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Recipients:
University of Cambridge

Results

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

Dynamic neural remapping across the sleep-wake cycle: A mechanistic link between sensory re-organisation and GABA 05 Sep 2017

Across a single day, we undergo behavioral, physiological and neurochemical changes, from vigilant wakefulness to unconscious sleep. Despite the loss of consciousness, sensory processing continues in sleep. Attempts to assess the degree to which sensory processing differs between wakefulness and sleep have yielded contradicting results with studies showing greater, smaller or comparable responses to the same stimuli when comparing the two states. Hence, it remains unclear precisely how sensory processing is modulated throughout the sleep-wake cycle. Most studies have focused on responses to specific stimuli, neglecting the relationship between different stimuli. We suggest a new comprehensive approach to elucidate how vigilance state dynamically shapes sensory processing, by combining electroencephalography (EEG), functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) together with state-of-the-art computational tools, measuring neural distances between stimuli to quantify sensory remapping across the sleep-wake cycle. We hypothesize that gamma-Aminobutyric Acid (GABA), an inhibitory neurotransmitter implicated in sleep regulation and correlated with sensory sensitivity, has a central role in sensory remapping. Thus, in this research proposal, the key goals are:(i) to elucidate the temporal and spatial dynamics of sensory remapping throughout the sleep-wake cycle, and (ii) to investigate whether sensory remapping across the sleep-wake cycle is GABA-dependent.

Amount: £99,935
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

Understanding the role of the viral polymerase in influenza virus virulence 31 May 2017

The development of novel strategies against influenza viruses depends on our understanding of influenza virus replication and pathogenicity. The former largely depends on the activity of the viral RNA polymerase, which copies and transcribes the viral genome, while the latter is multifaceted and influenced by both viral and host factors. Interestingly, recent findings show that the RNA polymerases of highly pathogenic influenza A viruses produce short RNAs, or mini viral RNAs (mvRNAs), which are non-contiguous in the viral genome and strong inducers of the interferon response. Because they are not made by RNA polymerases of seasonal influenza strains, mvRNA synthesis may be a transformational advance in our understanding of the ‘cytokine storm’ that underlies the pathogenicity of virulent influenza viruses. Unfortunately, our basic understanding of the influenza RNA polymerase is limited and it is unclear how the mvRNAs are made. I here plan to use single-molecule FRET, deep-sequencing and structure-guided mutagenesis to advance our basic understanding of influenza virus RNA synthesis, focussing on the molecular mechanics behind i) influenza transcription initiation, ii) the differences between the RNA polymerases of highly pathogenic and seasonal influenza strains, and iii) the action of influenza inhibitors that target the RNA polymerase.

Amount: £922,885
Funder: The Wellcome Trust
Recipient: University of Cambridge

Revealing how cells read the environment to regulate adult gut renewal 22 Feb 2017

The intestinal epithelium constantly regenerates from stem cells which adjust their behaviour to the changing physiological conditions the gut is exposed to. For example, stem cell proliferation rates can transiently increase to speed up regeneration after tissue loss, or in response to the diet, before reverting to steady-state levels once correct tissue size is reached. This plasticity is essential for intestinal function, as lack of regeneration causes tissue atrophy whereas unrestricted stem cell proliferation causes cancer. I propose to use the genetically tractable Drosophila gut to identify the secreted and physical factors regulating gut plasticity. Thanks to targeted genetic screens done in contexts that trigger reversible changes in gut size and functional analyses, I will identify novel extracellular signalling molecules regulating cell proliferation. I will also examine the relationships between physical remodelling of the gut and stem cell proliferation by characterising the transcriptional output of integrin signaling and establishing how physical remodelling of the visceral mesoderm (a source of growth factors in the gut) contributes to regenerate the intestinal epithelium. As the regulation of intestinal proliferation is largely conserved between Drosophila and mammals this work has the potential to uncover important new principles relevant to intestinal maintenance and degenerative diseases.

Amount: £990,874
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterization of the human extra-embryonic macrophage population, Hofbauer cells, phenotype and function 26 Oct 2016

Macrophages are among the first immune cells to seed embryonic tissues. They play important roles in early fetal development including tissue modeling and maintaining healthy tissue homeostasis. In humans, macrophages are present in the villous core of the placenta before a vascular connection with the embryo and these extra-embryonic macrophages, termed Hofbauer cells (HBC) are readily available for study. Developing our understanding of HBC and the role they play throughout gestation is important as they lie at the interface between the mother and fetus. HBC are likely to regulate placenta development, in particular the trophoblast cells that are the ultimate barrier between mother and fetus. HBC are also an important fetal defense against transplacental infections and in utero fetal infections are associated with pathogens that can survive in macrophages. However, the functions of HBC are poorly understood. Through this proposal, using some of the most advanced tools available today including multi-parameter flow cytometry, mass cytometry, RNA sequencing and organoid cultures, I will provide the first in-depth characterization of the human placenta extra-embryonic macrophages, HBC. I aim to describe the phenotype of HBC, their transcriptomic profile and functional properties. Keywords: Human extra-embryonic macrophages, Hofbauer cells, placenta, vertical-transmission, fetus, immunity.

Amount: £1,066,164
Funder: The Wellcome Trust
Recipient: University of Cambridge

From habits to compulsions: the role of glutamate and serotonin in Obsessive-Compulsive Disorder 09 Nov 2016

This proposal aims to characterize the neural basis of compulsion development. This requires neurobehavioural investigation of the hypothetical transition between habits and compulsions. To achieve this, I will invent a new behavioural paradigm capable of assessing not only habit formation but also habit perseveration. Three specific aims are defined. Firstly, I will characterize the behavioural mechanisms through which both healthy humans and patients with Obsessive-Compulsive Disorder (OCD) arbitrate between intentional and automatic actions after habits have been established by measuring post-training human preferences for habitual versus goal-seeking actions. I will compare the influence of both appetitive and aversive instrumental learning in the shift between purposeful and automatic actions between groups. Secondly, using functional Magnetic Resonance Imaging (fMRI), I will characterise the neural mechanisms underlying the transition from habits to compulsions, by disentangling the neural contributions of the goal-directed and habit systems in their interaction to control behaviour. I will test whether perseveration results from impairment in the goal-directed system, or hyperactive habit circuitry, or perhaps both. Finally, I will use Magnetic Resonance Spectroscopy (MRS) and Positron emission tomography (PET) to measure dynamic changes in glutamate, GABA and serotonin availability to further elucidate the neurochemical abnormalities which may underlie OCD.

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

Investigating the role of R2B receptor tyrosine phosphatases in developmental signalling pathways 27 Apr 2017

Tyrosine phosphorylation is a key post translational modification that is often dysregulated in disease. The balanced actions of kinases and phosphatases are required for cellular homeostasis. However, the substrates and functions of phosphatases are poorly understood. The receptor tyrosine phosphatase PTPRK was identified as a recurrent fusion partner of the oncogene RSPO3 – an amplifier of the Wnt pathway. Additionally, PTPRK was identified in a forward genetic screen for modulators of APC min driven intestinal tumorigenesis. Given these genetic links, and hints in the literature that PTPRK can dephosphorylate beta catenin, a Wnt transcriptional activator, we plan to investigate the signalling cross-talk between PTPRK and Wnt signaling. First, this project aims to discover whether Wnt signalling influences the regulation of PTPRK at the messenger RNA and protein level. Second, we plan to test how depletion of PTPRK affects Wnt signaling output using luciferase reporter assays and western blotting. The outcome of this project will be a comprehensive assessment of the interplay between PTPRK and Wnt signalling, with important implications for the role of PTPRK in colorectal cancer, which is one of the current focusses of the Sharpe Lab.

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

A Cluster for the Development of Dynamic 3D Nanoscopy 05 Jul 2016

Imagine if we could watch multiple molecules in living cells as they move and interact. This dream may seem years away, but it is now realistic to achieve real-time dynamic super-resolution imaging of multiple tagged proteins in three dimensions (3D) in cells and in tissues. This will allow biologists to discover large-scale patterns involving diverse structures including transport vesicles, ribosomes, and chromatin domains, all previously inaccessible because they lie in the gap between the resolution of electron (1- 2 nm) and light microscopy (200-300 nm). The "big picture" of cellular organization/information processing would emerge, with advances in understanding cell function in health and disease. While we can now do this in 2D, 3D imaging is needed to follow objects as they move out of the plane. Achieving 3D imaging is a major challenge and will require two orders of magnitude more information per cellular volume, and novel algorithms to classify, analyze, and visualize patterns from massive datasets. We propose specific innovations (Table 1) that, should allow us to achieve this over the next five years, given our team’s proven track record of success.

Amount: £660,923
Funder: The Wellcome Trust
Recipient: University of Cambridge

The connectome of olfactory memory circuits in the adult fly 05 Jul 2016

Connectomics, establishing comprehensive neuronal wiring diagrams at the resolution of single synaptic connections, is still in its infancy. Although most neuroscientists are confident that connectomics will eventually have a major impact, doubts remain about when this will happen. We propose a project that within 4 years could transform an important field of neuroscience – the circuit basis of learning and memory – by reconstructing the olfactory memory circuits of Drosophila. A consortium of laboratories at HHMI Janelia has generated a complete serial section transmission EM volume of an adult female Drosophila brain. This 106 TB volume (100x larger than any previously imaged whole brain) will have a major impact on over 200 laboratories working in Drosophila neurobiology. We will reconstruct input and output neurons of the primary associative learning centre, the mushroom body, along with selected upstream layers bringing teaching signals and downstream layers mediating descending control of behaviour. This will reveal the complete network and synaptic organisation of a memory centre, whose logical principles, including sparse coding, dopamine-dependent plasticity, valence segregated by neuronal population, and network recurrence, are all relevant to mammalian brains. This will enable a wealth of experimental circuit studies as well as piloting large-scale, geographically-distributed connectomics.

Amount: £3,250,123
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

Circadian rhythms in the bacterium Escherichia coli 08 Apr 2016

My laboratory investigates the molecular mechanisms that control the 24 hour (circadian) clock. This fundamental process is integral to the function of all cells. Our recent work has highlighted a critical role for a family of proteins called peroxiredoxins in the clockwork, and has shown that redox oscillations in mammalian cells contribute significantly to a cell's rhythmic properties. A Senior Fellowship would allow me to examine how the clockwork functions in 'real-time', using a variety of novel tools that we are developing to do this. We will also perturb redox pathways (that normally get rid of harmful oxidants produced because of respiration) and investigate the effect of this on the clockwork using these tools. A final goal will be to integrate redox oscillations with existing components of the clockwork, which rely on the process of gene transcription to work. The goal is therefore to fully characterise the mechanism of how a cell keeps time, particularly with respect to redox metabolism, which is a new and exciting area of study within the field.

Amount: £182,839
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. The role of EZH2 in the induction and maintenance of acute myeloid leukaemia. 23 Jun 2014

This proposal aims to delineate the role of the epigenetic regulator EZH2, whose function is perturbed in a number of cancers including leukaemia and lymphoma, in the induction and maintenance of acute myeloid leukaemia (AML). AML is an aggressive haematological malignancy with an overall poor outlook and limited treatment options in the relapse setting. We aim to provide genetic proof of the requirement of EZH2 across multiple subtypes of AML, employing both conditional knockout and overexpression approaches both in vitro using immortalised cell lines, and in in vivo experiments in mice. The primarygoal is to demonstrate the role of EZH2 in both the induction and maintenance of AML. Having established this,we will characterise which transcriptional programmes EZH2 alters in the maintenance of AML, utilising RNA-Seq/ChIP-seq analysis of AML cell lines following exposure to a novel EZH2 inhibitor and cells from theconditional knockouts generated in the previous aim. Additionally we aim to further preclinical testing of the efficacy of the EZH2 inhibitor in AML. Combining these three aims with an evaluation of the mechanism for EZH2 activation and any alternative functions of the EZH2 protein in the leukaemic phenotype, our key goal is to provide a robust assessment of the role of EZH2 in AML.

Amount: £29,399
Funder: The Wellcome Trust
Recipient: University of Cambridge

Quantitative proteomic analysis of latent human cytomegalovirus infection 27 May 2014

Following primary infection, HCMV typically establishes a latent infection in monocytes under the control of a healthy immune system. Little is known about the intracellular pathways manipulated by HCMV to maintain latency, or the phenotype of latently infected cells. I will: (i) identify cell surface targets of individual HCMV latency genes (ii) enrich ex vivo latently infected monocytes to characterise the most important biochemical pathways altered by latent HCMV infection. I have developed a new technique ?plasma membrane profiling? (PMP) to enrich plasma membrane (PM) proteins for proteomic analysis. I will employ the functional proteomics approach SILAC (Stable Isotope Labelling by Amino acids in Cell culture), to perform semi-quantitative analysis on plasma membrane proteins enriched by PMP. Using this approach I will determine how latent HCMV infection alters the cell surface proteome by analysing transduced cell lines expressing individual HCMV latency genes, and an in vitro model of latency. I shall use the markers I identify to enrich latently-infected ex vivo CD34+ monocytes. In addition, I will characterise biochemical pathways altered by latent HCMV infection in these cells using ?KAYAK? (Kinase ActivitY Assay for Kinome profiling), a novel proteomic technique. Candidate proteomic ?hits? will be biochemically characterised.

Amount: £2,833
Funder: The Wellcome Trust
Recipient: University of Cambridge

Public Engagement Provision 20 May 2014

The Cairo Genizah Collection at Cambridge University Library is the single largest and most important collection of medieval Jewish manuscripts in the world. Comprising approximately 200,000 leaves, the discovery of this treasuretrove 100 years ago revolutionised the study of medieval Judaism and our understanding of the broader economic, social and intellectual history of the Mediterranean world. Intended as a resting place for religious works, the Genizah ('religious storeroom') has in fact preserved an ample number of secular texts too, both literary and documentary, and conspicuous among these is a unique medical corpus of approximately 2000 manuscripts. The medical fragments of the Cairo Genizah (which date from the 10th century onwards) include a large number of Judaeo-Arabic renditions of Arabic translations of Greek medical texts and of Arabic medical works, often annotated by their medieval users, together with original works by prominent, and less well-known, Jewish physicians. Uniquely,the collection preserves numerous prescriptions, druggists' notes, and lists of materia medica. This project will build upon previous work in the Collection, and make these important items freely available through Cambridge University's digital library platform, in the form of a detailed electronic catalogue of all the items of medical content along with high quality digital images of the manuscripts themselves. These will form a unique source of research on the study, transmission and practice of medicine by Jews and Muslims in the medieval Mediterranean world, and we believe that the medical humanities community will greatly benefit from their enhanced availability.

Amount: £4,984
Funder: The Wellcome Trust
Recipient: University of Cambridge

Public Engagement provision 01 Apr 2014

The aim of my research is to understand the molecular mechanisms that govern polarized secretion at the immunological synapse. We will use the CTL model with a clear trigger (TCR) and end-point (target cell death) to identify and characterize proteins that play a role in polarization and secretion as the immunological synapse is formed. Our specific aims over the next 5 years will be to (i) Map the order of events leading to secretion at the immunological synapse using rapid microscopy to compare the sequence of events leading to secretion in wild-type versus mutant CTL. (ii) Identify novel mechanisms contributing to polarised secretion in CTL by identifying genes up-regulated by Hh signaling that facilitate centrosome polarization; analyzing CTL derived from ciliary mutations that disrupt Hh signalling, gene-deletion mice from the Sanger screen and using proteomics to identify interactions with known proteins. (iii) Determine whether the lysosome itself plays a role in controlling polarization and secretion at the immunological synapse by asking whether TFEB regulates gene expression of proteins required for CTL secretion, and whether localized release of calcium from lysosomes via TPC1 and TPC2 controls any of the steps leading to polarized secretion from CTL.

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