- Total grants
- Total funders
- Total recipients
- Earliest award date
- 07 Nov 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Unlocking the structure, mechanism and cellular assembly of key multiprotein complexes in human gene transcription. 03 Dec 2014
Human DNA contains ~20,000 genes, giving rise to ~100,000 proteins including isoforms andvariants. This enormous complexity is exploited by the cell to intricately assemble transient andstable multiprotein complexes, critical for cell homeostasis and development, in both health anddisease.Understanding structure is vital to explaining protein function and fundamental to drugdiscovery. Knowledge has improved dramatically over the past decades due to an enormousincrease in the number of structural analyses of individual proteins. Much less is known aboutmultiprotein complexes, often due to technical challenges in their provision and analysis, whichhave yet to be fully resolved.An essential first step in biogenesis is gene transcription. In humans, this process isregulated by complexes comprising often ten or more subunits, which arrange insuperstructures that cooperate at the interface of chromatin, fine-tuned by activating andrepressing modalities.How does the cell manage such complexity? How does it decide when to express whichgenes, and what are the functional architectures involved? How are proteins assembled intomultiprotein complexes, and what are the factors that assist in this process? The same proteinsmay exist in distinct complexes; are there specific mechanisms controlling their commitment?How do errors occur and how can we correct them?These questions are central to biology, which I plan to address in this proposal. We willstudy the archetypical general transcription factor complex TFIID, a multiprotein co-activator,SAGA (Spt-Ada-GCN5-acetyl-transferase) and a multiprotein co-repressor, NuRD (NucleosomeRemodeling and Deacetylation complex) in a comprehensive, integrated approach. As we havedone in the past, we expect to develop innovative tools in the process.My vision is to understand the cellular mechanisms of these protein machines, theirassembly process from gene to functional complex, their interdependence in gene regulationand the factors that control them. I aim to provide and roll-out tools and technologies requiredfor addressing questions of such complexity on a (more) routine basis. Understanding thesemechanisms will clarify how malfunctions can lead to pathologies. This in turn will help developstrategies for the design of new therapeutic interventions.
The focus of my research is head and neck cancer (HNC). HNC describes cancers arising from the mouth (oral cavity), voice box (larynx), throat/upper gullet (pharynx), salivary glands, nose and sinuses, primary bone tumours of the jaw and middle ear. Approximately 8000 new cases of HNC are diagnosed in England and Wales each year. Although progresses have been made in terms of diagnosing and treating these cancers, survival remains poor. For instance, five year relative survival for larynx cancer is around 66% and oral cavity 58%. During my PhD, I will be looking to identify biological and lifestyle predictors of outcomes in people with head and neck cancer. I will be using data collected from the Head and neck 5000 study, a UK-wide clinical cohort study in people with HNC, which is run by researchers from Bristol University.
Angiogenesis is the term given to the branching of new blood vessels from existing vasculature; this activity extends, matures and maintains the primaryvascular network formed during early embryogenesis. The resulting circulatory system plays an essential role in physiology and consequentially disruption toits formation and conservation is a contributing factor to a vast number of diseases. As a pre-requisite to the development of treatments for vascular diseases, a large part of scientific research focuses on understanding the mechanisms governing the angiogenic process. Although many questions still remain the importance of the cytoskeleton in blood vessel outgrowth is clear. For this project I will take three cytoskeletal-associated proteins previouslyhighlighted as candidate angiogenic regulators. I will be investigating the role of the GEF Dbs, the fomin Daam2, and the GAP srGAP2 in endothelial cells.Using a mixture of in vitro and in vivo techniques I wish to determine whetherthey contribute to angiogenesis, and if so what signals do they respond to andwhat are the consequences of their deregulation. It is through these answers that I hope to further characterise the complex network of regulatory signals governing the angiogenic process.
Studying ER to synapse trafficking of neuronal receptors to attempt to understand both the spatial segregation and the effect of synaptic activity on trafficking through the secretory pathway 02 Feb 2015
The overall theme of this project is to visualize the synchronous trafficking of multiple di fferent Neuronal receptors through the Secretory Pathway of primary Neurons. Neuronal receptors carry out their function at the Synapse but begin their journey whenthey are threaded into the lumen of the Endoplasmic Reticulum (ER). From the ER receptors journey to the Golgi to be post-translationally modified before trafficking to the synapse to fulfil their role in Synaptic transmission. The unique properties of Neurons and the still outstanding fundamental gaps in knowledge of Neuronal receptor trafficking through the Secretory Pathway are to be investigated. 1.Investigate the route that Golgi resident enzymes take to traffic to Golgi outposts from the ER. 2.Visualize multiple receptors (Heteromers or different classes of receptor) trafficking through the cell. 3.What effect does synaptic activity or lack of have upon Neuronal receptors at different points of receptor trafficking from the ER to the cell surface. 4.Combining RUSH with photoswitchable fluorescent proteins to understand the spatial restriction of the Secretory Pathway at Synaptic sites 5. Investigate disease causing mutations that effect domains of Neuronal receptors involved in trafficking.
A comprehensive comparison of signalling used in the accessing and regulation of cytolysis in cytotoxic T lymphocytes and natural killer cells 02 Feb 2015
Cytotoxic T cells (CTLs) and natural killer (NK) cells are essential defensiveimmune components which eliminate infected, damaged and tumourigenic cells. Both release cytotoxic granules in a highly specific manner to deliver a lethal hit to a single cell. Despite their functional similarities, different receptor repertoires mean the signalling pathways used by these cells to access and regulate cytolysis may be significantly different. Currently, a direct and comprehensive comparison of signalling in CTLs versus NK cells has never been performed, partly due to a lack of quantitative data regarding the highly complex signalling pathways occurring at the lytic synapse after targetcell recognition. Here we propose to utilise high resolution imaging protocolsdeveloped by the Wuelfing lab to generate an expansive data set on the spatiotemporal distribution patterns of signalling molecules at the lytic synapse1. Combined with biochemical studies and RNAi experiments, this approach will allow the construction of quantitative models describing key elements of cytolytic effector signalling in relation to function. Key differences in the signalling mechanisms used by CTLs and NK cells will also become apparent. We predict the unprecedented level of comprehension obtained by this study will contribute greatly to the field of cytolysis and therapeutic development.
A viral translating ribosome affinity purification (vir-TRAP) study of changesin gene expression in the hippocampal-prefrontal pathway during memory formation. 30 Jan 2015
Acute pancreatitis (AP) is a potentially lethal inflammatory disease which affects approximately 50 per 100,000 individuals, costing the UK ~£1 billion per annum in patient care. Those with severe AP are more likely to develop complications and have a much higher death rate. However, existing biomarkers of AP are mostly nonspecific and unreliable, and novel approaches necessary. Mitochondrial dysfunction is a core feature of AP. Major triggers of AP, such as bile acids and alcohol metabolites, induce sustained Ca2+ levels in pancreatic acinar cells, leading to mitochondrial depolarisation, ATP depletion and necrosis. Systemic inflammation ensues and feeds back to the pancreas in a vicious cycle. Recently it has been shown that blood cell bioenergetics are altered in several diseases, assessed using the BioenergeticHealth Index (BHI), derived from mitochondrial respiratory functional analysis. Such evidence has indicated that blood cells may serve as early biomarkers of severity in inflammatory diseases. Therefore the aim of this project is to assess bioenergetic profiles of leucocytes and platelets, using a Seahorse XF24 flux analyser, from AP patients (mild/moderate/severe/critical) and normal individuals, and from murine experimental AP models (caerulein, bile acid and alcohol) with a view to possible discovery of novel biomarkers to predict severity.
Understanding the role of mossy cells in the neural dynamics underlying hippocampus-dependent learning and epilepsy. 30 Jan 2015
The general aim of this project is to define the role of mossy cells in hippocampal circuitry and function. Mossy cells are critical components of hippocampal circuitry required for memory formation and learning. In addition, mossy cell pathological loss is a featureof temporal lobe epilepsy (TLE) rodent models. Previous work has shown that mossy cells are absent in adult mice lacking the transcription factor, Prdm8 and PRDM8 mutations have been implicated in patients with learning disabilities and epilepsy. Initially, in vitro electrophysiology in hippocampal slices will enable physiological analysis to be evaluated, with greater detail considering granule cell activity and morphology. This data will provide the bases for entire hippocampal formation recording in vivo as well as, investigation of seizure activity in the absence of mossy cells. Contextual fear discrimination protocols will be adapted to examine the impact of mossy cell loss on pattern separation. Finally, empirical data will be used to build and elaborate two dentate gyrus (DG) based computational models (Scharfmann and Myers. 2009 and Santhakumar et al., 2005), to understand the effect of mossy cell loss on memory performance and seizure activity in relation to underlying hippocampal neural dynamics.