- 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
When viruses infect a cell, they need to hijack host machinery to produce their own proteins from mRNA, in a process called translation. The host cell requires several factors for translation, including proteins called eukaryotic initiation factors (eIFs). EIF4F plays a central role in this process and is a complex made up of the proteins eIF4A, eIF4G, and eIF4E. Together, these proteins act along with other factors to recruit the cellular machinery required for translation to begin. Influenza can promote the translation of its own proteins whilst host protein synthesis is impaired. As viral and host mRNA are highly similar, influenza virus was thought to only use the same mechanism of translation as the host. However several findings, such as the fact that influenza can translate its proteins without eIF4E, suggest that this is not the case. My hypothesis is that influenza can employ a different mechanism of translation from the host. I will use several RNA/protein analysis approaches to identify the key components required for influenza translation, and attempt to dissect the mechanism(s) of translation used by influenza. Identifying key differences between host and viral processes is important for identifying novel therapeutic targets.
The regulation of gene expression is fundamental for cellular integrity and is partly achieved by the opposing action of repressive and activating histone modifications. One such histone modification is the tri-methylation of lysine 4 on histone H3 (H3K4me3), which is known to correlate with transcriptional activity. The SET1A complex is responsible for depositing the majority of H3K4me3 in mammalian cells and disrupting its function often leads to gene expression defects. However, the mechanisms by which SET1A regulates gene expression remain unknown. I will use the auxin-inducible degron system to rapidly deplete SET1A levels. A series of genomics technologies, including ChIP-seq and NET-seq will then be used to determine the effects of SET1A loss on chromatin architecture and transcriptional activity. Additionally, proteomics techniques will be used to identify the pathways perturbed upon SET1A loss, hence identifying the mechanisms by which SET1A supports active transcription and furthering our understanding of how gene transcription is regulated. This is essential for the development of novel therapies targeting genetic diseases in which the control of gene expression is perturbed.
We wish to apply for funds to develop the malaria CHIM application. These are for a Co-investigators/stakeholders meeting to be held in Bangkok, Thailand, on 30th and 31st January 2018 and to support a writing meeting of the PIs in February 2018 in Kilifi, Kenya.
This programme recruits clinicians of outstanding calibre nationwide. With the largest concentration of biomedical science in Europe in laboratories on the Campus or wider Cambridge, we offer research training of highest quality that spans the spectrum from basic science through experimental medicine to epidemiology and public health. Strong, ongoing, mentorship is central to our programme; this, coupled with carefully chosen placements in laboratories empowers fellows to make better-informed choices of research and supervisor, including interdisciplinary projects. During PhD training, we aim to maximise their potential to acquire research skills and achieve a doctorate linked to significant discoveries and publications. With continued, intensive, guidance postdoctorally via established mechanisms, we guide fellows into pathways (e.g. higher research fellowships, clinical lecturer posts) that are tailored to individual progress, balancing re-entry into clinical training with maintaining research momentum. Our vision is to strengthen and broaden this model to include fellowships at veterinary and MBPhD level; and, in partnership with the University of East Anglia, extend opportunities to trainees throughout the region and add research diversity with a new theme in Gastroenterology, Nutrition and Microbiology. The longterm aim of the programme is to produce the next generation of clinical academics.
First, the structure of the first genome layer of ?6 will be revisited with the goal of better separating the different conformations and obtaining a better resolution for each of them. Next, the pathing of the dsRNA and its interactions with the capsid will be studied to understand its organisation and connection to the inner layers at the molecular level. The calculated orientations will then be used to subtract the density of the first layer from the original images in order to examine the inner layers more accurately. The most important reason to continue examining the inner layers is to locate the RNA-dependent RNA polymerases and solve their structures together with the genome. This would facilitate the understanding of how they interact with the dsRNA and, by using inhibitors, different stages in the lifecycle of the virus could be trapped. As a result, a time-resolved mechanism for the packaging of the genome could be proposed. Consequently, the transcription of the dsRNA will be investigated by studying the viruses upon the incubation with a "reaction buffer". Ultimately, the optimized protocol will be applied to study biomedically more relevant viruses such as the human rotavirus.
The icosahedral, positive-sense RNA Foot and Mouth Disease (FMDV) remains a foe to the agricultural industry; causing vesicular disease of cloven-hoofed animals. Converse to other picornaviruses, FMDV has a significantly greater pH and temperature sensitivity. In the quest for thermostable vaccine development, many wild type and mutant structures of the seven Foot and Mouth Disease viral serotypes are now known. Despite this, the structural basis of infection, specifically at the point of RNA loss, remains elusive. We will exploit this pH sensitivity in time-controlled study of FMDV-RNA release. The primary technique will be time-resolved single particle cryo-electron microscopy, coupled with the existing arsenal of structural biology techniques. Time-resolution of single particle structures will be attempted by varying time delays between FMDV sample acidification using photo-sensitive caged-proton compound and vitrification. Time-dependent SAXs may also be employed to monitor conformational changes. Deterioration of icosahedral capsid symmetry may be captured using cryo-electron tomography. Tomography will also be applied to a model infection system, capturing FMDV binding and pH driven uncoating via a nanodisk-immobilised integrin alphavbeta6 receptor. From a methodological point of view, we hope to establish a framework that exploits the synergy between single particle, tomographic, and crystallographic methods.
This project aims to characterise the KDEL receptor (KDELR) structurally, biochemically and biophysically. The KDELR is a membrane protein resident in the cis-golgi, where it binds the K-D-E-L amino-acid motif present on resident ER proteins, which have been transported to the Golgi via bulk flow. Once KDELR binds cargo, it initiates transport back to the ER via COPI mediated vesicles, where it releases its cargo, ostensibly because of the differing pH. The molecular mechanisms concerning the actions of the KDELR are largely elusive and would be greatly aided by the structural determination of the KDELR, as well as the structures and characterisations of its interactions with native cargos. Furthermore, KDELR has been predicted to be a GPCR, but does not appear to share homology with proteins in the family. However, distant homology to the SWEET family of sugar transporters has been found, suggesting these ‘receptors’ are in fact transporter like proteins. Furthermore, this project has the potential to involve live cell imaging experiments (in collaboration with Prof. Francis Barr) to test hypothesis borne from the structural and biochemical data.