- Total grants
- Total funders
- Total recipients
- Earliest award date
- 12 Jan 2015
- Latest award date
- 14 Dec 2015
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The first phase of the proposed research is to establish the principles by which control structures are represented in the nervous system in motor control and sequential decision-making. The behavioural patterns revealed using well-established assays will be tested in order to provide evidence for an optimally efficient representation of the task structure as predicted by the common computational framework of Bayesian structure modeling. The second phase is to use neuroimaging techniques (fMR I) on humans in order to identify the neural substrates of a learning process which efficiently encodes the task structure. Parallel analyses will be performed on a rich, and already acquired, dataset composed of electrophysiological recordings from rodents. This will test whether the same model applies across species, and critically, relate the model to previously established neural phenomenon. The results of these two phases will be integrated into a novel neuro-computational model of the a cquisition of control representations in corticostriatal circuits and their use in decision-making. Based on the hyperactivity of the dopaminergic system, the resulting model will be probed for predictions of behavioural deficits which will then be tested in patients suffering from schizophrenia.
Using genomics to understand the role of cystic fibrosis pathogens in pulmonary exacerbations. 11 Nov 2015
CF is an inherited, life-limiting, multi-system disorder, for which acute deteriorations in lung function termed 'acute pulmonary exacerbations' (APEs) are the single most important cause of morbidity and mortality. Despite this, little is understood about the pathophysiological processes that trigger APEs, although they are thought to be driven by respiratory infections. However, there is no substantive evidence to date that the presence or load of individual species is driving this process. Th is may reflect the complex underlying microbial diversity found in the CF lung at both the inter and intra species level. Therefore, directly sampling of this diversity using high-throughput sequencing will enable major advances in our understanding of APEs. This project involves two approaches which may lead to the discovery of the microbial factors which drive the progression of APE's:(a)Targeted enrichment technology to enable genomic sequencing of multiple CF pathogens concurrently. This w ill enable a greater understanding of the evolutionary dynamics of CF pathogens in the context of APEs. (b)Temporal clonal analysis of Pseudomonas aeruginosa isolates which have been phenotyped for characteristics related to bacterial virulence. By applying a genome wide association analysis we will gain a greater understanding of the relationship between genetic diversity and phenotype.
Establishing an in vitro model for embryonic patterning using a novel micropatterning system 11 Nov 2015
An in vitro micropatterning system (MPS) was developed, using human ESCs, which apparently mimics patterning within the embryo. This 'embryo in a dish' develops a presumptive primitive streak, introducing the possibility of studying gastrulation dynamically in vitro. This MPS gastrulation model resembles 3D organoids emerging for a number of systems and enables signalling manipulation in time and 3D space. While this system was established in human, it cannot be validated by comparisons with in vivo human development. The mouse model represents an essential bridge between pluripotent cell cultures and the embryo. I will establish the MPS in mouse and compare the expression of lineage markers in the MPS directly to mouse embryos to ask whether this system recapitulates in utero development. I will use the MPS to compare mouse and human development and analyse the basis of patterning defects in mouse mutants. I will use transcription factor and signalling pathway fluorescent reporters to map the spatial and temporal requirements of BMP, Activin/Nodal and Wnt pathways for patterning at a quantitative single cell resolution in real-time. Using this data, in collaboration with the Siggia lab, mathematical models will be generated and tested to predict the phenotypic outcome of signalling combinations.
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.
Transcription, Trafficking, Translation: dissecting the spatiotemporal mechanisms underlying localised protein synthesis. 02 Dec 2015
The role of the mitotic spindle assembly checkpoint (SAC) protein BUB3 in tumourigenesis. 13 Apr 2015
The spindle assembly checkpoint (SAC) ensures the correct partition of chromosomes during mitosis. Depleting SAC proteins together with apoptosis inhibition leads to tumourigenesis. This project builds on a tumourigenesis model in Drosophila to address the role of SAC in hyperproliferation, metabolic regulation and tumour evolution. Initially I will study candidate genes uncovered by microarray analysis of a tumour generated by knocking down the SAC gene Bub3. As the cells' metabolic response ad apts to proliferation requirements it is clear that there must be a cross talk between cell cycle and metabolic control. To address this hypothesis, an enhancer/suppressor screen looking for metabolic proteins with links to cell cycle will be performed. The tumorigenic model derived from cell cycle defects affecting genomic integrity, will also be used to study tumour evolution. The use of a tumourigenesis fly model will exclude some difficulties of these studies in humans as tumours can be samp led at multiple stages. In addition, the tumour growth will not be limited by the life span of the hosts as the immortalized tumour can grow indefinitely through serial transplantations in inbred flies. Altogether the results will identify novel genomic loci and alterations responsible for tumour growth and cellular survival.
Germ cells exhibit unique and comprehensive erasure and re-establishment ofepigenetic information, which is critical for totipotency and the transmission of geneticand epigenetic information with long-term consequences for subsequent generations1.The principles of germline biology have the potential to provide core knowledge for thecontrol and manipulation of cell fates in developing and diseased tissues.A clear understanding of the transient state of competence is required first, together withhow these primed cells respond specifically to the critical regulators of mouse primordialgerm cell (PGC) specification. Importantly, with germ cells we also have a uniqueopportunity to identify and understand how epigenetic regulators can systematicallyreset the epigenome, even of the somatic nuclei when exposed in oocytes.Understandably, we know least about the largely inaccessible early human germ cells(hPGC), but we have opportunities to establish credible in vitro models through inductionof competence in pluripotent and induced stem cells (hESC and hiPS) for the generationand systematic studies of hPGCs.Accumulation of genome scale information on early mammalian germ cells mightimprove the prospects for the integration and modelling of dynamic changes regulatingkey germline properties, and allow testable predictions about the performance of thiscrucial lineage. This may also help to build experimental models that mimic keygermline properties and through this, a route to the experimental manipulation of cellfates and physiology.
High performance mass spectrometry: applications for the Cambridge biological sciences community. 11 Jun 2015
A major science focus across Cambridge is the application of state-of-the-art technologies to answer fundamental questions in biology, health sciences and translational medicine. These increasingly include high resolution proteomics and analysis of rare DNA and RNA modifications. Funds are requested to assist in the purchase of an Orbitrap Fusion Tribrid Mass Spectrometer, which combines quadrupole, Orbitrap, and linear ion trap mass analysers to provide an unprecedented depth of proteomic an alysis. Unique Tribrid architecture and Dynamic Scan Management allow simultaneous precursor isolation, fragmentation, and data acquisition in both Orbitrap and ion trap mass analyzers, maximizing the through-put and amount of high-quality data acquired. Improved sensitivity, scan rate, and mass resolution significantly increase proteome coverage and enhance the ability to positively identify more low-abundance proteins, while the use of novel SPS MS3 technology provides unparalleled accuracy of protein quantitation and identification when using isobaric mass tags. Overall, the instrument will: analyse the most challenging low-abundance or high-complexity samples; identify more proteins and their modifications; quantify their levels more accurately; and increase capacity of the Cambridge Centre for Proteomics, allowing greater user access and hence enhance science research.
To elucidate the structure of the mammalian mitochondrial ribosome attached to its translocon 20 Jul 2015
The emergence of widespread antimicrobial resistance poses a serious threat to modern medicine and global health. To address this growing threat, I will discover new antimicrobial agents with novel modes of action using a high-throughput combinatorial biosynthetic approach. Capitalising on the power of enzymatic reactions, I will create an automated platform for engineering thousands of host cells to express different combinations of native and modified biosynthetic enzymes taken from diverse or ganisms. My research will focus on utilising enzymes involved in the biosynthesis of quinolines, a highly promising class of natural products for targeting underexploited antimicrobial pathways such as intracellular microbial communication. I will engineer and reconstitute quinoline-based pathways involved in the biosynthesis of quorum sensing molecules from P. aeruginosa and medicinal alkaloids from C. acuminata. In addition to enzymes from these two pathways, I will also incorporate divers e quinoline-modifying enzymes from completely unrelated organisms, identified through literature surveys and predictive analysis of genomic data. Combinatorial expression of these enzymes in host cells will generate thousands of new bioactive molecules inspired by quinoline natural products. I will then conduct a range of biological assays to identify the best antimicrobial candidates that display unprecedented efficacy against multidrug-resistant microbial strains.
Burkholderia pseudomallei is a soil organism found in many parts of the world. Through direct contact with contaminated soil/water, humans acquire infection and develop melioidosis. The disease, often fatal, displays broad clinical manifestations, with different disease patterns reported from different countries. Little is known about factors influencing the disease outcomes and its geographical signatures. We hypothesise that bacterial genetics contribute to disease outcomes, and specificity th at (i) bacterial factors impact on acquisition, disease manifestations and severity; and that (ii) the prevalence of such factors are not homogenously distributed in bacterial populations in different endemic areas. A total of 985 B. pseudomallei whole genome sequences will be employed to address these hypotheses. A phylogeny constructed from 204 global isolates will highlight geographically distinct lineages and their evolutionary timeline. Routes of infection and progression to disease will be related to genetic relatedness of 331 disease and 450 environmental isolates collected from a circumscribed area in Thailand. Clinical manifestations linked to disease isolates will allow us to identify bacterial genetic factors associated with disease specificity, as to consider their prevalence in other geographical locations. Genetic variants predicted in silico will be tested in the zebrafish embryo infection model to validate computational hypotheses.
Decision-making concerning eating and drinking interventions for people with progressive neurological disease with and without decision-making capacity in the USA. 31 Mar 2015
Introduction: Decisions concerning eating and drinking for people with progressive neurological diseases are highly emotive and ethically challenging, particularly if the individual lacks decision-making capacity. These decisions are becoming increasingly common as the age of the UK population rises with the associated increase in the prevalence of neuro-degenerative diseases. In developing this project, our research group undertook a systematic literature review which revealed that most publish ed research into this area is based within the USA. Research question: How are decisions made concerning eating and drinking interventions for people with progressive neurological disease with and without decision-making capacity in the USA? Methods: Library-based research at Library of Congress and Georgetown University; 8-10 semi-structured US clinician interviews. Outcomes: (1) Research paper examining policy and best-practice on decision-making for people with progressive neurologic al disease in the USA (2) Academic and clinician network for future international collaborations (3) Establish an evidence base on policy and best practice internationally This grant provides excellent value for money as it will enable: a focused three month research project based in Washington, D.C.; and provide funds for a meeting of international collaborators to establish a network for a future project and funding bid.