- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Jan 2014
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The regulation of gene expression is fundamental for cellular integrity and is partly achieved by the opposing action of repressive and activating histone modifications. One such histone modification is the tri-methylation of lysine 4 on histone H3 (H3K4me3), which is known to correlate with transcriptional activity. The SET1A complex is responsible for depositing the majority of H3K4me3 in mammalian cells and disrupting its function often leads to gene expression defects. However, the mechanisms by which SET1A regulates gene expression remain unknown. I will use the auxin-inducible degron system to rapidly deplete SET1A levels. A series of genomics technologies, including ChIP-seq and NET-seq will then be used to determine the effects of SET1A loss on chromatin architecture and transcriptional activity. Additionally, proteomics techniques will be used to identify the pathways perturbed upon SET1A loss, hence identifying the mechanisms by which SET1A supports active transcription and furthering our understanding of how gene transcription is regulated. This is essential for the development of novel therapies targeting genetic diseases in which the control of gene expression is perturbed.
Membrane proteins account for ca. 20% of all genes, 40% of drug targets, and are mutated in many human diseases. The past decade has witnessed an exponential rise in the number of high resolution membrane protein structures. Interactions with lipids are of crucial importance for the stability, regulation, and targeting of membrane proteins, but structural and biophysical data on membrane protein-lipid interactions remain sparse. Molecular dynamics (MD) simulations provide a key tool for probing the interactions of lipids with membrane proteins. The overall aim is to apply multiscale simulations to predict specific lipid interactions of lipids with recently determined cryoEM structures of selected membrane proteins. This will be achieved by a serial multiscale approach. Coarse-grained simulations will be used to identify the interaction of membrane proteins with the lipids of complex membranes (i.e. in physiologically relevant mixed lipid bilayers based on lipidomics data). Atomistic simulations will be used to refine the resultant models. Predictions of protein/lipid interactions will be tested experimentally via our collaborators.
What Are The Roles Of MEIS1, BMI1 And HOXB Genes In Self-Renewal Of Acute Myeloid Leukaemia Stem Cells? 30 Sep 2018
Acute myeloid leukaemia (AML) is the commonest aggressive leukaemia in adults. Due to treatment resistance and relapse, the prognosis for most patients is poor. In normal blood cell development, stem cells are the most immature cells and can produce any type of blood cell. AML results when bone marrow cells acquire genetic alterations, called mutations. These mutations occur in early bone marrow cells and result in a ‘leukaemic stem cell’, which maintains growth of the leukaemia. Previous work in the Vyas laboratory has identified genes that are switched on in AML patients that cause leukemic stem cells to grow abnormally, including HOX genes. This project aims to further our understanding of the impact of these genes in leukaemic stem cells by answering questions such as: Is AML cell growth impaired when these genes are switched off? Do leukaemia cells behave like normal blood cells when these genes are switched off? Does switching on the genes make normal bone marrow cells behave like leukaemia cells? What mechanisms allow these genes to regulate the function of leukaemia cells? Our overall aim is to use this information to design treatment strategies to eradicate leukaemic stem cells.
The Effect of Priorizing Information in Working Memory on Later Behavioural Interference 31 May 2018
This experiment will investigate how prioritised information is represented in working memory (WM) through looking at the serial dependence effect. Myers and colleagues (2017) have suggested that items which are prioritised in WM are transformed into action-ready representations. Therefore, the theory predicts that the difference between prioritised and non-prioritised representations in WM will be reflected in behavioural findings. The serial dependence effect occurs when visual information from the recent past biases perception and behaviour at the present moment (Fischer & Whitney, 2014). If prioritised WM items were stored in an action-oriented format, we predict it will show these interference effects in behaviour more than non-prioritised information. By using an orientation adjustment paradigm, we will measure the serial dependence effect for prioritised WM items (which have been retro-cued) versus non-prioritised WM items. In addition, we will vary the type of testing (forced choice versus free recall), predicting that more interference will occur when the tests are the same than when different, due to the action-based nature of the WM representation. Initially we will use behavioural measures (reaction times) to measure the interference effects, extending to EEG to measure neural evidence for the carry-over effects.
The Role of Cyclophilins in Innate Immunity 30 Sep 2018
The Cyclophilins are a widely expressed, broad acting family of proteins defined by their common enzymatic domain. Among their multiple roles, they are reported to be involved in viral infections (including HIV, Hepatitis, and Influenza infections) both to the benefit and the detriment of the host. Despite this, much is still unknown about whether they play a role in the innate immune system. In the past this research has been limited due to the broad reactivity of the innate immune cells. However, with recent progress in stem cell research and CRISPR gene editing technology, we are now capable of manipulating these cells far more effectively. Therefore I intend to use these advances to knock out each member of the Cyclophilin family and then challenge my cells with a range of immune stimulants looking for changes in innate cell activation and protein secretion. Combining my panel with a pharmacological approach targeting virus-cyclophilin interactions, I also intent to determine whether HIV-1 uses only Cyclophilin-A during infection and discover novel Cyclophilin interacting proteins. These studies aim to lead to a better understanding of the fundamental functioning of cells in response to various threats, and may lead to pathogen specific drug therapies targeting Cyclophilins.
The proposed research addresses two of the major problems in psychotherapy research: How can effective psychological treatments be made available to the large number of people with mental health problems?, and How can researchers make rapid progress in making the treatments even more effective? The applicants have developed leading psychological therapies for three anxiety-related disorders (social anxiety disorder, posttraumatic stress disorder and panic disorder). They now propose to harness the power of the internet to solve both problems. Internet-delivered versions of the treatments will be developed and evaluated that require much less therapist time and can be delivered anywhere. Dissemination and evaluation of the treatments within NHS Improving Access to Psychological Therapies (IAPT) services will create a large database that will enable rigorous study of moderators and mediators of therapeutic change to identify targets for further improvements. Modifications of the treatment will then be evaluated in experimental treatment studies. The work will help realise the population level mental health benefits of previous Trust investment in psychological therapy research and align with the Trust’s new focus on maximizing the application of research to improve health by focusing on new product development and the uptake of patient-oriented research advances.
The hippocampus has long been considered a critical brain region for both episodic memory and spatial navigation. In addition, recent investigations have revealed that cells in the hippocampus also code for the passage of time. I aim to establish whether these temporal codes play a critical role in the organization of memory. To do so I will focus on the relationship between the hippocampus and entorhinal cortex. I will test the prediction that grid-cells in entorhinal cortex map the temporal dimensions of past experience, analogous to their well-established role in spatial processing. Furthermore, I will assess how temporal grid-codes organize memories to facilitate novel inference. The research will be conducted in humans, where there are well-validated fMRI tools for measuring entorhinal grid-codes and, unlike in rodents, complex behaviour can be easily assessed. These studies will provide insight into how the hippocampus and entorhinal cortex together contribute to episodic memory by organizing past experience across both space and time.
Signal transduction of the GPCR Smoothened: a key protein in Hedgehog-regulated morphogenesis and oncogenesis 30 Sep 2018
In complex multicellular organisms, cell-to-cell communication is often managed by morphogen gradients. The secreted Hedgehog ligands fall within this class, as they act in this manner during embryonic development. The Hedgehog signalling pathway (stimulated by these morphogens) tightly regulates crucial developmental processes including body patterning and symmetry. Serious developmental disorders result from inactivation of this pathway during embryogenesis, including holoprosencephaly and cyclopia. Hedgehog signalling is also active through stem cell programs throughout adult life, and aberrant Hedgehog activation, either ligand dependent or mutations in pathway components, can lead to cancer including medulloblastoma and basal cell carcinoma. The G-protein coupled receptor (GPCR) Smoothened is a key protein of this pathway, as it initiates the intracellular cascade, and is already targeted by anti-cancer drugs including Vismodegib and Sonidegib. However, the mechanism of signal transduction has only been poorly characterised. This project aims to explore this using both structural and biophysical approaches. We will study the mechanism and interplay of the two identified ligand-binding sites and the dynamics of agonist association with Smoothened. The ultimate goal is to determine the structure of active-state Smoothened and hence describe the mechanism by which its signal is transmitted across the plasma membrane.
Investigating principles of the regulatory chromatin context and incorporating them into computational models for gene regulation 30 Sep 2018
The mammalian genome is hierarchically structured into domains that restrict and shape the accessible chromatin environment for every genomic element. This context has fundamental implications for transcriptional regulation, by defining which regulatory elements have access to a gene at any given time. Novel experimental techniques are being used to investigate this folding at high resolution. Current computational methods for analyzing these data and models for predicting properties of gene regulation are limited in capturing the emerging principles of DNA folding. We will investigate the principles of chromatin folding with large scale, high resolution chromatin Capture-C experiments, mapping the regulatory domains of mouse embryonic stem cells and differentiated erythroid cells. We will develop computational methods better suited to analyze these data and explore models for integrating the large scale, three dimensional chromatin context to prediction tasks. We expect this to have a significant impact on our ability to interpret the vast amount of sequence mutations and polymorphism in the regulatory genome.
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.
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.
With the rise in multidrug resistance as a result of broad spectrum antibiotic use, bacteriocins have received attention as potential new antibiotics. Bacteriocins are bacterial toxins that kill closely related strains and species. Pyocin S5, a bacteriocin targeting Pseudomonas aeruginosa, a leading cause of multidrug resistant nosocomial infections, was shown to be effective against pneumonia in mice. Pyocin S5 depends on the iron receptor FptA and kills cells by depolarizing the inner membrane. Little else is known about its mode of action. Pyocin S5-producing cells harbour a gene encoding a small immunity protein, predicted to localize to the inner membrane, which protects from the action of this pyocin. In this PhD project, I aim to investigate the molecular mechanism of pyocin S5 binding to P. aeruginosa cells, its mechanism of translocation to the periplasm and the immunity protein’s mode of action. These aims will be approached using a combination of structural and biophysical methods as well as functional assays and a variety of fluorescence microscopy techniques.
Our overall objective is to experimentally identify the early immunological events which trigger a spontaneous breach of tolerance in genetically susceptible mice, and, which can be linked to the development of arthritis. We will analyse the immunological reactivity of the lungs of susceptible mice to environmental stresses such as microbes. Our purpose is to identify early biomarkers of autoimmune initiation, which will be assessed for suitability as treatment targets with translational relevance. We will seek to determine the benefits of administration of anti-microbial agents for amelioration of lung inflammation with a view to prevention of autoimmune disease progression.
Myeloid effector cells in inflammation 27 Apr 2017
Dysregulation of inflammation underlies a range of chronic inflammatory disease. By increasing our understanding of inflammatory mechanisms we may be able to identify specific therapeutic targets to treat disease. Using a murine model of acute, resolving inflammation, with zymosan as stimulus, we create a physiological inflammatory system where we can observe the spatiotemporal relationship of monocytes, macrophage and neutrophils which predominate this response. These observations in a controlled setting will give us insights into how these cells interact to orchestrate an inflammatory response. Gain of function IRF5 is associated with a range of autoimmune and inflammatory disease and promotes an pro-inflammatory phenotype in monocytes and macrophages. We will manipulate the system using mice deficient of IRF5 to modulate the monocytes phenotype and will be able to study the impact on neutrophil function and activation. These findings have the potential to be translated into more complex physiological systems and present new pathways for the study of disease.
The input required to control a prosthetic device greatly defines the subsequent precision that can be achieved. Robust mechanisms that are low-cost often use musculoskeletal motion for control. However, this often limits the level of control and applicability issues can arise when the system that is augmented also generates the power and drives the control. A device that is powered and controlled by breathing could expand the product options for patients and address certain requirements that are difficult to meet with the currently available prosthetic solutions. Computational modelling has been applied to asses if a Tesla turbine can be used for power and control. Positive results from the model and subsequent conceptual testing has indicated this innovative concept could indeed provide precision control for prosthetic users. The aim of the project is to design and produce a working prototype and test out the functional capabilities of the system using several predetermined tasks.
Design and evaluation of a modified vaccinia Ankara vector therapeutic vaccine for hepatitis B immunotherapy 30 Sep 2018
Hepatitis B virus (HBV) is a serious global health problem, with approximately 240 million people chronically infected. Long-term infection can lead liver failure, cancer and death. Current therapy controls but does not eradicate the infection. T cells are a type of immune cell necessary to fight HBV. During chronic hepatitis B these cells become less active. Checkpoint inhibitors are a form of immunotherapy that enables T cells to function again. In a study of woodchucks infected with a similar virus to HBV, treatment with vaccine and checkpoint inhibitor lead to better control of the virus. This project aims to use this combination of vaccine and checkpoint inhibitor, to treat patients with chronic HBV. A vaccine using a virus to carry the HBV proteins has been developed and shown to generate good immune responses in mice. We plan to develop a second vaccine to boost this response and test the vaccines together with checkpoint inhibitors in mice infected with the HBV virus. This will allow us to assess how effective this is at eradicating HBV. If the results from this study are promising, this could pave the way for clinical trials in humans with chronic HBV.
In the nucleus of every cell DNA is present as pairs of parentally-inherited chromosomes, from which genes are expressed to perform biological functions. In most mammals, including humans and mice, females tend to have two X chromosomes whereas males have one X and a Y chromosome, which lacks most of the genes present on the X. Thus in order to ensure that the dosage of gene expression from essential X-linked genes is similar between both sexes, almost all genes on one female X chromosome are silenced during development. X inactivation is mediated by a long non-coding RNA, Xist, which spreads to coat the chromosome and coordinates silencing through the recruitment of relatively few factors implicated in specific chromatin remodelling pathways. Beyond its intrinsic biological significance in mammalian development, it is a tractable model system for investigating general molecular mechanisms by which chromosomes are silenced. My reseach will focus on the question of how transcription factors that normally bind enhancers and promoters to activate genes are prevented from performing their functions as the X chromosome is silenced. I will investigate this question in cellular and in vivo models of X inactivation, including in mutant cell lines defective for chromosome silencing.
When cells divide, their genetic material is distributed between the new daughter cells. Problems at this stage can lead to genome instability, which may promote cancer. Centrioles (barrel-shaped structures in animal cells, surrounded by a layer of microtubules) organise cilia and centrosomes, the latter being the organelles that coordinate the mitotic spindle to pull the genetic material apart. Like the genetic material, centrioles must duplicate every cell cycle so each daughter cell inherits one centrosome. Consistently, the nascent centrioles grow until they reach the same length as the older centriole. I aim to gain insight into how this precise growth is achieved by studying CEP104, a protein implicated in centriole growth regulation. I will investigate the effect of Cep104 knockout on centriole growth in Drosophila melanogaster embryos. I will also study CEP104 dynamics in vivo using fluorescently tagged CEP104, and see how this is affected under different conditions and genetic backgrounds. This, together with interaction assays, will offer insight into the interactions occurring between centriolar proteins during centriole growth. Alongside this work, I hope to determine CEP104’s role in promoting cilia formation in quiescent cells, which represents an important switch between the centriole’s role in centrosome versus cilia organisation.
The neural network mechanisms of inferential reasoning The ability to make inferences, as defined by conclusions drawn from given evidence (Peirce, 1868), is a hallmark of higher cognitive function (Vasconcelos, 2008) that relies on internal models of past knowledge, including that of experienced environments (Markovits and Vachon, 1990; Piaget, 1987). The neural representation of such mnemonic models is thought to be shaped by life experience (Barlett, 1929, Lee, 2009) but the neural circuit-level mechanisms supporting the neural representation-to-behaviour translation of inferences remain to be identified. The goals of my project are: To investigate the neural circuit mechanisms underlying the ability to make an inference based on prior knowledge with large-scale neural recording techniques in the mouse brain. To test whether dopamine promotes neural mechanisms underlying inferential reasoning using state-of-the art neural manipulation methods.
Recently, experts agreed upon 4 consensus molecular subtypes (CMS) for the classification of colorectal cancer (CRC). CMS1 and CMS4 show a stronger stromal component together with poorer overall survival. Current CRC therapy only targets the tumour epithelium. Harnessing the power of the tumour microenvironment and immune system in CRC could represent a new drug paradigm. We will study the role the mesenchymal-epithelial cross-talk in colon homeostasis by focusing on gremlin-1. This secreted Bone Morphogenetic Protein antagonist is expressed exclusively by subepithelial myofibrobalsts in health. This protein maintains the stem cell phenotype at the bottom of the intestinal crypts, and dysregulation facilitates tumour initiation and progression. We will use mice and orthotopic xenograph models to assess the efficacy of BMP inhibition through an anti-GREM1 blocking antibody. Recent data supports the potential of immunotherapies in immunogenic MSI-H and polymerase epsilon (POLE) mutated tumours. We’ll receive blood and tumour samples from a clinical trial testing a combination of ipilumumab and nivolumab in MSI-H and POLE cases. We’ll use lymphocyte quantification, immunohistochemistry analysis and neo-epitope prediction to find determinants of response to these therapies. These studies will help better understanding and therapeutically exploiting the contribution of the mesenchymal and immune compartments to CRC pathogenesis.