- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The role of the Wallerian axon-death pathway in neuronal and axonal vulnerability in Parkinson's disease 24 Apr 2018
Parkinson’s disease (PD) involves preferential loss of substantia nigra pars compacta (SNc) dopaminergic neurons and their projecting axons to the striatum. SNc neurons have huge, highly branched and vulnerable axons, whose distal ends are lost first in PD, so preventing this will be essential for any disease modifying therapy. Our preliminary data suggest the involvement of an axon-death pathway in PD shared with the loss of injured axons (Wallerian degeneration). The Wallerian pathway is initiated by loss of the activity of the essential NAD-biosynthetic enzyme NMNAT2 in axons. Crucially, axons expressing lower levels of NMNAT2 are more vulnerable, raising the possibility that SNc neuron and axon susceptibility in PD reflects a particular sensitivity to Wallerian pathway activation. To test this hypothesis, I will use cutting-edge research strategies from three leading laboratories in axon degeneration and Parkinson’s disease, combining expertise in mouse primary neuronal cultures, human iPSC-derived dopaminergic neurons and mouse and zebrafish in vivo models of PD. The proposed research will greatly advance our understanding of mechanisms of SNc neuron and axon death in PD. In the longer term, this work has significant clinical implications since axons are lost early in PD and the Wallerian pathway can be potently blocked.
The maternal antibody paradox: Characterising mechanisms and devising solutions for rotavirus vaccination 23 May 2018
Maternal antibodies (MA) are transferred to fetus and infant via the placenta and through breast milk, providing protection against pathogens when the immune response is immature. However, MA also suppress the development of B cell responses to pathogens via mechanisms that are not well defined. MA can therefore result in poor vaccine performance in the infant, placing them at risk against potentially life-threatening pathogens such as rotavirus. Rotavirus infection poses a substantial threat to human health globally. The virus is a major cause of acute gastroenteritis in young children, resulting in ~215,000 deaths each year. Rotavirus vaccines have recently been applied with great success in developed countries, however it is unknown why rotavirus vaccines are much less effective in low-income countries. Whilst malnutrition and the gut microbiome may contribute to poor vaccine efficacy, interference by MA is also considered to be a major prohibitive factor. This study aims to unravel the mechanisms by which MA limit development of effective antibody responses to rotavirus vaccination in infants. This project also aims to translate mechanistic results into rational design of improved vaccines. This work has the potential to generate vaccines that induce protection against rotavirus in younger children across all economic areas.
Staphylococcus aureus is major cause of infection worldwide. This bacterium persistently colonises the nose (its natural niche) in around 20% of the population, which increases their risk of S. aureus infection. Why some people carry S. aureus while others never do is not understood, but is likely to reflect a complex trait influenced by multiple factors. This may include the human genome, host immunity, the nasal microbiota, bacterial-nasal epithelial cell interactions and lifestyle choices. We propose that key determinants for S. aureus carriage can be defined in a powered cohort study in which these parameters are established. Our study will capitalise on existing cohorts (INTERVAL & COMPARE) of healthy volunteers who have been extensively characterised through human genome sequencing and phenotypic profiling. We will screen 25,000 INTERVAL participants for S. aureus carriage, and using sequencing methods define their nasal microbiota composition. We will use existing as well as generate additional data on lifestyle. These datasets will be mined during a series of genome-wide and phenotypic association studies to identify factors that influence the nasal microbiota and S. aureus carrier status. Selected phenotypic and genetic variants of interest will then be tested in relevant experimental systems.
Proteomic characterisation of secreted antiviral factors in cell-mediated immunity to human cytomegalovirus 30 Sep 2018
Human cytomegalovirus (HCMV) is a widespread human pathogen, infecting 60-80% of the population. Infection is asymptomatic in immunocompetent individuals but causes disease in immunocompromised patients, such as transplant recipients. Current therapeutic tools are limited, with no available vaccine and a limited array of antivirals. HCMV triggers a broad and robust immune response involving both the innate and adaptive immune systems. Antiviral immunity is mediated in part by proteins secreted by immune cells and infected cells. In order to counteract this immunity, HCMV encodes numerous evasion factors that modulate the function of immune cells and the array of proteins they secrete (‘secretomes’). In this project, I will apply mass-spectrometry to generate comprehensive profiles of the secretomes produced by different immune cells when exposed to HCMV-infected cells. Using this technique, it will be possible to identify important and potentially novel secreted antiviral factors that can subsequently be validated and investigated to determine their mechanism of action. This will contribute to a better understanding of HCMV immunity and may facilitate the design of novel effective vaccine candidates and therapies.
Complete humanisation of adaptive cellular immunity in the mouse: Vaccine and therapeutic TCR discovery 30 Sep 2018
Adaptive cell mediated immunity is one of the central components of immunological homeostasis. While the basic mechanisms are conserved the components that encounter antigen are subject to rapid evolutionary change driven by species specific pathogens co-evolving with the host and divergence of the host genome against which antigen receptors are negatively selected. Thus, epitopes that direct protective immunological responses differ between species. Consequently, translation of results obtained from immunisations conducted in model organisms to humans remains a pernicious issue. The long term goals of this proposal are to identify and validate vaccine candidates and discover therapeutic T cell receptors To achieve these goals we will build mice in which all components of adaptive cellular immunity have been humanised, building on the technical success, biological insights and health-care benefits accrued from the construction of a mouse with a complete human immunoglobulin repertoire. We will use this humanised mouse as platform to isolate therapeutic T cell receptors for acute myeloid leukaemia in which the nucleophosmin gene has been mutated. In an independent and parallel work stream we will systematically explore the Plasmodium falciparum genome to identify vaccine candidates protective against the liver stage of the pathogen.
Epigenetic transgenerational inheritance of metabolic, reproductive, and endocrine phenotypes through the male germline: effects of developmental bisphenol A and dexamethasone exposure 30 Sep 2018
The majority of heredity is accounted for by transmission of genetic material from one generation to another. However, in recent years evidence has accrued that some environmental factors can cause variations in phenotype that are inherited through the germline without changes in DNA sequence – so-called environmental epigenetic transgenerational inheritance. We are interested in how metabolic/reproductive/endocrine effects of developmental exposure to two exogenous endocrine insults – bisphenol A, an endocrine disrupting chemical that leaches from plastics and thermal paper, and dexamethasone, a synthetic glucocorticoid administered to pregnant women at risk of preterm delivery – may be transmitted inter/transgenerationally through the male germline. We will expose mice to human-equivalent doses of these chemicals and breed for three generations to obtain both phenotypic data and spermatozoa for epigenetic analyses (using RNA-seq, RRBS, and ATAC-seq). We will investigate the functional significance of any spermatozoal epigenetic changes detected; for example, using zygote pronuclear microinjection to determine the role of spermatozoal non-coding RNAs. The ubiquity of human exposure to these chemicals means that even small inter/transgenerational epigenetic effects would have significant implications at the level of public health; we therefore expect this work to be of interest to the wider scientific and medical community.
Streptococcus pneumoniae (the pneumococcus) is a major disease causing pathogen and can cause sepsis, meningitis and pneumonia especially in at risk populations such as young children and the elderly. Understanding genetic factors in disease virulence, transmissibility, and drug resistance informs the management and treatment of infectious disease. By using deep sequenced patient samples of S. pneumoniae it is possible to build a clearer picture of its within host diversity. I aim to develop statistical and computational methods for the analysis of deep sequenced pathogen data that are also able to deal with large datasets, of the order of thousands of samples. I aim to apply these methods to the analysis of deep sequencing data derived from nearly 4000 S. pneumoniae samples taken from patients in the Maela refugee camp, Thailand. The methods I develop will help to identify significant genetic factors for disease dynamics and antimicrobial resistance. The project will contribute to the understanding of S. pneumoniae and will also provide tools of more general applicability to the investigation of deep sequenced pathogen data.
Having experienced the Ebola epidemic first-hand, we realised that the majority of the population did not know what a pathogen was, creating fear and misbeliefs that hampered outbreak control. There is a clear need for science engagement and an opportunity to provide it now. We have found school children to be highly tuned into discussions about Ebola and other pathogens. Now is the right time to broaden their awareness of infectious diseases beyond Ebola, and to engage their curiosity through science creating a positive legacy. We aim to: - Engage young people in Sierra Leone in the science of infectious diseases that are all around them, sparking their scientific curiosity and making conversations about pathogens commonplace. - Empower young people with the understanding that if they know how infectious diseases spread, they can prevent infections, improving their health and that of those around them. - Excite young people about science and encourage scientific studies and careers.
The association of menstrual synchrony with the moon relates back to ancient mythologies. Historians largely dismiss the relevance of a lunar theory of menstruation by the Middle Ages, but the moon’s ability to disturb a woman’s womb through her menstrual blood was continuously discussed by early modern medical and natural philosophical writers. This project asks how the sympathetic connection between menstruation and the moon was manifest in learned discourses, vernacular knowledge, and everyday practices. Answering this requires studying women’s knowledge, the relationship between natural and occult philosophy, and the link between theory and practice in medicine. This research draws together rich, diverse manuscript and printed sources to demonstrate how the influence of the moon over the female body was ubiquitous in early modern medicine and natural philosophy. In vernacular medical handbooks, the moon was a popular socio-cultural symbol of femininity and sexual difference. Its power over the female body was demonstrated through practice in recipe books, casebooks, female-authored almanacs and medical treatises on phlebotomy. The cause and consequences of its influence were debated through learned discourse, highlighting the temporal dynamics of menstruation, and the continuous significance of fluids to changing intellectual frameworks of the body.
Virtual Fly Brain 06 Jul 2017
Neuroscience is accelerating: the capability to generate circuit level hypotheses is now matched with the ability to visualise, manipulate and record from individual neurons, in vivo. Drosophila, with its complex adaptive behaviors, powerful genetic toolkit and small nervous system, for which we will soon have complete connectomes, is uniquely placed to contribute to this work. Virtual Fly Brain (VFB) is a unique resource for Drosophila neuroscience, integrating disparate, large-scale datasets and linking them to curated literature and other resources. VFB works with international data providers and bioinformatics resources to ensure efforts are complementary, non-redundant, and make best use of resources. VFB users browse and query curated information from many sources to understand structure, function and relationships in the brain. Critically, VFB provides the data to generate circuit hypotheses and identify research tools to test them. This proposal continues this vital service and extends it to incorporate rich new data types. We will incorporate synaptic resolution connectomic data, develop bridging registrations to make it bidirectionally queryable from light level data. We will add phenotypic and transcriptomic datasets and enhance tools that enable researchers to find reagents. We will enable users to upload, view and query their own 3D datasets.
Behaviour Change by Design: Generating and Implementing Evidence to Improve Health for All 11 Jul 2017
Reducing food, alcohol and tobacco consumption would dramatically reduce non-communicable disease and, since these behaviours cluster by deprivation, would also reduce health inequalities. However, progress in achieving such behaviour change is slow. Traditional approaches to behaviour change involve providing information with, at best, modest population-level effects and sometimes increased inequalities. Conversely, Choice Architecture interventions ("Nudges") have potentially larger, more equitable effects, involving re-designing environments e.g. reducing plate size to reduce food consumption. However, evidence of effectiveness in real-world settings and understanding of mechanisms are limited. We will bridge this knowledge gap through a novel collaboration between behavioural and cognitive sciences. In the most ambitious co-ordinated set of studies to date, we propose field studies to estimate effect sizes of promising Choice Architecture interventions to reduce food, alcohol and tobacco consumption. Enabled by unprecedented collaborations, these will be conducted in supermarkets, bars and cafeterias and interventions optimised through laboratory studies determining mechanisms. We will run international workshops, public engagement activities and a Behaviour Change Summit to facilitate implementing the evidence generated, overseen by an Implementation Advisory Panel. This will enable us to realise our vision of accelerating progress in changing behaviour by re-designing environments to improve health for all.
A role for RNA binding and processing proteins in the control of eukaryotic cellular processes and in disease, including cancer, is emerging . I led the initial sequencing of the myeloma genome at the Broad Institute of MIT and Harvard. A key finding was mutations in RNA processing genes, DIS3 or FAM46C in 25% of cases. These findings have been independently corroborated, establishing these mutations as genuine drivers of the disease. DIS3 is the catalytic component of the exosome, an essenti al RNA processing complex. FAM46C is poorly characterized, but available evidence suggests it has roles in RNA processing in a lineage-dependent manner. This proposal seeks to better characterize these genes and mutations. Characterization of FAM46C mutations will be performed by knock-out of the gene from the DT40 cell line, determination of phenotype and rescue experiments. Lineage-dependent transcriptional pathways affected by altered transcript stability will be identified by RNA sequenci ng and confirmed in primary myeloma samples. Known aberrant RNA processing phenotypes associated with DIS3 loss/mutation will be sought by RNA sequencing in primary myeloma samples. The pathways affected by mutant DIS3 in myeloma will be identified using yeast genetic screens and classical yeast complementation experiments.
DNA sequencing is a core technology for modern biomedical science, and our ability to sequence genomes with ease and use that information efficiently is still unfolding. I propose first to build new bioinformatics data structures and software to map sequence data, call genetic variants, and integrate phasing and imputation, scaling to millions of samples with high accuracy and making best use of new long read sequencing technologies. These will be based on sequence variation graphs and haplotype panels over them, effectively exploiting already-discovered genetic variation in the population. Second I will develop new statistical methods to infer the evolutionary history of genome sequences to identify ancestral populations, model gene flow between them, and date and place mutations into them. I will apply these methods to modern and ancient samples to elucidate Eurasian and African human population history. Finally, I will apply these methods to new data I collect from the Lake Malawi adaptive radiation of over 500 species of cichlid fish, to infer the evolutionary relationships in the radiation, test models of speciation, and identify genes involved in cranio-facial adaptation. These studies will empower future use of sequencing data in biomedicine, and advance our understanding of genome structure and evolution.
Specification of human primordial germ cells (hPGCs) occurs around gastrulation, a critical juncture when the specification of the primary somatic lineages also occurs. In combination with human preimplantation embryos, in vitro models and hPGCs from aborted fetuses, our objective is to elucidate the origin and properties of the early human germline. For the mechanism of the hPGC fate, we will use experimental models that simulate early human development. We aim to investigate how cells gain competence for germ cell fate, and then respond to combinatorial effects of the critical transcription factors, which induce hPGC specification. Altogether, this study will reveal the organisation of the very early human embryo, and mechanisms of hPGC and somatic outcomes, which is essential for advances in regenerative medicine. Following hPGC specification, epigenetic resetting of the early human germline leads to extensive erasure of DNA methylation and epimutations in response to the critical regulators of chromatin organisation and nuclear architecture towards the epigenetic ground state. Some conserved resistant loci ('escapees') evade reprogramming. We will explore if some escapees have been exapted to function as regulatory elements. If so, this may have a crucial influence on human development, including brain development and neuronal diseases.
This project plans to measure levels of tissue plasminogen activator (tPA) which is involved in fibrinolysis of blood clots within the CSDH lesions. This bleeding is an essential part of CSDH formation, followed by coagulation and fibrinolysis which is triggered by the cleavage of plasminogen by tPA to generate plasmin. tPA will be measured in these samples using the commercially available ELISA kit. I will determine whether levels of tPA are correlated with levels of other inflammatory markers in CSDH fluid or in blood, and also to examine if increased tPA levels at the site of the haematoma predicts risk of CSDH recurrence. If tPA concentrations in blood or CSDH fluid correlate with clinical outcome, this could be used clinically to decide whether surgical or pharmacological management are most appropriate for individual patients. Finally, the effects of dexamethasone treatment on levels of tPA and other cytokines will also be determined, by comparison of dexamthasone and placebo-treated patients. These patient samples are anonymised and will only be unblinded after measurement of the above analytes has been completed.
The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge 30 Sep 2018
Since 2013, the University of Cambridge Metabolic Research Laboratories (MRL) has developed into a world-leading centre for basic and applied research in obesity and related metabolic disease. Underpinning funding from Wellcome, which has provided new clinical research facilities and other crucial core support, has been central to this success. Importantly, this endeavour has been undertaken in partnership with the MRC, who have funded a new Unit, the Metabolic Diseases Unit (MDU), which is embedded in the MRL. The MRL, together with the MRC Epidemiology Unit (Dir. Wareham) and cognate clinical facilities, form the Wellcome Trust-MRC Institute of Metabolic Science (IMS) which operates seamlessly from basic science through to population science, translational research and delivery of ambulatory care within a single co-ordinated institute. The current bid is focused on further developing world-class metabolic research within the MRL through core support for clinical and animal model research as well as underpinning laboratory science at an internationally leading level. Given the centrality of bioinformatics to all contemporary biomedical research, we have placed a particular emphasis on development of this area for the next phase of our evolution.
Deciphering Notch signalling dynamics in vivo 17 Jul 2018
To make and organize different tissues, cells must decipher information from developmental signalling pathways. Transmitting this information accurately, so that cell-surface signals are translated into correct transcriptional responses, is of critical importance but how this is achieved mechanistically remains a major question. We propose to answer this focussing on the Notch pathway. Dosage and dynamics of Notch activity are fundamentally important for developmental decisions and tissue homeostasis and their mis-regulation underlies many diseases including cancers. Our ability to image events in real time within living fly embryos gives us a powerful system to investigate dynamic properties of Notch signalling in physiological conditions. Our overall goal is to decipher temporal, quantitative and mechanistic principles that govern how Notch activity is read by target enhancers in the living animal. Using cutting-edge strategies for measuring transcription responses and complexes we will address: (i) how Notch signals are decoded in real time in vivo, (ii) what mechanisms/partners are required to accurately transduce Notch signals, (iii) what roles tissue geometry and forces play in shaping signalling dynamics. Answers will provide new insights for manipulating Notch in a controlled way, enabling strategies for altering cell fates or for treating diseases driven by aberrant Notch signalling.
A multi-disciplinary approach to understanding and improving hearing by cochlear implant users 28 Nov 2017
Cochlear implants (CIs) restore hearing by electrically stimulating the auditory nerve. This allows many CI users to understand speech well in quiet, but even the most successful have poor pitch perception and struggle in noisy situations. We believe there are two main reasons for these limitations.(i) Although it is possible to elicit different pitches by stimulating different electrodes, the selectivity of this place-of-excitation cue is much worse than in normal hearing (NH). (ii) It is also possible to increase pitch by increasing the pulse rate applied to each electrode, but use of this temporal cue is also much worse than in NH. We will study both of these limitations by performing analogous experiments in cats and humans, using some of the same measures in the two species. This will allow us, for the first time, to link the limitations that occur perceptually to their underlying physiological bases, and to do so even for novel stimulation methods that are not possible with existing clinical CIs. The knowledge gained wiill allow us to propose and test modifications both to implant design and audiological practice.
The first phase of the proposed research is to establish the principles by which control structures are represented in the nervous system in motor control and sequential decision-making. The behavioural patterns revealed using well-established assays will be tested in order to provide evidence for an optimally efficient representation of the task structure as predicted by the common computational framework of Bayesian structure modeling. The second phase is to use neuroimaging techniques (fMR I) on humans in order to identify the neural substrates of a learning process which efficiently encodes the task structure. Parallel analyses will be performed on a rich, and already acquired, dataset composed of electrophysiological recordings from rodents. This will test whether the same model applies across species, and critically, relate the model to previously established neural phenomenon. The results of these two phases will be integrated into a novel neuro-computational model of the a cquisition of control representations in corticostriatal circuits and their use in decision-making. Based on the hyperactivity of the dopaminergic system, the resulting model will be probed for predictions of behavioural deficits which will then be tested in patients suffering from schizophrenia.