- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Dynamic neural remapping across the sleep-wake cycle: A mechanistic link between sensory re-organisation and GABA 05 Sep 2017
Across a single day, we undergo behavioral, physiological and neurochemical changes, from vigilant wakefulness to unconscious sleep. Despite the loss of consciousness, sensory processing continues in sleep. Attempts to assess the degree to which sensory processing differs between wakefulness and sleep have yielded contradicting results with studies showing greater, smaller or comparable responses to the same stimuli when comparing the two states. Hence, it remains unclear precisely how sensory processing is modulated throughout the sleep-wake cycle. Most studies have focused on responses to specific stimuli, neglecting the relationship between different stimuli. We suggest a new comprehensive approach to elucidate how vigilance state dynamically shapes sensory processing, by combining electroencephalography (EEG), functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) together with state-of-the-art computational tools, measuring neural distances between stimuli to quantify sensory remapping across the sleep-wake cycle. We hypothesize that gamma-Aminobutyric Acid (GABA), an inhibitory neurotransmitter implicated in sleep regulation and correlated with sensory sensitivity, has a central role in sensory remapping. Thus, in this research proposal, the key goals are:(i) to elucidate the temporal and spatial dynamics of sensory remapping throughout the sleep-wake cycle, and (ii) to investigate whether sensory remapping across the sleep-wake cycle is GABA-dependent.
Recent discoveries in neurodegeneration support the cell-to-cell transmission and replication of certain ‘prion-like’ proteins in a manner highly reminiscent of viral infection. This suggests that antiviral mechanisms could potentially be used to treat neurodegenerative diseases. The novel antibody receptor TRIM21 engages immune complexes in the cytoplasm and elicits their proteasome-dependent destruction. This activity prevents infection by viruses that enter the cell with antibodies attached to them. Preliminary data show that seeds of tau, a cytoplasmic prion-like protein that aggregates in Alzheimer’s disease, can similarly be neutralized in this way. This study will combine high-content cellular seeding assays, degradation assays and two mouse models of tau pathology to investigate the mechanism of antibody protection during immunotherapy. Using antibody engineering and knockout mice lines, I will quantify the contribution of TRIM21 and classical Fc receptors to immunotherapeutic protection against neurodegeneration. I will determine how cellular machinery elicits the inactivation of prion-like proteins. This combined approach will support an understanding of intracellular inactivation of prion-like proteins and relate it to disease progression. Current understanding has not translated into disease-modifying therapeutic interventions for neurodegeneration. These studies may inform new strategies aimed at limiting spread of pathogenic protein assemblies using antibodies.
Genetics and causality: towards more accessible and more reliable Mendelian randomization investigations 26 Oct 2016
I propose to advance methods for Mendelian randomization to make investigations more reliable and more accessible, and to build a team to develop and apply these state-of-the-art methods. I will continue with the development of robust methods that give consistent estimates even when the stringent instrumental variable assumptions are not fully satisfied, and compare how these methods perform with real data. I will extend existing methods, considering estimates of non-linear causal relationships, and approaches for variable selection with heterogeneous genetic variants in different gene regions, and with highly-correlated variants from the same gene region. I will develop novel approaches for using covariate matching and matching by design (such as the analysis of sibling pairs). I will disseminate these methods in explanatory papers aimed at applied researches, and in a software package. I will partner with leading epidemiological and clinical researchers to apply these methods to scientific questions of interest, and feedback difficulties from these analyses into further methods development. I will develop pipelines for the prioritization of biomarkers as targets for pharmaceutical or clinical intervention from high-dimensional datasets, where thousands of candidate risk factors have been measured and detailed analysis of each risk factor in turn is impractical.
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.
Developing an in vivo MT nucleation assay to investigate g-tubulin independent centrosomal MT nucleation 27 Apr 2017
Centrosomes are major microtubule organising centres (MTOCs) in animal cells. During mitosis they recruit large numbers of gamma-tubulin ring complexes (g-TuRCs), which nucleate and anchor the microtubules required for spindle formation. Recent work in the Conduit lab has surprisingly shown that centrosomes lacking g-TuRCs can still organise microtubules. Nevertheless, it remains unclear if these microtubules are generated at centrosomes, or generated in the cytoplasm and then anchored at centrosomes. I aim to establish an in vivo microtubule nucleation assay to test these alternative possibilities. Drosophila larval brains, which are highly mitotically active, will be dissected from either wild-type flies or from mutant flies where the centrosomes lack g-TuRCs. They will be cooled on ice for 40 minutes in order to depolymerise all microtubules and then transferred to 25 degrees and chemically fixed at different timepoints. The brains will be stained for microtubules, centrosomes and mitotic DNA using antibodies already available in the Conduit lab and images will be taken on a confocal microscope. The location and intensity of new microtubule growth will be assessed. If the g-TuRC negative centrosomes do nucleate microtubules, the assay will be used to test candidate proteins for their role in centrosomal non-g-TuRC mediated microtubule nucleation.
Rate of degradation of Aurora kinases 27 Apr 2017
Aurora kinases regulate the segregation of chromatids and are key enzymes in mitosis. AurA assembles the spindle poles; AurB faciliates cytokinesis of the daughter cells. Their ubiquitin-mediated degradation regulates the transition from mitosis back to interphase and show different kinetic profiles: AurA degrades 5-fold faster than AurB. Previous unpublished data from the Lindon lab showed that a AurA1-133-AurB78-345 chimera tagged with GFP degraded with similar kinetics to full-length AurA. Therefore all of the information required for rapid degradation of AurA resides in the 1-133 region. We plan to construct various AurA-AurB chimeras and express them in dividing cells. We will carry out a quantitative analysis of degradation of these chimeras using single-cell fluorescence timelapse assays. We aim to identify the the minimal sequence within AurA1-133 required to specify accelerated degradation kinetics. We plan to compare this with other known regulatory sequences for ubiquitin-mediated degradation ('degrons') and to gain a better understanding of how AurA engages the destruction machinery to affect its degradation kinetics. This information can assist the design of new therapeutic tools, such as PROTACs, that harness ubiquitin-mediated degradation to destroy targets not druggable by conventional means.
Ischaemia-reperfusion (I-R injury is a major cause of myocardial injury during acute coronary syndrome. Initial block of a coronary artery by plaque rupture and thrombosis leads to downstream myocardial ischaemia. Reperfusion is required to prevent extensive myocardial injury, but restoration of oxygen supply can trigger further injury to the ischaemic tissue. This represents a major unmet clinical problem. Inflammation is a component of I-R injury. Ischaemia and reperfusion trigger endothelial cell activation, followed by rapid recruitment and transmigration of neutrophils and further tissue damage. This project forms part of a wider effort to develop an in vitro model of vascular inflammation during I-R injury. I will characterise the response of human umbilical vein endothelial cells (HUVECs) to hypoxia followed by reoxygenation/normoxia, in the presence and absence of tumour necrosis factor (TNF)-alpha, to mimic an additional, tissue-derived inflammatory stimulus. HUVEC activation markers, including surface expression of P-selectin, E-selectin, ICAM-1 and VCAM, will be assessed using multi-colour flow cytometry and confocal microscopy. The consequence for neutrophil adhesion and transmigration will be assessed using confocal microscopy. These experiments will demonstrate the effect of hypoxia followed by normoxia of endothelial cell inflammatory responses, and increase our understanding of the mechanisms that underlie I-R injury.
Time-resolved genetic data offers a new and exciting opportunity to study pathogen evolution. Sequencing a population at multiple time points reveals genetic changes as they occur. Mathematical models based upon the dynamics of evolutionary systems allow for more accurate identification of alleles under selection, and better measurements of the magnitude of selection, than have previously been achieved. I will develop models to interpret time-resolved genetic data, so as to better understand the evolution of pathogens. Unified by the theme of modelling rapid evolutionary dynamics, this work will make progress in understanding multiple pathogenic organisms. Specifically, this project will use high-coverage sequence data to quantify the role of selection in the intra-patient evolution of influenza, relevant to the emergence of new pandemics. It will examine how immune and drug pressure, acting upon the HIV virus, affect viral diversity in the early stages of an infection. The project will develop methods to better interpret genetic data from drug resistance experiments, in order to identify genomic factors leading to drug resistance in malaria parasite, helminthes, and leishmania. Finally, I will investigate the potential of multi-locus genetic models of evolution to understand, and to predict, the evolution of seasonal influenza.
My laboratory investigates the molecular mechanisms that control the 24 hour (circadian) clock. This fundamental process is integral to the function of all cells. Our recent work has highlighted a critical role for a family of proteins called peroxiredoxins in the clockwork, and has shown that redox oscillations in mammalian cells contribute significantly to a cell's rhythmic properties. A Senior Fellowship would allow me to examine how the clockwork functions in 'real-time', using a variety of novel tools that we are developing to do this. We will also perturb redox pathways (that normally get rid of harmful oxidants produced because of respiration) and investigate the effect of this on the clockwork using these tools. A final goal will be to integrate redox oscillations with existing components of the clockwork, which rely on the process of gene transcription to work. The goal is therefore to fully characterise the mechanism of how a cell keeps time, particularly with respect to redox metabolism, which is a new and exciting area of study within the field.
Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia 06 Dec 2016
Secondary pneumonia following influenza infection is common, with considerable associated morbidity and mortality. Strikingly, secondary infections tend to arise from bacteria which live otherwise asymptomatically in the oropharynx. Based on existing data, I hypothesise that the development of secondary streptococcal pneumonia is dependent on a key immune-cell molecular pathway, namely Phosphoinsitol-3-Kinase delta (PI3Kdelta), and that inhibition PI3Kdelta will be protective via the following mechanisms. 1) Influenza-induced expansion of immunosuppressive regulatory T-cells (Treg) which depend on PI3Kdelta for suppressive functioning 2) Viral and Treg mediated suppression of neutrophil function 3) A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by Streptococcus pneumoniae. The goals are: 1) To determin whether PI3Kdelta-null animals are resistant to secondary streptococcal pneumonia. 2) To use tools including Treg depleted animals, conditional knockout animals and small molecule PI3Kdelta inhibitors to explore mechanisms of resistance. 3) To develop a more clinically relevant murine model secondary pneumonia, using a streptococcal colonisation model which when exposed to influenza will develop secondary pneumonia. 4) To characterise the respiratory microbiome of animals at various stages will be characterised, looking for factors that may facilitate or militate against development of secondary pneumonia.
21st Century Families: Parent-child relationships and children's psychological wellbeing 25 Jul 2017
New pathways to parenthood have recently emerged that did not exist, nor had even been imagined, at the turn of the 21st century. Individuals who were previously unknown to each other have begun to meet over the internet with the purpose of having children together; transgender men and women have begun to have children through medically assisted reproduction; single heterosexual men have begun to use surrogacy to become single fathers by choice; and women have begun to use identifiable egg donors to have children. These emerging family structures raise new ethical, social and psychological concerns, particularly regarding the potentially negative consequences for children. The proposed research will provide empirical evidence from a multidisciplinary perspective on the social and psychological consequences for children of growing up in family arrangements involving non-cohabiting co-parents, transgender parents, elective single fathers and identifiable egg donors. In this emotive area of family life on which people often hold strong opinions, our aim is to challenge prejudice and assumption with evidence on the actual consequences – good, bad or neutral – for children. The ultimate goal of the proposed research is to increase understanding of diversity in family life and improve the lives of 21st century children.
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
The cognitive neuroscience of over-eating: normative and clinical studies of goal-driven and stimulus-driven responses 05 Apr 2017
There is a pressing need to understand the phenotypic variations of obesity in order to elucidate the diverse pathways and mechanisms by which it arises and, ultimately, to offer suitably tailored interventions. My proposed work aims to provide insights into the cognitive neuroscience of health-harming over-consumption. Its ultimate goals are to characterise cognitive mechanisms underlying eating behaviours, exploring how these are selected and deployed in ways that are shaped by both internal and environmental signals. The work is based on the view that obesity is ultimately driven by a complex integration of environmental and bodily signals and that a comprehensive approach must characterise this integration in order to determine how it may be altered in over-eating. My proposal has the following goals: To understand how stimulus-driven (automatic) and goal-directed (reflective) reward behaviours are balanced in relation to eating choices and to explore how this balance may differ across hungry and sated, lean and obese people. To relate these underlying processes to hormonal/metabolic signals as well and to real-world eating choices. To characterise the effects of three specific perturbations to this integrated system: (i) elective gastrectomy, (ii) single gene mutations affecting hypothalamic circuitry and (iii) psychopharmacological manipulations
We aim to elucidate the circuit mechanisms underlying three key computations essential for memory-based behavioral choice: 1) updating valences attached to sensory cues, when actual and expected outcomes differ; 2) computing the “value” for each action, based on multiple, conflicting cues; and 3) selecting one action and suppressing other physically incompatible competing actions. One obstacle to progress in this field has been the problem of identifying underlying circuits with synaptic resolution, and causally relating structural motifs to their proposed function. Both insects and vertebrates have evolved cerebellar-like higher-order parallel-fiber systems specialized in forming large numbers of associative memories and in guiding memory-behavioral choice. However, no synapse-resolution wiring diagram of any such system has been available to guide analysis and inspire understanding. We have recently mapped the synaptic-resolution wiring diagram of one such system, the insect mushroom body, in Drosophila larva, which reveals multiple novel circuit motifs and provides clues about learning and decision-making models and their neuronal implementation. An exquisite genetic toolkit available in this model system allows selective manipulation of individual neuron types to establish causal relationships between their activity and behavior. We are now in a unique position to causally relate the identified structural motifs to their function.
Background: The risk for many common complex diseases, including type 2 diabetes, increases with age. Technological advances have recently enabled large-scale investigation of genomic markers of ageing in population-based studies. Whether genomic ageing contributes to the age-related rise of diabetes and related metabolic disorders is unknown. Aim: To systematically identify and study genomic markers of ageing, including telomere length, DNA methylation, and chromosome loss, and investigate their causal roles for morbidity and mortality from type 2 diabetes and other common complex diseases. My overall aim will be achieved by addressing the following specific objectives: Objectives: 1. To perform a systematic literature review of genomic markers of ageing to identify determinants and consequences and assess methods for their characterisation in epidemiological studies. 2. To identify and characterise genetic and modifiable behavioural and environmental risk factors of genomic ageing in large-scale population-based studies. 3. To investigate causal roles of genomic markers of ageing for morbidity and mortality from ageing-related diseases using Mendelian randomization methods, and conduct exploratory studies of the underlying pathways through detailed metabolomic characterisation.
Microtubule organisation in developing neurons 31 Jan 2017
Microtubule (MT) bundles found in neuronal axons are highly organised, as around 90% of MTs point with their growing end (commonly referred to as the +end) away from the cell body. This MT orientation is crucial for correct cargo localisation. Known for more than 30 years, the underlying mechanisms for axonal MT organisation are yet to be discovered. Preliminary experimental data from the Franze group suggest that correctly oriented (or "+end out") MTs in axons are selectively stabilised whereas oppositely oriented ones are not. The stabilisation requires both axonal cortex integrity and cytoplasmic dynein function, and MT destabilisation leads to the breakdown of MT organisation. In this project, I will focus on the exploration of the mechanism(s) that lead to the stabilisation of "correctly" oriented MTs. Furthermore, I will investigate how MT organisation could be related to common pathologies.