- Total grants
- Total funders
- Total recipients
- Earliest award date
- 13 Jan 2016
- Latest award date
- 27 Dec 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Imagine if we could watch multiple molecules in living cells as they move and interact. This dream may seem years away, but it is now realistic to achieve real-time dynamic super-resolution imaging of multiple tagged proteins in three dimensions (3D) in cells and in tissues. This will allow biologists to discover large-scale patterns involving diverse structures including transport vesicles, ribosomes, and chromatin domains, all previously inaccessible because they lie in the gap between the resolution of electron (1- 2 nm) and light microscopy (200-300 nm). The "big picture" of cellular organization/information processing would emerge, with advances in understanding cell function in health and disease. While we can now do this in 2D, 3D imaging is needed to follow objects as they move out of the plane. Achieving 3D imaging is a major challenge and will require two orders of magnitude more information per cellular volume, and novel algorithms to classify, analyze, and visualize patterns from massive datasets. We propose specific innovations (Table 1) that, should allow us to achieve this over the next five years, given our team’s proven track record of success.
Ebola Data Sharing Platform 30 Sep 2016
The purpose of the Platform is to assemble and harmonise all available clinical, laboratory and epidemiological data on Ebola virus disease in order to inform evidence based policy and practice; ultimately improving patient outcomes, reducing the impact of future outbreaks and saving lives. The impact of the Platform will extend beyond Ebola as a new model of governance for data sharing in tropical and emerging infectious diseases. The development and sustenance of this unique tri-partite collaboration partnership will open novel opportunities to implement research in emerging and re-emerging infections.
An Analysis Of The Animal/Human Interface With A Focus On Low And Middle Income Countries 30 Sep 2016
Fleming Fund: supporting surveillance capacity for antimicrobial resistance The animal/human interface with a focus on low and middle-income counties Stephen Baker – Oxford University Clinical Research Unit, Viet Nam Our core research themes aim to make defining contributions to the understanding of infectious diseases transmission and susceptibility; to develop new tools to prevent, control and treat antimicrobial resistant (AMR) organisms; improve clinical outcomes of the major endemic and emerging infectious and non-infectious diseases; and enhance public health policy in the region. Our unparalleled network of units, partnerships and collaborations, developed over time and spanning every level, enable us to deliver world-class research across these themes.
Faithful chromosome segregation is essential for the proliferation of all organisms. Although studies in popular model eukaryotes have found that macromolecular kinetochore complexes assemble onto centromeric DNA to facilitate segregation, it is not known whether this mechanism applies to all eukaryotes. To uncover fundamental principles of eukaryotic segregation machinery, I am studying kinetochore functions in Trypanosoma brucei, an evolutionary distant eukaryotic parasite. No kinetochore prot eins has been identified and thus how trypanosomes segregate their chromosomes remains a black box. In my pilot study, I carried out a localization-based screening and proteomics and identified 12 kinetochore proteins. In this proposal, I aim to identify the complete kinetochore proteomes in T. brucei. Identified kinetochore proteins will be characterized using various techniques both in vivo and in vitro to reveal the molecular mechanism of chromosome segregation in trypanosomes. By revealing w hich features are fundamental and which are species-specific, I aim to understand the design principles of kinetochores that facilitate chromosome segregation with exquisite accuracy. Understanding the mechanism of chromosome segregation in trypanosomes is also medically important to develop better treatment for these diseases.
We have made the novel and unexpected discovery that the lysosomal pathway deficient in a rare genetic lysosomal storage disease (Niemann-Pick type C (NPC)) is a hub targeted by multiple human pathogens, including Mycobaterium tuberculosis and Ebola. Our aims are therefore to: 1) understand the molecular mechanisms by which pathogenic microbes manipulate NPC1 function, 2) determine the breadth of human pathogens that have evolved strategies to target this protein to promote their survival, 3) interrogate NPC1 and acidic store Ca2+ involvement in Ebola infection and further the identification of anti-viral molecules and 4) define the roles that lysosomal Ca2+stores play in regulating inflammatory responses. We anticipate the insights gained from these studies will expedite development of new approaches to infectious and inflammatory disease treatment.
The proposed research addresses two of the major problems in psychotherapy research: How can effective psychological treatments be made available to the large number of people with mental health problems?, and How can researchers make rapid progress in making the treatments even more effective? The applicants have developed leading psychological therapies for three anxiety-related disorders (social anxiety disorder, posttraumatic stress disorder and panic disorder). They now propose to harness the power of the internet to solve both problems. Internet-delivered versions of the treatments will be developed and evaluated that require much less therapist time and can be delivered anywhere. Dissemination and evaluation of the treatments within NHS Improving Access to Psychological Therapies (IAPT) services will create a large database that will enable rigorous study of moderators and mediators of therapeutic change to identify targets for further improvements. Modifications of the treatment will then be evaluated in experimental treatment studies. The work will help realise the population level mental health benefits of previous Trust investment in psychological therapy research and align with the Trust’s new focus on maximizing the application of research to improve health by focusing on new product development and the uptake of patient-oriented research advances.
The objective is to understand mechanistically how the bacterial chromosome is organized and processed throughout the cell cycle, by addressing the molecular mechanism by which the SMC complex, MukBEF, acts in chromosome organisation and segregation. This will also generally inform mechanisms of SMC action, a crucial process in normal and pathological chromosome management in all organisms. The proposed research will use state-of-the-art methods to minimise ensemble averaging. By using quantitative live-cell single-molecule imaging that allows visualization of the assembly and action of molecular machines, alongside methods that allow the rapid production and removal of specific proteins, and which interfere with normal protein interactions, it will enable mechanistic in vivo biochemistry that will be complemented by elegant genetics and in vitro biochemistry. We will progress our work showing that the interaction between MukBEF and, TopoIV, is essential for timely chromosome unlinking, and that MatP, which binds multiple sites within the replication termination region, regulates the spatial cellular distribution of MukBEF and TopoIV. Finally, we will characterize the mechanism by which localised MukBEF clusters act to position and segregate newly replicated oris, while leading to global chromosome organization, timely chromosome segregation and efficient repair.
The transition to diets rich in meat and dairy is occurring at different rates throughout the world. It is a key driver of the increase in mortality and morbidity associated with diet-related disease and also of the increasing impact of food production on the natural environment. It also has huge cultural and economic significance. It is commonplace today to call for "food system thinking" when considering how diets might be changed to improve heath and sustainability outcomes, but much more rare for this to be put into practice. We shall build an interdisciplinary food system team to show what changes in meat and dairy consumption will provide the greatest health and environment benefits and develop interventions to help bring them about. Our programme will develop innovative global health models, based on novel epidemiological data, to radically improve policy development and provide multiple food system and environmental outputs. In both a developed and developing country setting we shall propose and test novel interventions for healthy and sustainable diets, understanding their interconnectedness and the social and political contexts underlying successful implementation. We shall provide an independent source of evidence to inform debates on meat and dairy.
There are 106 million cases of gonorrhoea each year that disproportionately affect women and new-born children, particularly in low-income countries. With increasing levels of anti-microbial resistance, there are growing concerns about untreatable gonorrhoea. There is a clear need for a vaccine against gonorrhoea, but none is available. Cal’s solution is to develop a Generalized Modules for Membrane Antigens (GMMA) vaccine candidate for gonorrhoea. It will exploit the ability of Gram-negative bacteria to shed outer membrane blebs displaying antigens including lipo-oligosaccharide and multiple membrane proteins which are targets of functional/bactericidal immune responses. GMMA are easy to manufacture and highly affordable. They are more immunogenic than equivalent subunit vaccines, having an adjuvant effect through delivery of signals to the innate immune system. The key goal of the project is to establish preclinical proof-of-concept for suitability of the GMMA approach for vaccine against gonorrhoea. The future potential healthcare benefits are a major global reduction in gonorrhoea, and improvement of reproductive and maternal/new-born health.
Oxford - Immunology, Infection and Translational Medicine
Oxford - Immunology, Infection and Translational Medicine
University of Oxford - Chromosome and Developmental Biology
The role of AMPA receptor calcium permeability in hippocampal interneuron plasticity, circuit 30 Sep 2016
Calcium-permeable AMPA receptors (CP-AMPARs), largely absent from principal cells in adulthood, are highly expressed in several interneuron populations, including hippocampal parvalbumin-positive basket cells (PVBCs). The contribution of CP-AMPARs to PVBC activity, plasticity and subsequently network functions is of great interest, given the role of these cells in hippocampal gamma oscillatory activity, implicated in information maintenance during working memory. However, the contribution of PVBC CP-AMPARs to network dynamics central to gamma oscillation generation, and consequentially effective working memory, hasn’t been established. We aim to look at multiple levels to ascertain the impact of CP-AMPAR manipulations on neural and behavioural function. First, we plan to characterize the effects of CP-AMPAR blocker philanthotoxin-433 on network dynamics and spatial memory. Second, we will selectively delete GluR1 in PV+ cells, resulting in constitutive loss of the primary CPAMPAR contributing subunit, and establish the impact of CP-AMPAR loss at each level. Finally, given that CP-AMPARs are defined by their lack of GluR2 subunit, and that PVBCs do not express GluR2, we aim to artificially overexpress GluR2 in PVBCs using an adenoviral agent in order to remove AMPAR calcium permeability without decreasing overall cellular AMPAR levels, and subsequently fully characterize the impact of this permeable-to-impermeable AMPAR switch.
Mechanisms of Post-ganglionic Sympathetic Neuronal Excitability in Hypertension: Modulation by 30 Sep 2016
Hypertension is characterised by enhanced cardiac sympathetic activity; a feature underpinned by aberrant neuronal intracellular calcium ([Ca2+]i) currents and enhanced neurotransmission at the end-organ 1,2. Increased [Ca2+]i is coupled to impaired nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling, and enhanced activity of voltage-gated Ca2+ (IcaN ) channels (Unpublished, Paterson). Why these ion channels have increased activity is not known. Additionally, recent evidence suggests that hypertension correlates with peripheral chemoreflex hypersensitivity and enhanced basal carotid body (CB) tonicity 3,4. Whether CB abnormalities develop prior to the onset of hypertension and indeed, underpin sympathetic hyperactivity remains to be determined. Molecular biology and fluorescence microscopy techniques will allow us to investigate dynamic signalling pathways and cellular adaptations in spontaneously hypertensive (SHR) versus normotensive Wistar rats. First, we aim to establish whether impaired cyclic nucleotide signalling within post-ganglionic sympathetic neurons (PSGNs) contributes to enhanced Ca2+-dependent exocytosis and the autonomic phenotype in hypertension, using both young pre-hypertensive and adult pro-hypertensive rats. Second, we aim to identify key molecular changes in type I cells which increase chemoreceptor sensitivity and investigate whether carotid sinus nerve ablation (CSA) rescues the sympathetic phenotype in hypertensive models. Third, we aim to combine pharmacological and genetic interventions to determine whether impaired NO-cGMP signalling is involved in abnormal chemoreflex responses in hypertension.
Using next generation chromatin conformation capture approaches to study the dynamics and 30 Sep 2016
Gene expression is controlled by complex networks of regulatory elements in the genome, involving promoters, enhancers, silencers and insulator elements. Chromatin conformation capture methods can be used to analyse these cis-acting networks by measuring the physical interactions between the regulatory elements involved. Recently, a high-throughput approach, Capture-C, has been developed, that can be used to analyse such networks for hundreds of loci in the genome, at high resolution, in a single experiment. This project aims to use novel variants of Next Generation Capture-C to study (1) the dynamics of regulatory networks in different stages of haematopoiesis and (2) the three-dimensional structure of the genome.
The landscape and mechanisms of self-antigen splicing in thymic epithelial cells at single-cell 30 Sep 2016
Thymic epithelial cells (TECs) are essential to avert autoimmunity through their ability to promiscuously express virtually the entire gene repertoire as a molecular library against which immature T cells are selected. Whether this process generates splice isoforms unique to TECs or identical to those found in the conforming peripheral tissues remains unknown. Similarly, it is not defined whether splice variants in TECs are generated by a splicing machinery common between TEC or, alternatively, by stochastic expression of splicing factors (SFs) in individual TEC. I therefore aim to describe first the TEC transcriptome at single-cell resolution, determine the number of isoforms per gene and compare their architecture to that of a peripheral tissue. Secondly, I seek to understand how this splicing landscape is achieved and suggest a mechanistic model for alternative splicing in TECs. Moreover, possible associations of specific SFs with differences in the splicing pattern will be analyzed in single TECs. Finally, I will directly test individual components of the proposed model in vivo by generating TEC-targeted loss-offunction mutations in mice that will be monitored for their competence to establish T cell tolerance.