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Recipients:
University of Oxford
University College London
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Results

Effects of sex on metabolic homeostasis in old age 31 May 2018

The main aim of our research is to determine the differences in the lifespan and physiology of male and female Drosophila melanogaster in response to increased levels of sugar (sucrose) in the diet. Current human diets are detrimental to health and obesogenic. The health outcomes are dependent on the sex of the individual, however the molecular and physiological mechanisms are not understood. The results of our study will help establish a Drosophila model that can be used to understand how nutrition and sex interact, which might contribute to a healthier lifestyle choices in humans leading to healthy ageing. The effects of diet on lifespan and diet-induced obesity of the two sexes will be recorded, as well as the feeding behaviour using the proboscis extension assay and blue-food assay. Gut morphology/function will also be examined since the gut appears to underlie the different response of the sexes to increased dietary protein. In particular, we will focus on age-induced hyperplasia by determining the number of proliferating cells (stained with anti-phospho-Histone 3). We will also monitor gut function by assessing the leakiness of the gut using a blue food. Finally, statistical analysis using suitable regression models will be performed in R.

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

Dynamical modelling of somatic genomes 28 Nov 2017

Cancers are complex and chaotic systems. It is becoming apparent that no two cells in a cancer are genetically identical or follow the same evolutionary trajectory. Chromosomal instability (CIN) is one way that cells generate this complexity and is a hallmark of all cancer and ageing. In cancer, it increases the level of variation available to cells and gives rise to intra-tumour genetic hetereogeneity, which makes the disease more agressive, drug tolerant, and harder to treat. We are still far from a complete understanding of how cells undergoing CIN evolve over time, in particular, we do not know how populations of cancer cells evolve and how selection acts to change these properties. Understanding this normal evolutionary behaviour will be key to separating the functional and non-functional aspects of intra-tumour heterogeneity. We will tackle this problem by understanding cancer as an emergent complex system, and use simple dynamic stochastic models to capture the essential biological features of the processes underlying CIN, including chromosome gain and loss, structural change, and genome doubling. We will use the vast amount of NGS data already available to fit these models using Bayesian inference and infer the evolutionary aspects of CIN in healthy and cancerous tissues.

Amount: £1,273,968
Funder: The Wellcome Trust
Recipient: University College London

Regulated mRNA stability and translation in neural stem cell development 28 Nov 2017

Understanding how the billions of varied cells in the human brain develop from a small number of neural stem cells (NSCs) is a central question in biology and medicine. This highly complex process has largely been explained by transcriptional regulation dictating the levels of protein expression in stem cells and their progeny. Using novel single molecule approaches to quantitate transcription and protein levels, we have discovered functionally important conserved examples where the levels of transcription and protein expression do not correlate. These include pros/prox1, the regulator of NSC proliferation and differentiation and myc, the proto-oncogene regulator of stem cell size. We will characterise the mechanism of post-transcriptional regulation of pros, myc and 21 additional functionally important examples we have discovered, all of which have extremely long 3’UTRs that are bound and regulated by the same conserved RNA binding proteins, Syp and Imp. We will also measure, genome-wide, mRNA stability and characterise the trans-acting factors and cis-acting signals regulating stability and translation. The proposed programme will characterise a hitherto under-studied layer of regulation acting in addition to transcription in complex tissues, providing major new mechanistic insights into how the brain develops in health and disease.

Amount: £1,972,007
Funder: The Wellcome Trust
Recipient: University of Oxford

Assessment of placental function in complicated pregnancy using advanced MRI 04 Dec 2017

Placental insufficiency underlies the major obstetric syndromes of fetal growth restriction (FGR) and pre-eclampsia and accounts for one third of stillbirths in high-income countries. There is an unmet clinical need for a method to properly characterise placental perfusion and determine if and when a placenta is likely to fail. The objective of this work is to develop an imaging method to assess placental function in complicated pregnancy. This work will help us to better understand placenta function in FGR. This project will compare placenta properties from appropriately developing and early-onset growth-restricted pregnancies to understand the differences in the appearance of the placenta in FGR. The key goals of this work are to assess a novel Magnetic Resonance (MR) Imaging method to measure fetal and maternal placental perfusion. This technique describes an MR signal that models the blood flow properties as they change between the maternal and fetal sides of the placenta. to link this to relevant clinical information including clinical ultrasound markers and fetal MRI. to use these results to establish a comprehensive imaging project for the placenta by providing an in vivo measurement of placenta function to complement information from ultrasound imaging and ex utero microCT.

Amount: £99,804
Funder: The Wellcome Trust
Recipient: University College London

Investigate the role of SET1A in the activation of gene expression 30 Sep 2018

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.

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

Dengue Controlled Human Infection Model - Development Grant 17 Nov 2017

Following a positive response to the preliminary submission for grant funding to establish a Dengue Controlled Human Infection Model (Dengue-CHIM ) in Ho Chi Minh City, Vietnam, I am submitting this request for a small grant to assist in refining and developing the main proposal prior to final submission in March 2018. During this pre-submission phase I plan to employ an experienced post-doctoral immunologist to carry out a) a scoping review of the current landscape of dengue vaccines in development, and b) a review exploring the current understanding of the immune response to/protection from DENV infection and disease, particularly focusing on immune correlates of protection. This will be the first application of a Dengue-CHIM approach in any dengue endemic setting, and raises a number of important bioethical concerns. Therefore I also plan to employ a Vietnamese social science research assistant for a period of 4 months to engage with key Vietnamese stakeholders to discuss the important issues surrounding endemic setting CHIMs, conduct preliminary informal interviews with these individuals, and help to develop the agenda for a 2 day workshop focused on Bioethics and Stakeholder Engagement related to endemic setting CHIMs that will take place in early March.

Amount: £23,690
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of E2F targets in oncogene-induced replication stress tolerance as potential new targets for cancer therapy 31 May 2018

In human cells, deregulated G1/S transcription, the transcriptional wave that commits cells to the cell cycle, is at the basis of many cancers and it is governed by the transcription factor E2F2. Oncogenes such as c-myc, deregulate G1/S transcription leading to uncontrolled cellular proliferation. We will induce expression of the oncogene c-myc in epithelial human cells, that directly leads to the increase in levels of E2F transcription. Unscheduled S-phase entry leads to replication stress and DNA damage, and thus genomic instability, which may lead to cell death or drive cancer initiation if the DNA damage repair is impaired. Paradoxically, this increased E2F-dependent transcription provides also a mechanism for replication stress tolerance to protect cells from catastrophic genomic instability. Some cancers have very high levels of replication stress, and by understanding how these cells are able to tolerate such high levels, we may be able to target these buffers for new cancer therapeutics. A large scale screen is being performed in the lab to identify these targets. I will investigate the role of one of these targets. Preliminary work in the lab and previous work in yeast suggests that the Smc5/6 complex may be such a candidate for oncogene-induced tolerance.

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

Appraisal of LRG1 antibody internalisation and as a dual acting antibody-drug conjugate 30 Sep 2018

Abnormal blood vessel formation contributes to diseases such as cancer, and is the result of inappropriate angiogenic signalling. In recent years, it has been shown that in the presence of the transforming growth factor beta1 (TGFbeta1), leucine-rich alpha-2-glycoprotein 1 (LRG1) promotes the formation of new blood vessels, via a process known as angiogenesis. Blocking the activity of LRG1 by using an antibody against it leads to reduced blood vessel growth, and thus, could be exploited to inhibit cancer growth. We aim to combine the blood vessel normalisation achieved by LRG1 blockade with affecting cancer cell deterioration. To do this, we aim to modify the LRG1 antibody vehicle, using state-of-the-art biotechnology, with a suitable fluorophore to evaluate internalisation into a cancer cell (i.e. its ability to deliver cargo), followed by decoration with a suitable toxic drug to evaluate efficiency in cells.

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

Structural studies of the host-parasite interactions at the heart of malaria pathogenicity 05 Apr 2018

Our proposed activities consist of two major strands. Firstly we wish to take our research on tour, developing a high quality interactive stall which will allow us to present our findings to those who visit science fairs. We have secured a place at the Royal Society Summer Science Exhibition in July 2018, as the first outing for our display and this provides the deadline by which we must have the stall in place. As this is one of the UK’s premier science festival, visited by ~13,000 people each year, this is a great opportunity to meet people and to share our research. We will also ensure that our stand is fully updateable in content – for example using interactive screens which can be altered over time. We will next present at the Oxford Science Festival in 2019 and 2020, at which the Biochemistry Department has committed space. We will also apply to present at another major science festival as soon as applications open (i.e. Cheltenham and Edinburgh) in each of 2019 and 2020. This will be supported by digital content, including a ~2 minute video which will describe our approach towards rational malaria vaccine design and will be posted on Youtube. We will also develop an interactive vaccine game in which players can allocate health budgets and see the effect on malaria prevalence. Together with informative content about our research, these will widen the accessibility of our research.

Amount: £49,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Exploring the role of Genome Architecture in Neuronal Development using an in vitro model system 31 May 2018

The research aim is to explore the role of genome organisation and three-dimensional configuration in regulating transcriptional responses during neuronal differentiation. To do so, expression of co-regulated candidate genes during differentiation from neuronal progenitor cells (NPCs) to post-mitotic neurons (PMNs) will be identified with qRT-PCR. NPCs will be dissected from E12.5 mouse cortices and cultured in basic Fibroblast Growth Factor (bGFG). Differentiation into PMNs will be induced by adding neurotrophin-3 (NT-3). The nuclear localisation of pairs of co-regulated genes will be detected using double fluorescence in situ hybridisation (D-FISH), assessing whether these genes relocate to transcriptionally active regions, like transcription factories, or transcriptionally repressive regions, like the nuclear periphery. Results will also compare transcriptional changes in neuronal differentiation with nuclear re-organisation patterns in the expression of activity-regulated genes (ARGs), like c-Fos and Gadd45b. This will allow the identification of genome architecture changes specific to cortical development. Possible gene co-localisation, genomic-wide contacts and loci interactions will be studied with 4C technology, which combines chromosome conformation capture (3C) methodology with high-throughput sequencing.

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

Molecular Simulations of Membrane Protein Lipid Interactions 31 May 2018

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.

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

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.

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

Molecular control of pathogenic neutrophil responses in inflammation 28 Nov 2017

Neutrophils cause immunopathology by overproducing anti-microbial activities that may lead to tissue damage in inflammatory and autoimmune diseases, including rheumatoid arthritis, vasculitis, and lupus. Recent data highlight the existence of neutrophil subsets with different pathogenic properties. However the molecular control of pathogenic neutrophil responses is largely unknown. We will identify the intrinsic transcriptional circuitry that controls neutrophil functional reprogramming and provide insights into neutrophil heterogeneity and pathogenic phenotypes at sites of inflammation. Our recent studies highlighted a number of candidate transcription factors that will be functionally validated during the course of this project. Our work and the results of others have shown that neutrophil accumulation in tissues during sterile inflammation is controlled by macrophages. We will characterise how protein and lipid signals produced by monocytes and macrophages in the tissue at the different stages of inflammation affect neutrophil accumulation and activation and whether these are under a unified transcriptional control. Understanding the control of pathogenic neutrophil responses and identification of key regulators of immunopathogenic phenotypes will help to redefine these understudied cells in chronic inflammatory disorders and may lead to new treatments reducing the burden of human chronic inflammatory disease.

Amount: £1,541,677
Funder: The Wellcome Trust
Recipient: University of Oxford

Mechanobiological control of immune cell activation 21 May 2018

Biomedical sciences increasingly recognise the importance of mechanobiology in health and disease. While most mechanisms of the immune response are adequately explained by cell-biology, biochemistry, and genetics, many of its features profoundly depend on biomechanical aspects. One such scenario involves the ability of immune cells to differently respond to antigens with similar binding affinities, highlighting additional parameters needed to fully explain antigen discrimination. Emerging evidence indicates that immune cells dynamically adjust their biomechanics to facilitate this process. The principle goal of this project is to uncover how biomechanical feedback modifies the mechanobiology of activating T-lymphocytes by altering the dynamic assembly and organisation of actin structures, hence adjusting the sensitivity of antigen recognition. With the advent of immune checkpoint blockade and T-cell re-direction there has never been more interest in controlling lymphocyte responses, and biomechanical signal integration has received relatively little attention despite the consistent failure of biochemical parameters to account for T-cell discrimination of different antigens. To address this research project, I will lead a team to apply new state-of-the-art force probing technology coupled with high-speed super-resolution microscopies, overcoming the limitations of previous approaches to generate a breakthrough understanding of mechanobiology in immune cell activation.

Amount: £98,263
Funder: The Wellcome Trust
Recipient: University of Oxford

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.

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

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.

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

Decoding the molecular identity of neurons 28 Nov 2017

Regulated gene expression underlies the specification of cell fate and the maintenance of cell-specific function. Cellular diversity is of particular importance in the brain where neural circuits are assembled from cells with unique properties. Many neurological and psychiatric conditions arise from dysfunction in the brain, and although molecules are the targets of therapeutic drugs, we know relatively little about those that are critical for specific neural functions. Here we propose to generate a single-cell resolution transcriptome of the entire fly brain using Drop-seq. In a unique collaborative effort we will mine this data set to uncover molecules that contribute to an array of important neural processes, including: 1. How does Kenyon cell diversity support memory-guided decisions? 2. What is the extent of input specificity to functionally discrete dopaminergic neurons? 3. How do particular peptidergic neurons respond to internal states? 4. How does sex-specific neuronal identity emerge? 5. Is there a rational transcription factor logic for cell-specific gene expression? Our endeavour also possesses significant technological value. Transcriptomic information, and the design of synthetic regulatory sequences that decode cell-specific patterns of gene expression, will improve the precision and resolution with which experimental effector genes can be targeted to pre-determined groups of neurons.

Amount: £3,500,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Pre-configured and learned properties of hippocampal circuits 10 Apr 2018

Despite recent advances in systems and computational neuroscience, very little is known about how the brain’s functional complexity arises during ontogenesis and which developmental mechanisms determine the emergence of complex behaviour. The proposed research aims to bridge this gap between developmental neurobiology and systems neuroscience by defining the relative roles of early embryonic events and post-natal learning in the development of spatial and non-spatial coding in the hippocampal formation. Our key goals are to: 1) establish whether the functional diversity in hippocampal place cells is defined by early embryonic divergence; 2) test whether ‘non-place’ coding in the hippocampus is intrinsic to the network (as place coding appears to be), or whether it requires late post-natal learning; 3) discover the relative contributions of experience-dependent and independent processes in creating the specific neural architecture (‘continuous attractor') underlying codes for direction and distance. We will deliver these goals using chronic in vivo recording of neural activity (high density electrophysiology and calcium imaging) in developing animals coupled with neuronal birth tagging, behavioural testing and functional inactivation of crucial targets, to discover which self-organised embryonic events and instructive signals are necessary to organise hippocampal circuits.

Amount: £1,097,310
Funder: The Wellcome Trust
Recipient: University College London

Exploring glial roles in sculpting brain development 21 Feb 2018

Although two broad cell types, neurons and glia, compose the brain, neurobiologists have tended to focus on neurons, the electrically excitable cells that process information. Glia were thought of primarily as neuronal support cells. Recent work challenges this view and shows that glia play essential roles not just in supporting neuronal function but also in instructing their development. I propose three aims to address how glia regulate two key aspects of brain development, neuronal birth and neuronal identity: (i) A major challenge in neurobiology is defining the origin of neuronal identity (and thus diversity). I will investigate how signals sent by glia to naïve precursors determine the unique neuronal fates that these cells adopt. (ii) Although the brain has little regenerative potential, under restricted circumstances differentiated glia can act as stem cells to generate neurons. I have identified one such example and will probe the signals that reprogramme glia to generate neurons. (iii) I will explore how different glial types differ in their regulation of neural development. I will begin with a systematic survey of the signals released by different glial-subtypes and then manipulate these while evaluating their effect on neighbouring neural precursors and neurons.

Amount: £1,198,593
Funder: The Wellcome Trust
Recipient: University College London

Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies 10 Apr 2018

Background: Over 1,800 autosomal recessive (AR) Mendelian-disease genes have been identified. Missense mutations account for 59% of protein coding region mutations, yet their precise functional effects remain largely uncharacterized. Two important questions in human genetics aim to explain interindividual variation in phenotypic severity and assign pathogenic mechanisms to different disease phenotypes (including independent phenotypes within the same syndrome). For AR disorders, it is thought that many missense mutations cause protein instability. For these hypomorphic mutations, disease phenotypes are defined according to quantitative genetic threshold effects within a protein interaction network. Project: We will focus on a subset of AR ciliopathies which are strongly enriched for missense mutations, where complete gene knockout is thought to be lethal (see Rationale-below). We will use gene-editing and quantitative protein-protein interaction analyses to systematically compare the phenotypic effects of frameshift (likely knockout/null) and missense mutations. We will test our hypothesis that these missense mutations disrupt only a subset of gene functions/protein interactions, using phenomics algorithms we have developed and unbiased phenotyping in cell lines and mouse models, allowing us to assign pathogenic mechanisms to disease phenotypes. In future, this approach could be extended to the estimated 10-20% of > 3,000 Mendelian-disorders enriched for missense mutations.

Amount: £1,706,863
Funder: The Wellcome Trust
Recipient: University College London