- Total grants
- Total funders
- Total recipients
- Earliest award date
- 11 Jan 2016
- Latest award date
- 07 Dec 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
We seek support to consolidate an advanced electron cryo-microscopy (cryo-EM) facility dedicated to structural studies of biological macromolecular assemblies. The facility would provide a revolutionary new tool to the large structural biology community in the University that would enable acquisition of critical data in support of a wide and diverse range of projects tackling fundamental problems in molecular biology relevant to human health. Currently, the named applicants primarily use X-ray crystallography to study large assemblies, but many of these samples cannot be readily crystallised. The recent development of a new generation of direct electron detectors, together with sophisticated data-processing software, has dramatically improved cryo-EM analysis, which now achieves routinely sub-nanometer resolution. Until recently, researchers in the university did not have access to cryoEM, but this has changed with the recent Wellcome Trust award to purchase a cryo-EM instrument for sample screening and intermediate resolution structure determination. We are building on this support, to develop the second phase of our strategy and seek funding for an advanced microscope capable of high resolution structure determination to complement and extend our existing instrumentations.
I aim to take advantage of the cichlid fish of Malawi to study the interaction between transposable elements, non-coding RNAs, epigenetics and heritability. This is in line with the overall goal of my Investigator Award. I believe this system to be superior to equivalent experiments we might conduct in mice. This is due largely to the high phenotypic diversity and low genomic diversity of these fishes. At the time of writing of my Wellcome Trust Investigator Award the cichlid model was too immature to proceed with an experimental plan. Now we have the required genomics, RNomics and epigenetics (DNA methylation) are all in place
We have recently identified a novel pathway for metabolic regulation of HIF1 alpha by the OGDHC1. To continue this new area of research, it is essential that we have the necessary funds to maintian our competitive edge within the field, without diverting resources from our successful ubiquitin studies. The initial research on HIFs has been conducted by a talented graduate student, Stephen Burr. The timing of this funding request is particularly important, as it will allow Stephen to transfer his skills with a sufficient overlap for a new postdoctoral researcher to pursue this project.
Computational tools for analysing developmental morphogenesis at the tissue-scale
The complete synaptic-level connectome of a nervous system and experimental connectomics 30 Nov 2016
Animals sense the local environment, learn and remember past events, predict future ones, and combine current and past information to choose appropriate motor responses. Underlying these capabilities is the nervous system, which continuously integrates multiple sources of information and chooses one response in exclusion to all others. Our vision is to study neural circuit function on the basis of known synaptic-level wiring diagrams. In Aim #1, we propose to map the complete wiring diagram of an insect, the Drosophila larval central nervous system, using serial electron microscopy. With the knowledge of the circuits formed by the identified and genetically accessible larval neurons we can study how circuits change either by experience or in disease. In Aim #2 we propose to read out the engrams, the persistent yet reversible structural circuit patterns that form in response to learning and that underlie long-term memories, using associative memory in the larval mushroom bodies as the model system. For circuits to assemble correctly while remaining plastic, hundreds of genes need to work in concert. In Aim #3, we will study the effects of mutations in select genes associated with neural diseases on the synaptic-level circuit structure, causing the disease phenotype.
Characterization of the human extra-embryonic macrophage population, Hofbauer cells, phenotype and function 26 Oct 2016
Macrophages are among the first immune cells to seed embryonic tissues. They play important roles in early fetal development including tissue modeling and maintaining healthy tissue homeostasis. In humans, macrophages are present in the villous core of the placenta before a vascular connection with the embryo and these extra-embryonic macrophages, termed Hofbauer cells (HBC) are readily available for study. Developing our understanding of HBC and the role they play throughout gestation is important as they lie at the interface between the mother and fetus. HBC are likely to regulate placenta development, in particular the trophoblast cells that are the ultimate barrier between mother and fetus. HBC are also an important fetal defense against transplacental infections and in utero fetal infections are associated with pathogens that can survive in macrophages. However, the functions of HBC are poorly understood. Through this proposal, using some of the most advanced tools available today including multi-parameter flow cytometry, mass cytometry, RNA sequencing and organoid cultures, I will provide the first in-depth characterization of the human placenta extra-embryonic macrophages, HBC. I aim to describe the phenotype of HBC, their transcriptomic profile and functional properties. Keywords: Human extra-embryonic macrophages, Hofbauer cells, placenta, vertical-transmission, fetus, immunity.
Cellular and network mechanisms of hippocampal -prefrontal coordination during memory consolidation 09 Nov 2016
Consolidation of newly acquired memories takes place during sleep and involves the interaction of hippocampus and prefrontal cortex. The cellular mechanisms and synaptic pathways underlying this process are not fully understood but it has been hypothesized that synchronous hippocampal ripples and prefrontal cortex spindles mediate it. The present project proposes a multimodal approach to investigate these mechanisms in rodents. The first goal will be to dissect the fine-scale dynamics of memory reactivation in hippocampus and cortex during sleep after learning of a spatial memory task. This aim will be achieved with simultaneous large-scale recordings in both structures and advanced analysis of population activity. The second goal will be to unveil which anatomical regions and synaptic pathways are mediating this inter-regional synchronization. Simultaneous electrophysiological and functional magnetic resonance recordings will be performed in sleeping rats before and after the task and wide-brain activity will be assessed at times of high hippocampal-prefrontal synchrony. The last goal will be to causally verify the participation in inter-areal coordination and memory consolidation of the key synaptic pathway(s) pointed out in the previous stage. To achieve this, closed-loop optogenetic silencing of specific cellular populations would be performed at times of hippocampal-prefrontal synchrony during sleep memory consolidation.
The control of limb movements has been richly investigated both at the level of behaviour and in cortical electrophysiology. However, a unified theoretical understanding of how limbs are controlled by collective neuronal dynamics is lacking. The core of this proposal is an analysis-by-synthesis approach to relate the dynamics of the motor cortex to the computational objective of limb control. In this pilot project, we will make use of recent developments in the fields of stochastic optimal control and optimization to build model cortical networks that robustly control reaching movements, in the presence of noise at all processing stages and under key physiological constraints inherent to brain circuits. We will then 1) dissect the dynamical strategies used by the model networks to achieve robust control of limb trajectories, 2) relate the model's activity to cortical electrophysiology, and 3) use the models to guide future experiments (involving optogenetic perturbations during movement planning an execution) in collaboration with Karel Svoboda's lab at Janelia Research Campus. In the long term, such models will provide unique insights into the dynamical regime of the motor cortex and suggest optimal ways of interacting with neuronal populations to restore lost function via closed-loop neuroprosthetics.
DNA viruses, such as Herpes Simplex Virus 1 (HSV-1), exploit specific host DNA repair mechanisms to assist their replication. More recently, the DNA repair machinery that senses damaged self-DNA was shown to function in the innate immune sensing of viral DNA during infection. We aim to understand how a specific DNA repair pathway, non-homologous end joining, affects HSV-1 infection and how this virus exploits or evades these host responses. This work will further our knowledge of cell-intrisic immunity and DNA repair as well as leading to the rational design of improved vaccines and oncolytic viruses. Our preliminary data indicate that two NHEJ proteins, DNA-PKcs and PAXX act to restrict HSV-1 in different ways, via activation of innate immune responses or by directly affecting virus replication. This study will provide the mechanistic basis of these observations and compare these data with the other components of the NHEJ machinery and how they regulate HSV-1 infection. This work will therefore explore two hypotheses: NHEJ proteins regulate innate immune sensing of HSV-1 DNA NHEJ proteins restrict HSV-1 replication in the nucleus
Neural Circuits for Selective Auditory Filtering 05 Apr 2016
To facilitate sensory processing in complex environments, the brain can selectively filter auditory input to enhance neural responses to relevant sounds and suppress responses to background distractors. Neural correlates of selective filtering have been observed in auditory cortex (AC), but the underlying neural circuitry has not yet been identified. A synthesis of existing results and our preliminary data suggests that selective auditory filtering arises through interactions between AC and two thalamic structures: the medial geniculate body (MGB), which sends direct excitatory input to AC and receives direct excitatory feedback from AC, and the thalamic reticular nucleus (TRN), which relays indirect inhibitory feedback from AC to MGB. In this proposal, we outline a plan to answer three key questions related to selective filtering: Q1: Are selective spectral and temporal filtering evident in the auditory thalamus? Q2: How do thalamocortical interactions contribute to spectral and temporal filtering? Q3: How does attention modulate spectral and temporal filtering? The proposed experiments will lead to significant advances in our knowledge of the general mechanisms that underlie active sensory processing in all mammals, while also helping build toward a detailed understanding of the neural circuitry that allows humans to understand speech in noisy environments.
Functional characterisation of the human virome through expression screens in human cells 19 Apr 2016
Viruses manipulate the machinery of their host cell to permit their efficient replication whilst simultaneously evading detection by the host immune system. Deciphering the mechanisms by which viral genes achieve these goals, therefore, is informative not only for understanding the mechanisms of viral pathogenesis, but also for elucidating the basic biology of the cell. However, no large-scale approach is currently available to identify viral genes that modulate a particular cellular pathway. I will overcome this limitation by creating a large-scale plasmid library of viral genes, which will be introduced into human cells to carry out expression screens. My primary goal is to use this approach to identify novel viral genes that antagonise the sensing of viral nucleic acids, using fluorescence-activating cell sorting (FACS) to isolate cells that - as a result of expressing a single viral gene - can no longer mount an interferon response to transfected DNA or RNA. Overall this work will 1) reveal new insights into the mechanisms by which cells respond to viral nucleic acids, and 2) develop a method that will be broadly applicable to enable the identification of viral genes that modulate theoretically any cellular process important for viral replication or immune evasion.
Developmental progression is linked to accumulation of epigenetic information mainly in the form of chemical modifications of the chromatin. One of the most striking examples of that is random X chromosome inactivation (XCI) in female mammalian embryos. This process is dependent on coating of one X chromosome by a long non-coding RNA, Xist. This in turn promotes rapid and dramatic remodelling of the chromatin. The functional relevance and exact spatio-temporal dynamics of this process remains elusive. Here I propose to address these questions by using an integrated approach. Firstly I will use an ex vivo embryo culture system to monitor the dynamics of XCI. I will further integrate that information with single cell and population based epigenomic to generate in vivo and in vitro datasets accounting to a roadmap for XCI. I aim at identifying the initial stages of epigenetic programming leading to transcriptional repression as well as genomic loci involved in nucleating these changes. I will finally address the functional relevance of X chromosome epigenetic programming by using gene knockout models and genome-wide single cell transcriptomics approach. Such work will have wide-raging implications beyond the field of XCI and can be extrapolated into other epigenetic regulatory mechanisms.
Genome-wide association studies (GWAS) have greatly improved our understanding of human disease genetics, and are beginning to be applied to pathogens. Current pathogen GWAS have largely focused on the identification of variants behind bacteria and parasite drug resistance. A neglected application is identifying variants determining infectiousness for viruses such as HIV-1. HIV transmission is influenced in large part by an individual’s set point viral load (spVL), which itself is determined by variation in the viral genome. Given HIV’s short genome and large amount of common genetic diversity, spVL provides a tractable target in terms of potential pathogen GWAS with large global health implications. During this fellowship I will first adapt GWAS to HIV whole genome sequences by focusing on drug resistance, a phenotype where many variants are already well understood. Once the methods are perfected, I will analyse spVL in the PANGEA_HIV sample of 20,000 whole genome sequences. Identified variants will be combined with demographic data to understand how they influence transmission on a population level. They will also be tested for interactions with host genetic variants, to understand the biology of immune escape. This will allow for a better understanding of transmission risk.
MetaboFlow - the development of standardised workflows for processing metabolomics data to aid reproducible data sharing and big data initiatives 16 Jun 2016
The processing and analysis of mass spectrometry and nuclear magnetic resonance spectroscopy data in metabolomics is largely performed on an individual basis following local laboratory methodologies. Metabolomics lacks reproducible computational workflows based on internationally accepted standard operating procedures and this is impacting on the field in terms of reproducibility of studies and subsequent sharing of data. Furthermore, with improvements in reproducibility in analytical equipment, individual laboratories are acquiring larger, more complex datasets, which are a significant challenge to process. We propose to build, test and deliver the cloud-based Galaxy workflow, MetaboFlow, which will have computational capacity to process datasets with 1000s of samples and simultaneously capture all metadata associated with the users’ data processing workflow to allow rigorous reproducibility. We will formulate the workflow using several popular processing, feature extraction and compound identification tools and provide functionality to readily use on-line databases including our international repository, MetaboLights. The tools will be selected based on our current survey of the international metabolomics community. This proposal is a re-submission following consultation with the Trust. Specifically we have developed and implemented a plan to capture the communities’ needs, and have made significant cost savings by integrating our work with other initiatives using Galaxy.
A computer assisted system to reduce auditory hallucinations unresponsive to antipsychotic medication 30 Sep 2016
About 25% of people with schizophrenia continue to suffer with persecutory auditory hallucinations despite drug treatment. Their capacity to work and make relationships is grossly impaired, often for the rest of their life. Professor Julian Leff from University College London and colleagues at Speech, Hearing and Phonetics, UCL have developed and evaluated a novel therapy based on computer technology which enables each patient to create an avatar of the entity (human or non-human) that they believe is talking to them. The therapist promotes a dialogue between the patient and the avatar in which the avatar progressively comes under the patient's control. This translation award aims to refine the system, streamline the technology to make it more user-friendly and evaluate the system by a randomised controlled trial conducted by an independent team of researchers at the Institute of Psychiatry, King's College London.
Determination of the prevalence breast cancer predisposition genes in South East Asian women and development of an Asian polygenic risk assessment tool 05 Jul 2016
Breast cancer is rising rapidly in Asia and is the most common cause of cancer related deaths in Malaysia. Notably, whereas 80% of breast cancer in the UK occurs in post-menopausal women, only 40% occurs in post-menopausal women in Malaysia, and the proportion of risk attributable to genetic factors is likely to be correspondingly higher. In the absence of population-based screening, targeted screening provides a cost-effective alternative to reducing breast cancer mortality. Unfortunately, there remains a significant gap in knowledge and access to counseling and testing of BRCA1, BRCA2 and other cancer predisposition genes in most of Asia. With the decreasing cost of genetic testing, there is an opportunity to bridge that gap. We plan to: (1) characterise the prevalence of genetic susceptibility to breast cancer in the South East Asian population in Malaysia and Singapore; (2) provide risk estimates for BRCA1 and BRCA2 in our population; and (3) calibrate risk assessment models to accurately predict an individual’s risk of carrying germline alterations and their risk of cancer. The findings of this research will enable shared decision making and inform the development of appropriate management to ensure that healthcare resources can be used efficiently for targeted screening and prevention.
Climate change threatens to undermine the foundations of human wellbeing, and to reverse the last five decades of gains in global health. The 2015 Lancet Commission on Health and Climate Change concludes that the barriers to tackling climate change and improving public health are no longer economic or technological, but largely political. The report also concludes that "tackling climate change could be the greatest global health opportunity of the 21st century", with reduced greenhouse gas emissions yielding substantial health (and economic) gains. The Commission is an institutional collaboration between European and Chinese academic centres, led by University College London, Tsinghua University (Beijing), the University of Exeter, and Sweden’s Stockholm Resilience Centre and Umea University. It published its work on the 23rd of June, 2015 in The Lancet, with 11 launch events around the world. The authors of the Commission report recognise the need to carry their work forward- and to help deliver the required change. They propose a "Countdown to 2030: Global Health and Climate Action" as a mechanism for tracking progress on the implementation of policies designed to respond to climate change and protect public health. This idea draws upon the success of the Countdown to Child Survival, which galvanised evidence, interest and action to improve progress on child mortality over the past decade. The Countdown will exist as an independent, international, and multi-disciplinary coalition of organizations. The combined networks of The Lancet and the partner institutions will be utilized to ensure global reach to academics, policymakers, and the health community. It will produce an annual synthesis report on (i) the health impacts of climate change; (ii) progress in mitigation policies and the extent to which they protect and promote public health; (iii) progress with broader adaptation action to reduce population vulnerability, to build climate resilience, and to implement low carbon, sustainable health systems. The Countdown will continue its collaboration with The Lancet, who commit to publishing these Countdown Reports, as well as a number of related country- or issue-specific articles throughout each year.
Liver disease is the 5th commonest cause of death in the UK and the only one of the top 10 currently rising. Approximately 110,000 patients with symptoms of advanced cirrhosis, (commonly related to alcohol excess) e.g. jaundice, confusion and bleeding from the stomach, were admitted to UK hospitals in 2011-12. The most common cause of death in these patients is infection. These patients have a weakened immune system making them highly vulnerable to infection and no effective strategy exists to improve this. A research group headed by Dr Alastair O'Brien at University College London discovered that the cause of this vulnerability is an increase in blood levels of a lipid hormone called Prostaglandin E2 (PGE2) which reduces white blood cell function, the cells that fight infection. They have discovered that their immune systems can be boosted for at least 24 hours by infusing albumin into a vein which reduces PGE/s effects. This safe process is currently given when patients need extra fluid e.g. those with kidney damage. They propose this new exciting use for albumin to be given daily to improve cirrhosis patients' immune systems and therefore prevent infection. They hope that this will save lives and reduce health-care costs and propose to investigate this in a large scale clinical trial
Created Out of Mind will shape public and professional perceptions of dementia through a dynamic fusion of scientific and creative experimentation. Our Hub residency will support the active connection and collaboration of previously disparate cultures (scientists, artists, commissioners/policymakers) and infuse the insights and skills of people living with dementia, communications professionals and collaboration experts. Common (mis-)conceptions of dementia will be challenged through integrated artistic and scientific investigation of less recognised symptoms associated with typical and rare dementias. The project will investigate the neuroscientific, artistic and social bases of artistic engagement, enjoyment and change across multiple art forms. Interdisciplinary discussion, disagreement and creativity will also challenge and develop thinking regarding the principles, priorities, practice, health benefits and methodologically-robust evaluation of arts in dementia. Our inspiration comes directly from the intriguing experiences, heart-rending questions and puzzling uncertainties of people living with dementia. Team members will become creative collaborators whilst maintaining their professional ‘essence’, yielding a richly and meaningfully interconnected network of multi-skilled science/arts researchers, practitioners and communicators. We will also enrich understanding about dementia by raising provocative questions about the healthy brain, our emotional reactions to change in ourselves and others, and the attributes by which we value and define humanity.