims (6) To uncover how cultural expectations shaped the way early modern people wrote about marriage.

Amount: £151,620
Funder: The Wellcome Trust
Recipient: University of Cambridge

Contextual determinants of surprise in health, development and disorder. 31 May 2017

The goal of this research proposal is to build a theoretical and experimental framework to understand the contextual determinants of "surprise" (expectation violations/prediction errors) in health, development, and disorder. I have the following three aims: 1) To exploit high-field neuroimaging and pharmacological manipulations in healthy adults to reveal the precise neural mechanisms that alter surprise processing in response to volatility, and validate different pupil metrics as a window into central neuromodulatory function. 2) To conduct model-based neuroimaging in infants, for the first time, to predict risk for the dimensional symptoms of autism, and reveal the computational neurodevelopment of probabilistic and volatility learning in infants. 3) To develop a unified computational framework of surprise-driven learning that has the specificity to reveal separable mechanisms of psychopathology in different neuropsychiatric conditions and the potential to be used as a clinical tool. To achieve these objectives I will utilise the same cognitive tasks, pupillometric measurements and computational models of learning across three research themes. This ensures that while the individual projects are strongly hypothesis-driven the findings can be directly translated across developmental, adult, and disordered states. Key words: autism, neurodevelopment, predictive coding, surprise, computational models, 7T fMRI, pharmacology, noradrenaline, psychosis.

Amount: £983,275
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neurophysiology of nutrient rewards 22 Feb 2017

Optimal human food intake goes beyond reactive consumption and involves sophisticated behaviours that fine-tune food acquisition to our specific needs. Every day, we form decisions and consumption-plans to pursue our favourite foods, and model food choices from our social partners. This proposal develops a novel translational approach to study the neural mechanisms for realistic food-intake behaviours involving planning, decision-making, and social learning. We perform  single-neuron recordings in amygdala, hypothalamus, and orbitofrontal cortex during feeding behaviour for clinically relevant nutrients, including fats and sugars. Separate research aims focus on two aspects of food intake: (1) planning and decision-making for specific nutrient rewards; (2) social influences on food choice.  Neuroimaging with identical foods and behaviours extends single-cell data to brain networks, functional connectivity, individual differences, and real-life eating phenotypes. We advance the field by identifying explicit neuronal signals that underlie formation and pursuit of nutrient consumption-plans; by formalizing behavioural conditions for social nutrient-reward learning; and by identifying neuronal signals that underlie such learning and related social influences on food choice. By studying sophisticated, typical food intake in single neurons, neural systems, and behaviour, we aim to uncover basic neurophysiological mechanisms and lay foundations for clinical studies in obesity.

Amount: £1,690,913
Funder: The Wellcome Trust
Recipient: University of Cambridge

Explaining the heterogeneity and topography in inferior temporal cortex with deep neural networks 19 Apr 2017

Object recognition is accomplished by the ventral visual pathway, also known as inferior temporal (IT) cortex. IT contains regions that respond preferentially to faces, color, and places. However, we still do not understand the principles underlying the emergence and organisation of these regions. Currently, there are no computational models that take into account the heterogeneity of IT, including the spatial clustering of neurons with similar selectivity and the spatial organisation of these clusters on the cortical surface. Therefore, we would like to answer two questions regarding IT: 1) Does the heterogeneity of IT simply emerge from exposure to many images, or are specialized mechanisms and/or innate constraints involved in its development? 2) What are the organisational principles reflected in IT topography? We will determine whether the heterogeneity of populations of units, like that empirically observed in IT, can emerge spontaneously in deep neural networks (DNNs) without specialized architecture, or whether we need an architecture that specifically accounts for it. We will then build a DNN that incorporates the spatial information about selective populations of units and assigns these populations to topographical maps. We will test the models’ predictions using electrophysiology and fMRI data.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Exploring Disorganised Attachment: Unravelling Developmental Pathways and Outcomes using Data Mining 30 Jun 2017

Disorganised attachment is an important assessment of infant mental health, introduced by Main and Solomon (1990). Disorganisation is thought to result from an infant having in some way experienced trauma within the context of the relationship with their caregiver (e.g. observing severe domestic violence). Infants classified as disorganised have an elevated risk of psychological problems, most notably conduct disorders (Fearon et al. 2012). The possibility of a finer-grained measure emerged out of archival research, under Duschinsky's New Investigator Award, on the original Berkeley dataset from which disorganised attachment was first identified. As a result of the significant stakes for research and clinical practice, we have been offered unprecedented access to a remarkable longitudinal dataset to explore a) how the finer-grained measure fares against the standard construct in predicting a range of negative outcomes, and b) whether particular forms of disorganisation have specific antecedents. Given that the goal is exploratory and the array of relevant measures is extensive, data mining will be used rather than hypothesis-testing. The research offers the prospect of a significant transformation of research in this area. Three focus groups with clinicians will be conducted to facilitate clinical input and translation.

Amount: £25,976
Funder: The Wellcome Trust
Recipient: University of Cambridge

ISA-InterMine: accelerating and rewarding data sharing 06 Jul 2017

There is a growing recognition that research should be carried out in an open fashion, making data available early and in a reusable form to maximise worldwide research output. However, fulfilling this promise requires front-line researchers to comply with current data management standards as required by the data policies of funders and journals. These are additional burdens to research that will give them little immediate return. Thus we propose to create a cloud-based, open-source, extensible data collection and presentation platform that will provide scientists with: (1) immediate reward for their annotation efforts through sharable data visualisation, integration outputs and exploration tools; (2) standardised web services to facilitate script-based data manipulation and analysis; (3) an easy-to-use pipeline for preparing their data for publication; (4) incentives to improve data quality, accessibility, and machine-actionability at the appropriate level of granularity; and (5) allow institutions and other parties to host the platform to ensure its availability and reliability. We will do this by building on the success and complementarity of the ISA tools suite (Oxford) and the InterMine platform (Cambridge) to make it quicker and easier to generate rich integrated dynamic web sites at single paper/lab scale up to consortium scale.

Amount: £670,410
Funder: The Wellcome Trust
Recipient: University of Cambridge

Developing an in vivo MT nucleation assay to investigate g-tubulin independent centrosomal MT nucleation 27 Apr 2017

Centrosomes are major microtubule organising centres (MTOCs) in animal cells. During mitosis they recruit large numbers of gamma-tubulin ring complexes (g-TuRCs), which nucleate and anchor the microtubules required for spindle formation. Recent work in the Conduit lab has surprisingly shown that centrosomes lacking g-TuRCs can still organise microtubules. Nevertheless, it remains unclear if these microtubules are generated at centrosomes, or generated in the cytoplasm and then anchored at centrosomes. I aim to establish an in vivo microtubule nucleation assay to test these alternative possibilities. Drosophila larval brains, which are highly mitotically active, will be dissected from either wild-type flies or from mutant flies where the centrosomes lack g-TuRCs. They will be cooled on ice for 40 minutes in order to depolymerise all microtubules and then transferred to 25 degrees and chemically fixed at different timepoints. The brains will be stained for microtubules, centrosomes and mitotic DNA using antibodies already available in the Conduit lab and images will be taken on a confocal microscope. The location and intensity of new microtubule growth will be assessed. If the g-TuRC negative centrosomes do nucleate microtubules, the assay will be used to test candidate proteins for their role in centrosomal non-g-TuRC mediated microtubule nucleation.

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

An Investigation into the potential Th17 phenotype of ALCL 27 Apr 2017

Anaplastic Large Cell Lymphoma (ALCL) is a paediatric T cell lymphoma whereby tumours have an 'activated' cell surface protein expression phenotype, defined by the presence of CD30. However, it has long been an enigma as to why these supposed ‘transformed T cells’ do not express a T cell receptor (TCR) despite having the capacity to do so (as evidenced by the presence of molecular rearrangements of VDJ genes). The presumed cell of origin is a cytotoxic T cell as the large majority of tumours produce perforin and granzyme B yet in many cases expression of the helper T cell protein CD4 is also observed. We have refined the tumour cell phenotype to show expression of RORgt and production of cytokines including IL26, IL22 and IL17 hence suggestive of an origin in an innate lymphoid 3 cell (perhaps when the TCR is 'missing') or Th17 cells (when the TCR is expressed) that develop into tumours as a consequence of an inflammatory environment. Hence, the aim of this project is to establish this cellular phenotype and define the role of the (sometimes missing) TCR.

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

Virus remodelling of host-cell endomembranes 18 Oct 2017

Enveloped viruses appropriate host-cell membranes to assemble their progeny. Large DNA viruses achieve this by dramatically remodelling the host-cell endomembrane system. I work at the intersection of virology and membrane trafficking, exploiting the intimate connection between viruses and their host cells to gain insights into both virus biology and the dynamic regulation of cellular membranes. I will combine biophysics, biochemistry and cell-based infection assays to investigate the conserved mechanisms by which human herpesviruses change the composition and architecture of intracellular membranes, addressing two questions: What is the role of ceramide transport in the biology of enveloped viruses? We have identified a direct interaction between a conserved herpesvirus protein and a cellular ceramide transporter. This suggests that herpesviruses actively modify the ceramide composition of intracellular membranes during infection, a new paradigm in virus:host interactions. How do enveloped viruses bend membranes during assembly? We have identified a conserved protein complex that promotes herpesvirus membrane wrapping, potentially via palmitoylation-dependent sensing and/or stimulation of membrane curvature. A detailed molecular understanding of how viruses subvert host-cell membranes not only expands our knowledge of host and virus biology, but it provides the basic underpinning science for the next generation of vaccines and antiviral therapies.

Amount: £599,947
Funder: The Wellcome Trust
Recipient: University of Cambridge

The chemical biology and function of natural modified DNA bases in genomes 28 Nov 2017

I aim to elucidate the function of natural, chemically-modified DNA bases in the genomes of model organisms, using chemical 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 and 5-hydroxymethyluridine and their potential links with transcription regulation. 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 natural DNA base modifications, building on and augmenting chemical methodologies I have developed to discover and profile modified bases in RNA. 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. Keywords: chemical biology, nucleic acids, DNA, modified bases, epigenetics, sequencing

Amount: £2,198,391
Funder: The Wellcome Trust
Recipient: University of Cambridge

Building and breaking epithelial integrity in the neural tube: an optogenetic approach 18 Oct 2017

Using an innovative optogenetic approach within the zebrafish neural tube, I will directly explore how the polarity of individual cells drives the tissue organisation of a whole organ. In combination with 4D live imaging and functional abrogation, I will use light to specifically and reversibly manipulate apicobasal polarity, cleavage furrow formation and PI3K pathway signalling on a subcellular level. I will assess how apicobasal polarity and division are interrelated during morphogenesis of vertebrate epithelial tubes and how this relationship contributes to tissue integrity. Early zebrafish neuroepithelial divisions are highly predictable and coincident with de novo apicobasal polarisation. This provides a tractable model to assess a potential feedback loop between apical protein localisation and cleavage furrow positioning during epithelial establishment. The PI3K pathway is likely key to integrating apicobasal polarity with division. Within established epithelia, PI3K pathway defects are prevalent in cancers. I will manipulate PI3K pathway signalling within individual cells or groups of cells within an otherwise normal zebrafish neural tube. This in vivo method for manipulating cancer-linked signalling will allow me to test whether apicobasal polarity dysregulation is a cause or consequence of tissue disruption, providing clues to the cellular mechanisms of disease initiation.

Amount: £977,448
Funder: The Wellcome Trust
Recipient: University of Cambridge