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Funders:
Paul Hamlyn Foundation
The Clothworkers Foundation
The Wellcome Trust
Amounts:
£0 - £500

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Results

Nanomagnetism in cancer treatment: How Iron Oxide Nanoparticles can be used to target therapies to the brain 31 May 2018

Iron Oxide Nanoparticles (IONPS) are a class of nanoparticles used in targeting therapies towards tumour sites. The emerging field of nanotechnology has garnered a lot of interest in tumour therapy especially for brain tumours. IONPS can be coupled with an anticancer drug and with the use of magnetic field (Muthana et al., 2015) can be ‘steered’ towards a desired site within the body. This technology would hope to increase the amount of drug concentration to the tumour site which also means that the amount of drug delivered systemically could be reduced. In this project, the student will learn how to use FEMM (Finite Element Mathematical Modelling) to create magnetic array (a special arrangement of magnets) to optimise the magnetic field strength. This will be tested through a range of in-vitro experiments for its efficacy. Laboratory training will include isolating human peripheral mononuclear cells (PBMCs), flow cytometry to examine PBMCs cell viability/cell death following the addition varying concentrations of IONPS. Data analysis will involve using a software called FlowJo (used for flow cytometry) and Prism software to carry out statistical analysis. The student will be able to learn how to operate a confocal microscope, carry out immunohistochemistry and processing tissue samples.

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

microRNAs in Oscillatory gene networks 31 Jan 2017

MicroRNAs are key regulators of gene function that have emerged as highly represented connectors within gene networks. Current work in the field suggests that microRNAs primarily serve a role in the buffering and regulation of transcriptional and translational network motifs. Unpublished data suggests that microRNAs are found in certain network motifs, such as double feedback loops, more frequently than would be expected by chance. Dynamic gene expression is a field which has recently been shown to be important in the understanding of progenitor cell maintenance and differentiation. Modulation of dynamic gene networks by microRNAs has been shown to be able to control the timing of progenitor cell differentiation in neuronal progenitor cells. It is not currently understood how microRNAs integrate into oscillatory gene networks or if they perform similar regulatory roles in other oscillatory network motifs. Using a top down computational approach gene interaction maps will be generated for human transcription factors and microRNA target predictions. Utilizing this map potentially oscillatory gene network motifs will be identified and their interactions with microRNAs predicted. A subset of neuronal transcription factors which are found within potentially oscillatory network motifs will be selected, validated and the functional analysis of the microRNA interaction investigated.

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

Biological and lifestyle predictors of outcomes in people with head and neck cancer 31 Jan 2017

Using data collected from a prospective clinical cohort of people with head and neck cancer (HNC)-Head and Neck 5000 (H&N5000), I will examine the potential value of baseline (pre-treatment) biological, clinical and lifestyle factors in predicting HNC prognosis at one year and three years post diagnosis. I will look at the association between tobacco and alcohol consumption and measures of outcome- overall survival, disease-free survival, metastasis, and second primary tumour (SPT) development. I will investigate whether behavioural change i.e. abstaining from, or reducing the consumption of alcohol and tobacco improves clinical and self-reported health outcomes in this population. To better understand how smoking and drinking behaviours may be influencing prognosis, I will analyse the methylation and metabolite profiles of baseline blood samples. I will explore whether there is an association between DNA methylation and metabolite levels and tobacco and alcohol consumption. Should I identify sites that are differentially methylated in smokers and drinkers, or metabolites that vary by smoking/drinking intake, I will evaluate whether they could potentially act as biomarkers for cancer progression and survival. I will look to develop a risk score that incorporates clinical, biological and lifestyle risk factors, which could be developed for use in clinical decision-making.

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

The entropy of behaviour under stress 31 Jan 2017

Stress is both widespread and difficult to detect, with massive health and economic impact on both humans and the millions of animals we care for. Individual differences in response to stressors show behaviour can become more repetitive and stereotypic or more unpredictable and chaotic, so universal behavioural indicators of stress have been elusive. We propose that entropy, a key concept in information theory which captures how chaotic or disordered a sequence of data is, will be a useful approach to apply to behavioural signals, with stress causing extremes in entropy on either side of the spectrum. We propose to test this theory by:   (i)            Developing methods to extract measures of behavioural entropy from automatically collected accelerometer signals;  (ii)           Studying the change in behavioural entropy under acute stress, with individuals selected to provide a variety of response valences;  (iii)          Investigating the effects of individual behavioural differences and personality as predictors of the directional change in entropy.  The overall aim of this research will be to develop a robust and versatile behavioural indicator of stress, with far-reaching applications to understand the neurological changes stress causes, and improve detection of poor animal welfare.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

Characterising the spatial determinants of antimalarial resistance in P. falciparum malaria 31 Jan 2017

At present artemisinin-based combination therapies (ACT) are recommended for the treatment of uncomplicated malaria and are hoped to limit possible development of antimalarial resistance. Recent observations of ACT resistance in Southeast Asia however indicates that the emergence of clinical resistance is occurring, indicating that parasites may be developing resistance to both components of the ACT. It is thus imperative that a course of action for balancing both the longevity of antimalarial efficacy and the immediate public health impact is identified. We aim to develop a spatial individual stochastic model of malaria transmission that incorporates both the epidemiological and within host process in order to better understand the drivers of ACT resistance emergence. Through this endeavour we aim to identify strategies at regional levels within Southeast Asia in order to slow the speed of ACT resistance. Finally we will predict and map the potential future burden of ACT resistance within Southeast Asia.

Amount: £0
Funder: The Wellcome Trust
Recipient: Imperial College London

Profiling n3-PUFA modulation on Ras nanocluster organisation and function 31 Jan 2017

Ras proteins are molecular switches that regulate signalling pathways involved in cell proliferation and survival. These form transient nanoclusters on the plasma membrane, whereby Ras effectors are recruited. The spatiotemporal organisation of lipids within the Ras nanoclusters determine Ras function in signal transduction. Incorporation of dietary fats such as omega 3 polyunsaturated fatty acids (n3-PUFA) into the membrane phospholipid bilayer alters their biophysical properties. In addition, n3-PUFA has been associated with cancer prevention and attenuation of Ras signalling. We propose that n3-PUFA modulation of Ras nanoclustering is responsible for the attenuated signalling response. Different Ras isoforms occupy distinct nanoclusters. In addition, both isoform and oncogenic mutation-specific Ras signalling differ. It is unclear whether the role of n3-PUFA is highly context specific or if they are pan-Ras modulators. Therefore, to test our hypothesis and determine the specificity of n3-PUFA effects, we will profile the proteome microenvironment of different Ras isoforms and mutation variants treated +/- n3-PUFA. In parallel, studies measuring the nanoclustering responses of the same Ras variants to n3-PUFA will also be performed. These results will be correlated with studies profiling the signalling network response. Together, these studies will define the extent to which n3-PUFA modulates oncogenic Ras signalling.

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

Regulation of KIFC1 expression and centrosome clustering by deubiquitylases 31 Jan 2017

KIFC1 (HSET) is a minus-end-directed kinesin whose depletion promotes multipolar mitosis in cancer cells carrying additional centrosomes. Centrosome amplification often occurs in breast and ovarian cancers where KIFC1 is also frequently overexpressed. While cancer cells usually overcome the presence of additional centrosomes by clustering them into two groups to form pseudo-bipolar spindles, they lose this ability in the absence of KIFC1. As multipolar mitosis is usually lethal, targeting KIFC1 may selectively kill cancer cells without affecting non-transformed cells. This exciting hypothesis currently lacks systematic validation. Here, the KIFC1 requirement for normal mitosis and survival will be addressed in a panel of cancer and non-transformed cell lines. Stability of proteins in cells may be regulated by a family of ~90 deubiquitylase (DUB) enzymes, which recently aroused interest as potential drug targets. Targeting a DUB that stabilizes KIFC1 would be predicted to promote KIFC1 degradation and multipolar mitosis. In this project we will identify DUBs that maintain cellular levels of KIFC1, then characterize the effect of their depletion and their mechanistic interaction with KIFC1. Lastly, we will assess the clinical relevance of our findings, by evaluating expression of KIFC1 and its regulatory DUBs in breast cancer patient tissues and performing clinicopathological correlations.

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

Defining mycobacterial host-pathogen interactions: the role of the secreted protein MPB70 31 Jan 2017

Tuberculosis is an infectious disease which in humans is caused by Mycobacterium tuberculosis and in cattle by Mycobacterium bovis. The genome sequences of these two bacterial species are 99.95% identical, with deletion of genetic information leading to a reduced genome size in M. bovis and no unique genes per se in M. bovis compared to M. tuberculosis. The high degree of genetic identity contrasts with the distinct host preference of the pathogens, and suggests that host preference is likely driven by differences in the expression of key genes between M. tuberculosis and M. bovis. We are particularly interested in two genes coding for secreted proteins, MPB70 and MPB83, which show significant differential regulation between the two species. Through combined in vitro infection assays with bacterial mutants, proteomics studies and in silico evolution studies of these genes and their regulon, we will investigate if MPB70 and MPB83 play a specific role in the host-pathogen interaction and the nature of this interaction. By elucidating the role of these proteins in host preference, we hope to increase our knowledge of host-pathogen interaction and to open new avenues for the development of disease control approaches in both human and bovine tuberculosis.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Genome evolution in the Candida clade 31 Jan 2017

The CUG-Serine clade, a group of yeasts including the common human pathogen Candida albicans, has been known to translate the codon CUG as serine instead of leucine for over 20 years. Recently, a sister species that translates CUG as alanine was discovered. In my bioinformatics rotation I discovered a second, independent CUG-Ser clade as well as a CUG-Ala clade and three separate CUG-Leu clades.In my PhD project I will examine tRNA gene evolution in these clades and test the hypothesis that they descended from a catastrophic event in their common ancestor in which the CUG- decoding tRNA was lost. I will perform experiments to artificially push a yeast species to change its CUG translation from Ser to Leu by replacing a tRNA gene, and monitor the effect on the proteome. In parallel, I will study centromere evolution in yeasts, which show an extraordinary diversity of centromere types, by using ChiP-seq to find centromeres across the Candida clade and beyond. This project will develop valuable new tools for manipulating Candida genomes, including transformation vectors that completely lack CUG codons and should work in any species, and potentially also new centromere-based plasmids for use in C. albicans.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College Dublin

Discovery of small molecules that modulate transient protein-protein interactions leading to amyloid formation 31 Jan 2017

The development of anti-amyloid drugs has been hampered by the mechanistic complexity of amyloid formation pathways. In order to gain a greater understanding of the conformational changes and dynamic motions associated with fibrillogenesis, this project aims to develop and use small molecules to study an archetypical amyloid protein, beta2-microglobulin (beta2m) – specifically, the amyloidogenic truncation variant, DeltaN6. Small molecule fragments which are compatible with site-directed screening methods will be synthesised, so as to allow amyloid-modulating regions of DeltaN6 to be targeted. Hits which are identified in site-directed screens will be optimised as necessary, in order to produce small molecules which are capable of perturbing amyloid formation pathways upon binding. Understanding the link between small molecule-induced changes in DeltaN6 dynamics (to be studied using nuclear magnetic resonance spectroscopy), and changes in the rate and outcome of fibrillogenesis, will provide both beta2m-specific and generic insights into amyloid formation pathways.

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

Mechanisms of transport of the leaderless protein galectin-3 to the cell surface 31 Jan 2017

Unconventional protein secretion is a poorly understood physiological process in which proteins without an N-terminal signal sequence exit the cell. There are currently four proposed pathways by which unconventionally secreted proteins are thought to exit the cell: by direct translocation across the membrane, via secretory lysosomes, by release from exosomes or multivesicular bodies, or through membrane blebbing. No complete mechanism has been described for any of these pathways, representing a significant gap in our knowledge of protein trafficking. Unconventionally secreted proteins play important extracellular roles physiologically, but abnormal levels are associated with several human diseases, including metabolic disease. As such, this mechanism is interesting to gain an insight into disease as well as to broaden our understanding of cell biology. I will investigate the unconventional transport of galectin-3 to the cell surface. Galectin-3 will here be used as a model to understand the mechanism of unconventional secretion. Data-driven and hypothesis-driven approaches will feed into each other to form a picture of how galectin-3 is secreted. A CRISPR-Cas9 screen has identified potential proteins that decrease cell surface galectin-3, providing the starting point for further investigation. Hypothesis-driven experiments will be used to investigate aspects of the models previously proposed.

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

Structural studies of bacterial nucleic acid transport proteins 31 Jan 2017

Horizontal gene transfer contributes to genetic plasticity in bacteria and is of great clinical relevance as it contributes to the spread of antibiotic resistance genes. One mechanism of horizontal gene transfer in bacteria is transformation. While the phenomenon of transformation has been known for many decades, little is known about the mechanistic steps of exogenous DNA uptake into bacterial cells. The most obvious problem is how the DNA gets past the cell envelopes. ComEC is believed to be the protein that forms an aqueous pore that allows transport of DNA into the cytoplasm through the bacterial plasma membrane. The protein represents a novel transport protein, and no structural and very little functional information is available. The aim of the project is to structurally and functionally characterize ComEC proteins using modern protein expression and screening techniques, advanced structural approaches (X-ray crystallography, cryo-electron microscopy) and functional studies (fluorescence microscopy, biophysics), in order to build a model for DNA transport across the plasma membrane into the cytoplasm.

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

KDEL Receptor Stuctural Determination & Biochemical Characterisation 31 Jan 2017

This project aims to characterise the KDEL receptor (KDELR) structurally, biochemically and biophysically. The KDELR is a membrane protein resident in the cis-golgi, where it binds the K-D-E-L amino-acid motif present on resident ER proteins, which have been transported to the Golgi via bulk flow. Once KDELR binds cargo, it initiates transport back to the ER via COPI mediated vesicles, where it releases its cargo, ostensibly because of the differing pH. The molecular mechanisms concerning the actions of the KDELR are largely elusive and would be greatly aided by the structural determination of the KDELR, as well as the structures and characterisations of its interactions with native cargos. Furthermore, KDELR has been predicted to be a GPCR, but does not appear to share homology with proteins in the family. However, distant homology to the SWEET family of sugar transporters has been found, suggesting these ‘receptors’ are in fact transporter like proteins. Furthermore, this project has the potential to involve live cell imaging experiments (in collaboration with Prof. Francis Barr) to test hypothesis borne from the structural and biochemical data.

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

Genetics and urban environments in the development of autistic spectrum traits 31 Jan 2017

Cities are now home to more than half the world’s population and this number is expected to increase dramatically over the century. Previous research has shown that urban living is detrimental to mental health conditions such as autistic spectrum traits, so it is now more important than ever for us to understand the environmental causes of this increased risk and how our genetic background exacerbates or mitigates environmental influences. My PhD will use complementary methods to triangulate on these causes with data from UK and international population cohorts. The methods I will use include structural equation modelling of geocoded twin and DNA data, and Mendelian randomisation analyses to investigate causal influences. The results of my project may inform policy and health service provision for the next generation of urban planners.

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

Dissecting Polo kinase recruitment to the centrosome 31 Jan 2017

Polo kinase is an important cell cycle regulator and it is essential for the correct assembly of centrosomes, major cell organisers. Centrosomes are formed by a pair of cylindrical centrioles surrounded by pericentriolar material (PCM). Polo controls PCM assembly (at least in part through Cnn phosphorylation) and also centriole disengagement and assembly. How Polo is recruited to centrioles and centrosomes is mysterious. During my rotation I have obtained evidence that the PCM protein Spd-2 is necessary for Polo recruitment to centrosomes. During my project I aim to characterise if Polo binding to Spd-2 is necessary for Cnn phosphorylation and correct PCM organisation, what happens when Spd-2 cannot bind Polo and what upstream regulators facilitate this interaction. Furthermore, I aim to identify the other centriole/centrosome proteins involved in Polo recruitment. To do this, I will make use of biochemical assays and advanced microscopy techniques, coupled with fly genetics and a powerful mRNA injection assay to rapidly test the effects of different mutants in fly embryos. Ultimately, I hope to be able to describe in molecular detail which proteins are phosphorylated by which kinases to allow Polo to be recruited to fulfil its many functions at the centrioles and centrosomes.

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

Structure and Action of the Metazoan Disaggregase Complex 31 Jan 2017

The metazoan Hsp70 disaggregase system is the only known human protein complex capable of resolubilising aggregated protein, conferring a protective phenotype for a range of pathologies. Disaggregation occurs through the dynamic assembly of a Hsp70/110 complex, initiated by J-protein recruitment of substrate. The structure of the active complex is currently unknown, as is the mechanism of disaggregation. This project will employ an interdisciplinary approach to structurally characterise the disaggregation of alpha-synuclein amyloid fibres in vitro by the human proteins DNAJB1 (J-protein), Hsc70 (Hsp70) and Apg2 (Hsp110). There will be a primary focus on understanding two particular elements of disaggregation. Firstly, how do J-proteins recruit substrate to activate disaggregation? This will be investigated using electron tomography, taking advantage of the recent "resolution revolution" in the electron microscopy field. Secondly, what is the mechanism of the active disaggregase complex as it is resolubilising aggregates? To answer this, we aim to track individual alpha-synuclein fibres by atomic force microscopy and total internal reflection fluorescence microscopy as they are solubilised during disaggregation. Given the role of aggregation in a broad range of debilitating diseases, increasing the understanding of disaggregation in humans has the potential to eventually lead to significant public health benefits.

Amount: £0
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Organisation of pericentromeric chromatin in Saccharomyces cerevisiae 31 Jan 2017

Successful cell division relies on faithful chromosome segregation. Central to this process is sister chromatid cohesion by cohesin that topologically entraps sister chromatids. Cohesin shows increased association with chromosomal regions surrounding the centromere, called pericentromeres. Pericentromeric cohesin is crucial during both meiosis and mitosis. In meiosis I, when homologous chromosomes segregate, pericentromeric cohesion is protected from separase-dependent cleavage ensuring that sister chromatids stay together until they segregate in meiosis II. In mitosis and meiosis II, pericentromeric cohesin facilitates chromosome biorientation by establishing preferred kinetochore geometry for capture by microtubules. How exactly pericentromeric cohesion facilitates chromosome biorientation is unknown. It was proposed that pericentromeric cohesin establishes intramolecular linkages allowing the pericentromere to adopt a cruciform structure. This would facilitate a back-to-back geometry of kinetochores and would promote kinetochore capture by microtubules from opposite spindle poles. This project aims to characterise the conformation of the pericentromere in budding yeast. I will examine how the conformation of pericentromeric chromatin responds to the presence and absence of tension that is exerted on chromosomes during biorientation. The research will extend to mitotic and meiotic cells, with wild type and cohesin-deficient backgrounds. Ultimately, this will further our understanding on how kinetochore geometry facilitates accurate chromosome segregation.

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

Machine Learning methods for microscopy image data in high-content screening 31 Jan 2017

An important area in drug development is understanding low-level molecular processes and pathways that cause diseases. These cellular phenotypes are high-dimensional and are increasingly being captured using single-cell assays and high-content imaging. In understanding natural cell trait variation and engineered variants, we can elucidate the cellular consequences of disease mutations. In my project, I will exploit cellular images in a range of contexts to investigate the link between genetic variation and cell trait variability using both natural genetic variation and engineered variants. To do so, I will develop machine learning methods to extract features from high throughput microscopy data, and to accurately account for genetic, environmental, and experimental sources of variability in them. Furthermore, I will work on integrative approaches using public genomic data to bring in other omics modalities, thereby tackling key challenges in the larger aim of deciphering disease and fostering drug development. I will use existing data from the HipSci project, high throughput drug screens from AstraZeneca, and, in addition, will design and oversee the generation of datasets through high-throughput CRISPR knockouts as part of Leopold Parts’ group at the Wellcome Trust Sanger Institute and Oliver Stegle’s group at the European Bioinformatics Institute.

Amount: £0
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

Functional proteomic analysis of novel antiviral restriction factors in primary leukocytes 31 Jan 2017

This project aims to identify and characterise novel antiviral restriction factors (ARFs) that play key roles in preventing infection of primary leukocytes. ARFs may function by preventing viral entry or exit at the cell surface, or replication at various intracellular stages. I will focus on the subset of plasma membrane (PM) ARFs, which will be identified by two properties: interferon (IFN) induction and virally-induced downregulation. For this I will employ tandem mass tag-based MS3 mass spectrometry, enabling quantitation of PM proteins in primary leukocytes. Key Goals: 1. Use IFNs and infection with two important human pathogens, human cytomegalovirus and HIV as a functional screen to identify novel cell surface ARFs 2. Investigate how these ARFs inhibit viral infection, and how are they targeted for destruction by viruses. The use of IFN as part of the functional screen will additionally enable exploration of the difference in effects between IFNalpha, beta and lambda at the PM, a subject which is currently surprisingly poorly understood. This will provide important insights into human immunity in its own right. Understanding how viruses interacts with and targets ARFs for destruction will have important implications for therapy.

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