- 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.
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
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.
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.
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.
During this MPhil course, I will undertake historical research investigating how twentieth and twenty-first century medical technologies have influenced interconnected medical, social, and political categories of the human body, including disability, race, gender. I am interested specifically in how new medical technologies that are targeted toward particular kinds of people can then contribute to the making and remaking of those kinds. For my dissertation, I propose to specifically examine the way that categories of race and ethnicity are deployed in the context of genomic medicine by using the ongoing East London Genes and Health project and its historical background as a case study. I will investigate how the immigrant, ethnic, socioeconomic, and health status of east London's Bangladeshi and Pakistani population has made it the target of a geographically-bounded genome sequencing project. By illuminating the relationship between the local and global history of genomics as a medical intervention and that of the groups of people for which and in which it is being mobilized, my research will call attention to the way old categorizations of the human body are being reimagined and reinscribed in the context of new medical technologies.
Farming, food, and forecasting: developing outbreak resilience and sustainability in global agricultural systems. 24 Mar 2016
Crop and livestock diseases continue to pose threats to agricultural production and the provision of safe and balanced diets for healthy human populations in Sub-Saharan Africa. The problems are especially acute for invasion and spread of exotic and novel pathogen strains. Examples include rift valley fever, zoonotic diseases such as cysticerosis and echinococcus, and wheat stem rust, maize lethal necrosis and cassava brown streak disease in staple crops. The impacts and risks of epidemic spread are intensified by changing patterns in the agricultural landscapes, driven by population growth and urbanisation, and exacerbated by climate change. Conventional responses to epidemic outbreaks tend to respond reactively, inefficiently and de novo to each new threat. Building upon recent developments in the effective use of modelling to inform epidemiological policy, we have assembled a group of animal and botanical epidemiologists, together with experts in health, economics, social science and policy, to develop and test a robust framework for Sub-Saharan Africa. The epidemiological framework will address multiple scales (farm, district, national and regional) and provide planners, regulators and others with tools to minimise the risks of outbreaks, prepare for and manage outbreaks efficiently, and assess likely impacts of disease on food security, health and livelihoods.
Glucagon is secreted from pancreatic alpha-cells during times of hypoglycaemia. It binds to receptors on the surface of liver cells promoting gluconeogenesis, while simultaneously inhibiting glycolysis and glycogen synthesis. While this has beneficial effects during starvation, for people suffering from type 2 diabetes this significantly contributes to their overall hyperglycaemia. Little is currently known about the mechanisms by which glucagon secretion is modulated. The incretin hormone glucagon-like peptide-1 (GLP-1) inhibits glucagon secretion, but the mechanism by which it achieves this remains unclear. Expression levels of the GLP-1 receptor are extremely low in alpha-cells and GLP-1 can inhibit glucagon secretion in pancreatic cells obtained from GLP-1-/- 'knockout' mice. We therefore hypothesise that GLP-1 mediates its effects using a non-cognate receptor. GLP-1 has been documented to bind and activate the glucagon receptor (GCGR), a receptor that has been demonstrated to show coupling to various effector proteins. Thus this research project aims to characterise the precise signalling properties of the GCGR when stimulated with GLP-1 in a physiologically relevant cell line. To achieve this we will use the pancreatic alpha-cell line (alphaTC1.6) that responds to GLP-1 and secretes glucagon.
Imperial College London - Theoretical Systems Biology and Bioinformatics
University of Cambridge - Metabolic and Cardiovascular Disease