- Total grants
- Total funders
- Total recipients
- Earliest award date
- 04 Jan 2017
- Latest award date
- 31 Dec 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
My aim is to complete a quantitative analysis of the dynamic signalling pathways that control mitosis. By combining mass spectrometry with cutting-edge microsopy I intend to measure the number of active molecules of the key mitotic regulators and determine how and where they interact to generate a highly responsive signal transduction network that ensures genomic stability by controlling sister chromatid separation and mitotic exit. I have four main aims: 1) Measure the numbers of the mitotic regulators controlling chromosome separation and analyse how they are modulated by post-translational modifications (PTMs). 2) Determine the dynamics of the spindle assembly checkpoint (SAC) in living cells by measuring the generation of the SAC effector complex and the flux of its components through the pathway. 3) Determine how changes to a kinetochore affect its ability to catalyse the generation of the MCC. 4) Determine how a defined change in the number of molecules of specific regulators alters the dynamics and strength of the SAC, and in consequence their effect on genomic stability. Together, these studies will be used to inform and discriminate between models of mitotic control to determine how the SAC combines the properties of potency and responsiveness.
Dissecting Androgen excess and metabolic dysfunction – an Integrated SYstems approach to PolyCystic Ovary Syndrome (DAISY-PCOS) 28 Nov 2017
Polycystic ovary syndrome (PCOS) affects 5-10% of all women; androgen excess is one of its major diagnostic features. While often perceived as a reproductive disorder, PCOS is now emerging as a lifelong, complex metabolic disorder, with increased risk of type 2 diabetes, hypertension, cardiovascular disease, and, as recently documented, non-alcoholic fatty liver disease (NAFLD). However, there has been no recent breakthrough regarding risk stratification or therapeutic intervention in PCOS. Our work has provided evidence for a key role of androgens in the development of PCOS-related metabolic complications. We will combine cutting edge in vivo physiology techniques, state-of-the-art metabolomics and machine learning-based computational approaches to address our overarching hypothesis that androgens are major drivers of metabolic risk in PCOS. We will use an integrated set of in vitro, ex vivo and in vivo experimental medicine studies to test this hypothesis and answer our specific questions: Does the control of androgen excess improve metabolic function? What is the role of different androgen pathways in conveying metabolic risk? Can we integrate phenome and metabolome data by machine learning to predict metabolic risk in PCOS? Our overall aim is the identification of novel personalized approaches and therapeutic targets for patients with PCOS.
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.
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.
Pathogenic Neisseria species continue to cause harmful infections in humans. Neisseria meningitidis causes life threatening meningitis and septicaemia infections, particularly in infants, and Neisseria gonorrhoeae causes the sexually trasmitted infection gonorrhoea. There is an urgent need to further study these pathogens particularly N. gonorrhoeae as gonorrhoea cases are on the rise and it is increasingly in the news due to the sharp increase in cases with resistance to antibiotics, leading to the fear that gonorrhoea could soon become untreatable. We will investigate the role that toxin/antitoxin modules play in Neisseria biology. In other pathogens, these systems have been observed to include a toxin able to stall bacterial replication and an antitoxin that neutralises the toxin's activity. When under stress, the antitoxins are degraded leaving a free toxin to arrest bacterial growth. In this non-growing state bacteria are tolerant to antibiotic challenge. There is very little known about how the toxins of Neisseria function and what their role is in infections. This proposal will address this lack of knowledge by discovering the biological systems targeted by the toxins and assessing their effect on Neisseria metabolism.
Regulation of tissue neutrophil function and survival by the interplay between oxygen and metabolite sensing pathways 28 Nov 2017
Neutrophils are essential for host defence but widely implicated in disease. A fine balance exists between maintaining effective host pathogen responses and limiting host-mediated tissue damage. Innate responses to bacterial challenge are critically regulated by oxygen availability. We have implicated different components of the HIF/hydroxylase pathway in regulating these outcomes. We also showed exposure to hypoxia can reprogramme subsequent neutrophil responses to infection. More recently, we observed that changes in oxygen availability and HIF/hydroxylase activity are associated with alterations in neutrophil metabolic status. I propose that neutrophil adaptation to oxygen and nutrient deprivation at inflamed sites is a consequence of interplay between HIF/hydroxylase activity and metabolic specialization, which defines the magnitude and duration of the neutrophilic response. The goals of this proposal are therefore to: 1. Define the mechanisms by which hypoxia reprogrammes the inflammatory response. 2. Dissect the mechanisms by which HIF/hydroxylase pathway members regulate neutrophil metabolism and subsequent biological function. The ultimate goal is to identify tissue-specific factors that can be targeted to limit detrimental inflammation whilst preserving systemic immunity. This is an area of significant clinical need, with no current strategies that target neutrophil mediated inflammation either in the context of sepsis or chronic inflammatory disease.
Roundworms (Nematoda) and flatworms (Platyhelminthes) are among the most species-rich animal groups. They include free-living animals, but also parasites with a dramatic impact. Worm infections (helminthiasis) ruin farm animals and plants, and infect more than half of the worldwide human population decreasing birth outcome, cognitive development, and school and work performance. Understanding their biology is imperative to fight these organisms with a huge socioeconomic importance. This is a pilot study to apply evolutionary genomics to the origins of parasitism and drug targets detection. Genomes compared under the light of their evolutionary relationships will define differential genetic content (gene gains and losses) between parasites and non-parasites. This will provide new insights on how harmless organisms became parasitic at genome level, but will also detect new targets to fight these diseases. Parasite-specific gains will constitute ideal drug targets, providing high specificity; gene losses will indicate deficiencies in the parasites physiology that can be also attacked. The application of evolutionary biology to discover drug targets is highly original, building on the emerging field of evolutionary medicine, and has never been applied to macroscopic parasites. This project will be the basis of future research and collaborations to further develop drugs to target these diseases.
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.
Development of small molecule inhibitors of the Pseudomonas aeruginosa biofilms to treat chronic infections in cystic fibrosis patients 01 Oct 2017
Cystic fibrosis is the most common lethal, hereditary disease in Caucasian populations, affecting 1 in every 3,500 births in Europe with a current life expectancy of about 38 years. Most disease-related morbidity and mortality in CF is caused by progressive lung disease as a result of bacterial infection and airway inflammation, primarily associated with the effects of chronic Pseudomonas aeruginosa (PA) lung infection and the persistence of PA biofilms. The Trust has awarded Antabio €4.0m over 2 years to fund the development of a small molecule inhibitor of PA biofilms to be used in combination with standard-of-care antibiotics. The objective of the project team, led by Principal Investigator Dr Martin Everett, Head of Biology at Antabio, is to identify a potent and selective lead series with efficacy in animals which will be capable of further development into a drug to augment the effectiveness of antibiotic therapy and result in enhanced suppression of the infection.
Fungi detect and adapt to stressful environmental changes by reorganizing their messenger RNA (mRNA) and protein. Better understanding of how this works is essential to counter the global human health threat from fungal pathogens. I propose three interlinked aims that bring together mechanistic insight, high-throughput biology, and machine learning to investigate this: 1. Which sequences in the terminal/3’ regulatory region (3’UTR) of an mRNA encode its stress-responsive localization, translation, and decay? I will synthesize a large library of chimeric mRNAs, measure their mRNA processing in Saccharomyces cerevisiae by RNA sequencing, and use modelling to find out which combinations of sequence and stress inputs drive which outputs. 2. How does the conserved RNA-binding protein Ssd1 enable fungal stress tolerance and virulence? Ssd1 is essential for fungi to survive stress, regulating specific mRNAs through their 3’UTRs, but its exact RNA-binding sites are unknown. I will measure these sites, before and after stress, to discover Ssd1’s mechanism of action. 3. How does the fungal pathogen Cryptococcus neoformans begin infecting a human lung? I will use RNA sequencing and other high-throughput approaches to characterize the transcriptional and post-transcriptional processes enabling C. neoformans to adapt and grow in a lung-like environment.
The circadian clock and viral pathogenesis 18 Oct 2017
Diverse biological processes exhibit circadian rhythms that are driven by cell-autonomous biological clocks, including most facets of the immune response. Using herpesviruses and influenza A virus, I recently demonstrated that circadian rhythms affect virus progression in vivo and replication in cells. Furthermore, I discovered that disruption of circadian rhythms enhances infection. I now want to understand, mechanistically, how the circadian clock influences viral pathogenesis. I will investigate whether cell-intrinsic antiviral pathways are under circadian clock control, using comparative transcriptomics to monitor responses to herpesvirus and influenza A infection at different circadian times and in different ‘clock mutants’. Circadian rhythms in candidate pathways will then be ablated or inverted to assess their impact on time-of-day differences in viral replication in single cells, and as the virus spreads. I will delineate the relative contribution that these endogenous cellular rhythms make to viral pathogenesis, compared with circadian rhythms in systemic host immune responses by examining infection in mice with desynchronised peripheral circadian rhythms compared with tissue-specific ‘clock knockouts’ (arrhythmic epithelial, myeloid-lineage or lymphocyte-lineage mice). Collectively, my research will address the constraints that host circadian rhythms place on viral infection and whether viruses exploit the predictability that biological timekeeping confers upon host physiology.
The causal map of the human phenome 18 Oct 2017
This fellowship is focused on maximally exploiting GWAS summary data and 2SMR methodology. I will: 1. Create a computational framework that can construct and represent the causal map of the measured human phenome. Using existing (MR-Base) and upcoming (e.g. GoDMC, UK Biobank) data sources I will construct a graph of pairwise causal relationships between thousands of traits. Each causal relationship will be assessed using all available 2SMR and sensitivity methods to ensure transparency and highest standards for hypothesis-driven causal inference. 2. Exploit the graph to improve a) reliability of causal estimates by empirically assessing pleiotrpy; b) statistical power by exploiting outliers in the data to search for putative novel associations, and using graph traversal algorithms to find links for which direct associations are underpowered; c) interpretability by deconvolving the mediating relationships between arbitrary numbers of traits. 3. Use the causal graph as a tool for phenomic modelling. Example 1: linking molecular phenotypes to new or existing drug targets will enable the prediction of the efficacy and safety of developing interventions. Example 2: using MR against fitness related traits to obtain selection coefficients for each phenotype, I will construct models of human evolution, investigating the cost of complexity and evolutionary trajectories.
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.
An investigation of the causal pathways from childhood conduct problems to poor health outcomes and criminal behaviour in adulthood 08 Nov 2017
Conduct problems (CPs) are common across childhood and adolescence and there is increasing evidence from prospective, longitudinal studies that they may impact on a wide range of adverse outcomes in adulthood including antisocial behaviour and offending, psychiatric disorders, and poor physical health. However, there is little empirical evidence regarding processes underlying the strong associations observed. Additionally, less is known about the long-term consequences of CPs in low- and middle-income countries. Using two population-based birth cohorts in the UK and Brazil, the aims of this proposal are to: 1) Examine how different patterns of CPs across childhood and adolescence relate to adverse outcomes in adulthood (criminal behaviour, psychiatric disorders, cardiovascular disease risk). 2) Test three hypothesised explanations for the associations observed, comprising: a) Exposure to ongoing adversity across the life-course; b) Shared genetic and early-life environmental risk factors; c) Potential "snares" in young adulthood (i.e. mediators of the association between CPs and adverse outcomes). The overarching goal of this research is to identify a short-list of potential intervention targets to reduce the risk of negative consequences arising from childhood CPs. Therefore, I will also conduct a feasibility study to examine the potential of modifying the intervention targets identified from the research.
The discriminatory ability of pre-treatment HIV-1 low frequency drug resistance variants to predict antiretroviral treatment outcomes 21 Nov 2017
Because of the increasing levels of HIV drug resistance (HIVDR), genotypic resistance testing (GRT) is currently recommended for clinical care in developed settings and for surveillance purposes in resource limited settings. However, the inability of GART to detect resistance mutations at frequencies Our project aims to determine the discriminatory ability of pre-treatment low frequency HIVDR mutations to predict antiretroviral treatment outcomes. Data and samples (n=1,386) from the REALITY study; a multifactorial trial carried out in 8 sites from 4 sub-Sahara African countries, will be used. Whole genome sequencing (WGS) will be done for all baseline (pre-treatment) samples using a Miseq illumina platform with an established bioinformatics pipeline. The prevalence of pre-treatment low frequency HIVDR variants and their effect on treatment outcomes will be determined. End-points include virologic suppression (viral load, VL 1000 copies/ml at 48 weeks), opportunistic infections (Tuberculosis, Cryptococcus, Candida, severe bacterial infections) and hospital admissions. An attempt will also be made to define cut-off thresholds of clinical significance. Not only will this project build capacity for HIV-1 WGS and assembly, but will also inform HIVDR surveillance policy in sub-Saharan Africa.
Despite their widespread clinical use in cancer treatment, platinum(II) complexes, including cisplatin, present critical issues such as severe side effects and onset of resistance. Furthermore, their mechanism of action is not fully understood and no reliable patient stratification tool exists. Novel prodrugs based on photoactivatable platinum(IV) complexes are reduced to cytotoxic platinum(II) species upon irradiation with visible light, providing spatial control of their cytotoxicity. Photoactivated complexes are active in cisplatin-resistant cell lines suggesting a different mechanism of action. I will investigate the mechanism of action of platinum-based anticancer drugs on- and off-target, with focus on photoactivatable complexes and clinically established drugs. The cellular targets will be identified by functional genetics experiments (RNAi/CRISPR-Cas9 screening) and the fate of platinum in vivo will be evaluated by SPECT imaging with platinum-195m labelled complexes in mouse xenograft cancer models (Goal 1). The positron-emitting isotope copper-64 will also be used to evaluate copper-transporter Ctr1 as a biomarker to predict response to platinum-based chemotherapy (Goal 2). Based on these findings, I will modify photoactivatable platinum(IV) complexes (i) to reduce their off-target toxicity by attachment to antibodies targeting specific cancer-cells receptors and (ii) to enhance cytotoxic effect upon photoactivation, by attachment to light-harvesting chromophores (Goal 3).
Antibody drug conjugate (ADC) development has been hindered by synthetic strategies which result in heterogeneous mixtures of products each with their own pharmacokinetic profile. Whilst more drug per antibody molecule, the drug-to-antibody ratio (DAR), is preferable for cytotoxicity, the different aggregation potentials and pharmacokinetics of these higher DAR species typically results in reduced efficacy and non-specific toxicity. Using both chemistry and biology, my aim is to overcome the limit on DAR associated with the site-specific labelling. The project will focus on two principal areas: (a) the development of heterotrifunctional linkers, based on my previous work (Beal et al., 2012), which will enable site-specific DAR increase and investigation of drug synergies; and (b) exploitation of protein kinases as novel tools for the site-selective modification of proteins via the transfer of modified phosphates from gamma-modified ATP analogues. By combing these novel technologies with existing site-specific modification methods including disulfide bridging and unnatural amino acid incorporation, an assessment of these new materials against previous generations of ADC and commercial ADC will be undertaken. This research will be a step change in ADC development and enable a new generation of ADCs with a greater cytotoxic potential than previous iterations and therefore enhanced clinical outcomes.