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Currency:
GBP
Recipients:
University of Cambridge
Amounts:
£0 - £500

Results

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

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

Investigation into the role of RBM8A/Y14 in the development and function of megakaryocytes and platelets using a human pluripotent stem cell model of haematopoiesis 30 Sep 2018

Platelets are small blood cells, which cause blood to clot, preventing bleeding after injury. They are produced by megakaryocytes, large cells in the bone marrow. In people with low platelet counts (thrombocytopenia), life-threatening bleeding occurs spontaneously or after injury. Studying platelet and megakaryocyte development and function is important in understanding a) diseases causing thrombocytopenia, such as genetic disorders and other conditions, particularly cancer (and chemotherapy) and b) strokes and heart attacks, where platelets are excessively activated, forming clots that block vessels. Using stem cells (special cells capable of becoming any cell type) derived from adult skin or blood samples we grow & study megakaryocytes and platelets in the laboratory. We study a rare genetic disease, Thrombocytopenia with Absent Radii (TAR) syndrome, in which babies are born with very few platelets and abnormal bone formation (particularly the radius in the forearm). Our group discovered the cause of TAR, due to abnormalities in a gene called RBM8A, which helps cells control what proteins are produced; however precisely why this causes TAR is unclear. We believe our research will uncover the mechanism of this condition, helping to treat patients with TAR and improve wider understanding of how megakaryocytes & platelets develop and function.

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

Epigenetic control of neurodevelopmental gene regulatory networks linked to neurodegeneration 30 Sep 2018

Dementia is predicted to affect 130 million people worldwide by 2050 according to the World Alzheimer 2015 Report30. Some familial forms of dementia inherited in autosomal-dominant fashion are linked to mutations altering gene dosage2,8,14,16,19,23,25. Patients with the mutations display a long pre-symptomatic phase during which cellular changes may take place before the onset of the disease decades later23. The cellular changes are reflected in gene regulatory networks3,4,5,12,28,31. As evidence from other neurodevelopmental conditions suggests10,13,17, changes during early neural development may lead to onset of the disease decades later. In order to study the neurodevelopmental gene regulatory networks and their links to dementia, I would like to focus on two forms of their regulation: small RNAs and demethylation escapees. Demethylation escapees are regions of the genome that escape epigenome resetting during early embryonic development27. Small RNAs have an important role in neural development and gene regulatory networks controlling them1,6,20,24. In order to address the question, I will use RNA and whole genome bisulfite sequencing methods of neurons derived from human stem-cells from familial dementia patients, combined with bioinformatics analyses. Focusing on small RNAs and demethylation escapees, the project might hint at neurodevelopmental gene regulatory pathways dysregulated in autosomal familial dementia.

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

Regulation of Neural Stem Cells 30 Sep 2018

Of all the tissues and organs in the human body the nervous system is the most intricate and complex, consisting of more than 100 billion neurons. These neurons make precise connections with each other to form functional networks that can transmit information at amazing speed over considerable distances. Neurons are produced by neural stem cells, which renew themselves at each cell division while also giving rise to all of the diverse types of neurons in the brain. The Brand lab is interested in how the environment influences stem cell behaviour, in particular how nutrition regulates neural stem cell proliferation. Uncovering the molecular mechanisms that control whether a stem cell chooses to proliferate or remain dormant is crucial for understanding tissue regeneration under normal and pathological conditions and in response to ageing. It is critical to learn not only how stem cell proliferation is induced but also how stem cells can return to a dormant (‘quiescent’) state, as uncontrolled stem cell division can lead to cancer, including brain tumours like glioma. A thorough appreciation of the signals, both extrinsic and intrinsic, that control stem cell behaviour is necessary to understand how homeostasis is achieved and maintained in the brain.

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

Analysis of Inflammatory markers in chronic subdural haematoma 31 May 2018

This project plans to measure levels of tissue plasminogen activator (tPA) which is involved in fibrinolysis of blood clots within the CSDH lesions. This bleeding is an essential part of CSDH formation, followed by coagulation and fibrinolysis which is triggered by the cleavage of plasminogen by tPA to generate plasmin. tPA will be measured in these samples using the commercially available ELISA kit. I will determine whether levels of tPA are correlated with levels of other inflammatory markers in CSDH fluid or in blood, and also to examine if increased tPA levels at the site of the haematoma predicts risk of CSDH recurrence. If tPA concentrations in blood or CSDH fluid correlate with clinical outcome, this could be used clinically to decide whether surgical or pharmacological management are most appropriate for individual patients. Finally, the effects of dexamethasone treatment on levels of tPA and other cytokines will also be determined, by comparison of dexamthasone and placebo-treated patients. These patient samples are anonymised and will only be unblinded after measurement of the above analytes has been completed.

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

Investigating the role of mechanical forces in cell exit from the Zebrafish tailbud 30 Sep 2018

During the elongation of the embryonic body, groups of stem cells within the tip of the embryo continually generate progenitor cells that later make up the spinal cord and segmented vertebrae. Interestingly, differentiation of other embryonic cell types has been shown to be influenced by mechanical forces from the environment surrounding the cells in culture. Over the course of my PhD I will investigate the influence of the native mechanical environment on the differentiation of progenitor cells in the zebrafish embryo into cell types contributing to the formation of specialised tissues. This will aid in our understanding of how mechanical properties of tissues, such as their stiffness, can influence cell differentiation. Firstly, I will characterise cell movement, cell shape, and environmental stiffness coinciding with cell state transitions in the tailbud. Secondly, I will investigate the influence of mechanical forces on differentiation and epithelial to mesenchymal transitions. Finally, I will investigate the role of YAP in regulating differentiation into spinal cord and mesodermal cell types. These studies will provide important insight into the fundamental problem of how cell fate decisions and cell movements are coupled during embryonic development.

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

Mechanisms of lineage commitment during exit from pluripotency in vivo 30 Sep 2018

In early mammalian development, a pool of cells in the embryo can generate all cell types of the body, an ability referred to as 'pluripotency'. Specification of the cells is regulated by selective activation of genes that define tissue identities. These developmental programs are regulated by proteins known as 'transcription factors' that direct expression of other genes. However, the precise mechanisms that control cell fate specification are still poorly understood. The aim of my project is to understand the molecular mechanism of how genetically identical cells can be instructed to differentiate. I will focus on understanding the functional role of covalent 'epigenetic' DNA modifications in cell lineage priming and specification. To be able to address this fundamental question, I will use mouse embryos and stem cell culture systems, linked to imaging and single cell technologies to study the effect of perturbation of DNA modifications on cell fate specification. The results from my project will help us to understand how cells regulate their fate in early development. This is of great importance to understand developmental defects and learn how to instruct stem cells in culture for differentiation for potential use in cellular therapies in regenerative medicine.

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

Investigating the effect of the Drosophila mitochondrial genome on complex phenotypes 30 Sep 2018

The mitochondrion, known as the powerhouse of the cell, contains its own genome (mtDNA). The multi-copy mtDNA works with the nuclear genome to control energy production and various cellular activities. To date, mtDNA mutations are among the most common genetically inherited diseases and the mitochondrial replacement therapy has been approved in the UK to make three-parent babies. However, our knowledge of mtDNA biology and how it can affect organismal traits is rather limited. This is largely due to a lack of powerful genetic tools to study mtDNA. A recent study in Ma's group shows that Drosophila mtDNA can undergo homologous recombination12. Further, they established a system to induce recombination at specific sites and select for different recombinant genomes. This work not only provides a definitive resolution to the existence of recombination in animal mitochondria, but opens up the possibility of developing a recombination system for functional mapping and manipulating animal mtDNA. In this project, I will isolate recombinant mitochondrial genomes to map/define mtDNA variations responsible for longevity and fertility to accelerate our understanding of how mtDNA impacts health. Meanwhile, I will identify key components of the recombination machinery to better understand how mtDNA is maintained during aging and evolution.

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

Mycobacterial Determinants of Extracellular Success 30 Sep 2018

Tuberculosis (TB) is a severe infection which affects over ten million people a year, causing 1.7 million deaths annually. Treatment takes at least six months and four different drugs, and resistance to these drugs is an increasing problem. The causative bacteria, Mycobacterium tuberculosis (Mtb), lives mainly inside human cells. However, it must ultimately escape those cells to spread to the next host, a stage associated with worsening clinical disease. Despite its importance, little is known about how Mtb survives and thrives in this extracellular stage. This research will focus on understanding how the bacteria escape immune cell uptake, and whether they are using specific tactics such as 'biofilm' formation and 'quorum sensing'. Biofilm formation and quorum sensing are forms of bacterial behaviour that allow individual bacteria to ‘talk’ to each other via chemical signals, and set up collaborative, hardy, multifunctional colonies that can resist stresses including the immune response and antibiotics. In many other chronic human infections, biofilms are commonly seen and make the disease very hard to treat. This research will seek information about the genetics, regulation, and impact of biofilm formation in TB in order to unlock new knowledge about drug treatment and onward transmission of disease.

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

Proteomic characterisation of secreted antiviral factors in cell-mediated immunity to human cytomegalovirus 30 Sep 2018

Human cytomegalovirus (HCMV) is a widespread human pathogen, infecting 60-80% of the population. Infection is asymptomatic in immunocompetent individuals but causes disease in immunocompromised patients, such as transplant recipients. Current therapeutic tools are limited, with no available vaccine and a limited array of antivirals. HCMV triggers a broad and robust immune response involving both the innate and adaptive immune systems. Antiviral immunity is mediated in part by proteins secreted by immune cells and infected cells. In order to counteract this immunity, HCMV encodes numerous evasion factors that modulate the function of immune cells and the array of proteins they secrete (‘secretomes’). In this project, I will apply mass-spectrometry to generate comprehensive profiles of the secretomes produced by different immune cells when exposed to HCMV-infected cells. Using this technique, it will be possible to identify important and potentially novel secreted antiviral factors that can subsequently be validated and investigated to determine their mechanism of action. This will contribute to a better understanding of HCMV immunity and may facilitate the design of novel effective vaccine candidates and therapies.

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

Statistical Methods for the Analysis of Deep Sequenced Pneumococcal Data 30 Sep 2018

Streptococcus pneumoniae (the pneumococcus) is a major disease causing pathogen and can cause sepsis, meningitis and pneumonia especially in at risk populations such as young children and the elderly. Understanding genetic factors in disease virulence, transmissibility, and drug resistance informs the management and treatment of infectious disease. By using deep sequenced patient samples of S. pneumoniae it is possible to build a clearer picture of its within host diversity. I aim to develop statistical and computational methods for the analysis of deep sequenced pathogen data that are also able to deal with large datasets, of the order of thousands of samples. I aim to apply these methods to the analysis of deep sequencing data derived from nearly 4000 S. pneumoniae samples taken from patients in the Maela refugee camp, Thailand. The methods I develop will help to identify significant genetic factors for disease dynamics and antimicrobial resistance. The project will contribute to the understanding of S. pneumoniae and will also provide tools of more general applicability to the investigation of deep sequenced pathogen data.

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

Generation and validation of chemosensitisation screens to identify genes interacting with an inhibitor of Menin, a protein with an established role in AML 27 Apr 2017

Dr Vassiliou’s team have recently used the Streptococcus pyogenes-derived type II CRISPR–Cas system to perform genome-wide drop-out screens in acute myeloid leukaemia (AML) cells. Some of the identified AML specific cell-essential genes are being pursued as potential therapeutic targets in AML. The team has adapted this system to perform "chemosensitisation screens" to identify genes whose inhibition collaborates with anti-leukaemic compounds to enhance leukaemia cell kill. I propose to perform chemosensitisation screens to identify genes interacting with an inhibitor of Menin, a protein with an established role in AML. By performing CRISPR-Cas knockout screens in the presence of a cytostatic or low cytotoxic drug doses, genes can be identified whose loss can synergise with the drug. Both resistance (enriched sgRNAs) and sensitization (depleted sgRNAs) genes can be identified by quantitative sequencing of the sgRNA cargo of cells in the presence and absence of the drug. Selected interactions can then be validated using targeted disruption of the targets with sgRNA, an approach that is well-established in the laboratory. Use of chemical inhibitors of target genes, together with the Menin inhibitor, can be used to validate the interaction pharmacologically.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge
Amount: £1
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of genomic markers of ageing for the risk of metabolic disease 31 Jan 2017

Background: The risk for many common complex diseases, including type 2 diabetes, increases with age. Technological advances have recently enabled large-scale investigation of genomic markers of ageing in population-based studies. Whether genomic ageing contributes to the age-related rise of diabetes and related metabolic disorders is unknown. Aim: To systematically identify and study genomic markers of ageing, including telomere length, DNA methylation, and chromosome loss, and investigate their causal roles for morbidity and mortality from type 2 diabetes and other common complex diseases. My overall aim will be achieved by addressing the following specific objectives: Objectives: 1. To perform a systematic literature review of genomic markers of ageing to identify determinants and consequences and assess methods for their characterisation in epidemiological studies. 2. To identify and characterise genetic and modifiable behavioural and environmental risk factors of genomic ageing in large-scale population-based studies. 3. To investigate causal roles of genomic markers of ageing for morbidity and mortality from ageing-related diseases using Mendelian randomization methods, and conduct exploratory studies of the underlying pathways through detailed metabolomic characterisation.

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

Dynamics of KLF17 expression in human naive pluripotent stem cells 27 Apr 2017

Conventional hPSCs represent a relatively late stage of embryonic development, termed the primed phase of pluripotency. Their use in research and medical applications is problematic because they display a differentiation bias and do not generate all cell lineages efficiently. The Smith laboratory has recently defined culture conditions that capture cells in an earlier phase, termed naïve pluripotency. Naive hPSCs have potential implications for more effective stem cell therapies because they don't display a differentiation bias. Very little is known about the genes that govern human naïve pluripotency in culture. The transcription factor KLF17, which is present in naïve hPSCs but absent in primed hPSCs, is of particular interest because it is specific to primates and not well studied. The key goal of this project is to generate a fluorescent reporter for KLF17. Alternative reporter designs will be trialled by fusing fluorescent proteins to either the start or the end of the endogenous KLF17 protein, in order to achieve optimal fidelity and sensitivity. The reporter(s) will then be exploited to monitor the dynamics of KLF17 expression in live cells both following withdrawal of factors to initiate differentiation, and also during the process of generating naïve cells by resetting.

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

The effect of nutrients on maximal fat oxidation rates in adult humans measured using indirect calorimetry. 31 May 2018

I aim to study the effects of nutrient availability and mitochondrial transport capacity on the variability of maximal fat oxidation (MFO) during exercise in healthy adults. Less than half of MFO can be predicted by variables such as gender, VO2max and body composition. There are two possible reasons for this. First, nutrient availability may have a large effect on MFO and current protocols may not adequately control for it. Second, VO2max - which combines two variables with opposite effects on MFO (oxygen uptake and fat mass) - may not be the optimal predictor. Here, I will test whether heart rates at a given power are a better predictor of MFO and whether short-term fluctuations in nutrient availability can explain some of the variability of MFO seen within the general population. Nutrient availability will be altered using a glucose meal and by glycogen depletion. I will also use nitrate supplementation to test whether MFO can be increased by induced-expression of fat oxidation enzymes. The key goals are to determine to what extent short-term changes in nutrients and the expression of fat oxidation enzymes can alter MFO and whether the resultant fat oxidation rates can be predicted using simple heart rate data.

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