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Recipients:
University of Cambridge

Results

Identification of the active eIF4E in trypanosomes 27 Apr 2017

A detailed understanding of the initiation of translation in kinetoplastid pathogens is still elusive. There is an innate complexity due to the number of isoforms of eIF4E and eIF4G, two of the three components of eIF4F. Second, there has been no simple way to rapidly ablate expression of a protein to render an immediate phenotype. RNAi is available but it takes 3 to 4 cell cycles to dilute the eIF4E sufficiently to detect a phenotype and then is difficult to distinguish primary and secondary phenomena. We have recently developed a system for the inducible ablation of a specific protein in less than 60 minutes. This summer studentship will exploit this method to ablate separately the two isoforms of eIF4E that probably are responsible for mRNA cap binding during translation initiation. An analysis of the qualitative and quantitative effect on protein synthesis after ablation will inform on whether the two eIF4E isoforms have different, overlapping or identical functions. The work builds on expertise in the lab and utilizes a new technique to answer a long standing question.

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

Amulets and the material culture of healing 25 May 2017

The goal of this project is to investigate how amulets represent varying forms of value and power across differing chronologies. The Science Museum's collection will allow me to comprehensively examine a diverse range of objects, and research different forms of medical, magical and scientific worth and potency unavailable by studying textual sources alone. This project will ask three questions: How do objects with both similar and antithetical social values–from the rare to the quotidian, the expensive to the ubiquitous–represent differing forms of remedial power? In which different ways do these amulets represent the patients' experience of illness and healing and how can we as historians and museum curators afford these objects ‘voices’ without being anachronistic and jeopardising their original power? Finally, what material features have led to certain objects being considered as curative, prophylactic or apotropaic, and to what extent do function and potency depend on manmade and natural materials? This project will use these amulets to help answer important questions about European healing practices from medieval period to present day. A direct, material analysis of the objects and collections will elucidate the historical importance of these objects, and what they can contribute to our knowledge of health and healing.

Amount: £15,523
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

Socio-cultural factors in Zika virus outcomes in Lusophone African countries 30 Sep 2016

What is the research question?1) What social barriers to, and enablers for, effective public health responses/adoption ofpreventive measures can be identified in health beliefs and practices associated withthe Zika virus, with particular attention to variations between countries with differentincidence of the disease, socio-demographic groups, and over time? ( WT-DFIDChallenge One)2) What are the affordances and limitations in the context of epidemics for this method ofdynamic social data analysis and health communications/monitoring amonghard-to-reach populations, and how can it contribute to the rapid dissemination ofinformation and knowledge in mitigating future epidemics? ( WT-DFID ChallengeThree)

Amount: £123,126
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

Institutional Strategic Support Fund 07 Sep 2016

Not available

Amount: £3,000,000
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

Duplication and Cellular Functions of Drosophila Centrioles 05 Jul 2016

Centrioles, at the core of centrosomes, orchestrate structure and function in the interface and mitotic cell. Here we aim to understand how centriole duplication is controlled. This requires Plk4 kinase to phosphorylate Ana2 in part so it can bind Sas6. Here we address how phospho-Ana2 interacts with other core procentriole components, Dragon, Ana3 and Rcd4 and how these events are spatially regulated to achieve duplication. Second, we aim to characterize how centriole to centrosome conversion is regulated giving newly formed centrioles competence to duplicate and nucleate cellular microtubules. We will determine how Polo kinase regulates formation of the Cep135, Ana1, Asl network essential for centriole conversion. We will also assess roles of Polo and Plk4 in anchoring peri-centriolar material (PCM) to the centriole and Plk4’s role at the peri-centriolar satellites to mobilise centrosomal molecules. Thirdly, we address how centrosomes can organise membranous vesicles. We focus upon Dragon, a molecule present in the centriole and the Golgi apparatus, and Rosario, counterpart of lysozyme-like vesicle protein LYST, required to evenly distribute centrosomes in the syncytial embryo. We will characterize the process whereby primordial germ cells form in the syncytium, an event triggered by interactions of centrosomes with the embryo’s polar cytoplasm.

Amount: £1,543,160
Funder: The Wellcome Trust
Recipient: University of Cambridge

Achieving Selectivity in Space and Time with DNA Double-Strand-Break Response and Repair: Molecular Stages and Scaffolds Come with Strings Attached 05 Apr 2016

Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) are the two major pathways of DNA double-strand break (DSB) repair in human cells. The aim of my research is to understand how NHEJ repairs DSBs directly without a DNA template but with maximal selectivity. Biochemical, structural and functional studies of individual components and complexes involved in NHEJ, carried out in my lab and elsewhere, suggest that several mechanisms operate throughout synapsis, end processing and ligation to maintain correct co-localisation of components over time. These are: (i) a stage provided by Ku-heterodimer interacting with DSBs supporting DNA-PKcs, APLF, BRCA1, PAXX amongst others; (ii) a second stage, DNA-PKcs, which links the kinase with DNA, Ku, PARP1, BRCA1 and Artemis; (iii) a temporary scaffold, which facilitates repair operations, constructed from XRCC4-XLF filaments, assembling to bridge Ku bound at DSB ends. Lig IV bound to XRCC4 C-termini likely terminates the scaffold, bringing LigIV close to DNA broken ends; (iv) a string provided by Artemis C-terminal-extension, which is intrinsically disordered, but includes short inear "epitopes" that recognise DNA-PKcs, DNA LigIV and PTIP, and keeps components closeby. My specific objectives are to study how these different but complementary ways provide colocalisation and efficient DSB repair.

Amount: £1,236,018
Funder: The Wellcome Trust
Recipient: University of Cambridge

Farming, food, and forecasting: developing outbreak resilience and sustainability in global agricultural systems. 24 Mar 2016

Crop and livestock diseases continue to pose threats to agricultural production and the provision of safe and balanced diets for healthy human populations in Sub-Saharan Africa. The problems are especially acute for invasion and spread of exotic and novel pathogen strains. Examples include rift valley fever, zoonotic diseases such as cysticerosis and echinococcus, and wheat stem rust, maize lethal necrosis and cassava brown streak disease in staple crops. The impacts and risks of epidemic spread are intensified by changing patterns in the agricultural landscapes, driven by population growth and urbanisation, and exacerbated by climate change. Conventional responses to epidemic outbreaks tend to respond reactively, inefficiently and de novo to each new threat. Building upon recent developments in the effective use of modelling to inform epidemiological policy, we have assembled a group of animal and botanical epidemiologists, together with experts in health, economics, social science and policy, to develop and test a robust framework for Sub-Saharan Africa. The epidemiological framework will address multiple scales (farm, district, national and regional) and provide planners, regulators and others with tools to minimise the risks of outbreaks, prepare for and manage outbreaks efficiently, and assess likely impacts of disease on food security, health and livelihoods.

Amount: £29,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Mathematical Genomics and Medicine 30 Sep 2016

University of Cambridge - Mathematical Genomics and Medicine

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge - Infection, Immunity and Inflammation 30 Sep 2016

Cambridge - Infection, Immunity and Inflammation

Amount: £133,716
Funder: The Wellcome Trust
Recipient: University of Cambridge

Stem Cell Biology and Medicine 30 Sep 2016

Not available

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Mathematical Genomics and Medicine 30 Sep 2016

Imperial College London - Theoretical Systems Biology and Bioinformatics

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

Stem Cell Biology and Medicine 30 Sep 2016

Not available

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

University of Cambridge - Developmental Mechanisms 30 Sep 2016

University of Cambridge 4 year PhD Programme - Developmental Mechanisms

Amount: £133,023
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge - Infection, Immunity and Inflammation 30 Sep 2016

Cambridge - Infection, Immunity and Inflammation

Amount: £133,716
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterisation of fate choice regulators in single mouse haematopoietic stem cells 30 Sep 2016

Virtually nothing is known about the exact molecules responsible for orchestrating haematopoietic stem cell (HSC) self-renewal and lineage differentiation. Identifying molecules governing stem cell self-renewaland differentiation will not only provide a greater insight into stem cell biology but may also uncover novel therapeutic targets for cancer since cellular mechanisms regulating clonal expansion in cancer are likely analogous to those operating in stem cells. My PhD will focus on the identification and assessment of molecular drivers of stem cell fate choice and has two aims: 1) Identification of genes directing lineage choice in HSCs. Two approaches will be taken to identify candidates: i) Clustering of single HSC gene expression profiles and functional transplantation outcomes based on cell surface marker expression, allowing the correlation of functional outcome with a particular gene expression profile. ii) Gene expression profiling of single HSCs and their direct progeny in conditions which support either self-renewal or promote differentiation. 2) Functional validation of gene candidates in vitro and in vivo with respect to effects on self-renewal and differentiation. This will be achieved by perturbing gene function and by performing a series of single cell functional assays.

Amount: £44,049
Funder: The Wellcome Trust
Recipient: University of Cambridge