- 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
We will engage Scottish cinema patrons and spark their interest in understanding brain formation and function by relating to the cinema experience (eye development, nerve impulse transmission, sensory input, and cognition). Our main message, Mind yer brain it's still mainly amystery' will promote interest in neuroscience research. The format is a short 30s film for screening in the pre-main feature slot in Edinburgh cinemas during Brain Awareness Week (BAW) and subsequently on the Web. We will encourage the audience to engage by visiting a mindyerbrain' website andconnecting with BAW and other fun and neuroscience research links.
UK Maker Faire Biomedical Maker Zone. 10 Oct 2012
Generations of amateurs have participated in electronics, rocketry, astronomy, engineering and other disciplines. Extraordinary creations have emerged from their garages and garden sheds enriching both their lives and the subjects they work in. In the 21st century a new collective noun, Makers, has become the term to describe these amateur technologists. Until recently, working with biomedical science and technology has not been an amateur pursuit. Now, as knowledge spreads and digital techno logies enhance what is possible, a new breed of amateurs working in this area is beginning to appear, demystifying research that used to be restricted to labs. (See http://blog.ted.com/2012/06/26/do-it-yourself-biotech-ellen-jorgensen-at-tedglobal-2012/ ) Groups of Makers share their creations with the public at Maker Faires (http://makerfaire.com/). These huge, playful international gatherings allow sharing between Makers and attract vast numbers of the public (see http://vimeo.com/2325 8452). We want to pilot a biomedical science and technology zone at the 2013 Faire with a view to having larger biomedical zones for future UK Maker Faires. It is intended to feature: - Five groups of international makers who use biomedical science and technology having stands at the Faire - An interactive art installation by a Maker artist working with biomedical science and technology at the Faire - One mass participation community poject involving makers using biomedical sci ence and technology with its output at the 2013 Maker Faire
Science is for Parents Too - Extension. 16 Sep 2013
The project will promote adult engagement with biomedical sciences through a sustained learning programme for parents (with limited scientific education) of primary school children. As a result of this science enrichment initiative, parents will be better able to support their children's education and career options with regard to the sciences. Broadly aligned to the Key Stage 2 science curriculum, we will focus primarily on biomedical science, with elements of complementary chemistry, physics a nd maths through a biomedical lens to demonstrate the relationships between the sciences. Our proposition is that raising aspiration is best effected by cascading learning through the family, to ensure that education becomes recognised as a viable proposition for all within a household. The intention is to make an impact on both the adults who engage directly and their immediate family circle, in an attempt to make bioscience a topic for family conversation, encourage scientific questioning, and erode past negative experiences. The learning experience will be delivered in a creative and imaginative way, with practical demonstrations of concepts, complemented by science site visits and experiments which can be undertaken with the family. We perceive this as a pilot which will develop a sustainable teaching resource that could be deployed elsewhere. It will be delivered in partnership with the National Science Learning Centre which will host taught sessions; the possible longer-te rm ambition however is to upscale the project and deliver via the regional Science Learning Centres and NSLC partners in the devolved nations, to gain national coverage.
The aim of this study is to generateInduced Pluripotent Stem Cells ( iPSCs) and subsequently reprogramme these cells into mature T-cells. We aim to investigate further the use of defined T-cell populations using the following objectives: 1.To generate iPSC lrom defined human T-cell popual tions using lentiviral vectors OCT 4/SOX2/Klf4/c-MYC. (Garcia] 2 To further develop the modelshown recently that iPSC can be made from reprogrammed defined EBV-specific T-cell clones.These T-cell derived iPSC can subsequently be developed to target a specific disease process e.g.viralinfection, tumour proliferation. The purpose of this is to develop a cell therapy with the potential to treat both viral and malignant disease. (Anderson/Cobbold] 3 To assess functional competence of the T-cells which are obtained from the model in Objective 2 using both in vitro and in vivo models (Cobbold]. 4.Identify phosphopeptides present in paediatric liver tumours e.g. hepatoblastoma, hepatocellular carcinoma,and use this to target potential therapeutic options.(Cobbold] 5. Develop iPSC from tumour specific T-lymphocytes which can be differentiated into competent T-lymphocytes. (Cobbold]
Mechanism based drug descovery. 24 Jun 2013
The interactions of small molecules and proteins are highly dependent on their shape complementarity and electronics. Exploration of the shapes of protein binding sites through in silico analysis and relation of these to the shapes of exemplified ligand space could enable us to tune the shapes of the molecules in screening libraries to specific drug discovery targets. This analysis could also allow us to identify protein binding site shapes for which hit molecules are scarce and by giving attention to this, could be used to generate hits for targets that are considered 'undruggable'. Initially, conformational analysis of the bound shapes of endogenous ligands will be conducted in order to learn from nature's balance between protein binding site space and ligand space.
Mechanism based drug descovery. 24 Jun 2013
Tankyrase recognises a peptide motif, with consensus RXX(P/G)XGXX, in substra tes through its ankyrin repeat clusters (ARCs). My aim is to develop tool compounds to disrupt the sankyrase : substrate protein-protein interaction (PPI). Targeting the ARCs is a novel method of inhibiting tankyrase function. Several approaches will be taken to develop non-peptidic inhibitors targeting the ARCs,by modification of a short peptide binding partner from the tankyrase substrate 3BP2. A peptidomimetic approach aims to find non-peptidic replacements for residues that mimic the peptide sidechain and backbone interactions. A fragment-based approached will also be taken to widen the chemical space sampled and if fragments are found that have binding affinity to ARCs, tha t can be detected crystallographically, then these can be incorporated into the peptide or grown chemically into more drug-like molecules. The peptidomimetic and fragment-based approaches will complement each other,and both ultimately have the same goal of designing potent tool compounds that are selective for TNKS and TNKS2 over other PARP family members,are cell permeable unlike the parent peptide,and have good aqueous solubility.
Mechanism-based Drug Discovery. 24 Jun 2013
The first aim of the project is determine those cancer types that are sensitive to single agent CHK1 inhibition and identify potential biomarkers of this phenotype,such as replication stress (RS). CHK1i have shown single agent activity in certain cancer types, including neuroblastoma and B cell lymphoma, the literature suggests this may be due to increased replication stress. Which leads on to the second aim of the project,which is to establish models of RS to determine if it enhances single agent CHK1 sensitivity. This will be done looking a t foci indicative of replication stress. Finally, the Iast aim of the project is toidentify those gene products whose loss is synthetically lethal with CHK1 inhibition in cancer cells, which could allow the therapeutic activity of CHK1 inhibitors to be broadened through use with appropriate molecularly targeted agents. This will be done by screening 2 CHK1i resistant cell lines, with and without CHK1i,aqainst the Dharmacon druqqable qenome siRNA library.
Structural characterisation of nutrient and innate immunity factor uptake by trypanosomes. 30 Aug 2013
Human African Trypanosomiasis is caused by the protozoan parasite Trypanosoma brucei, and is fatal if left untreated. Each trypanosome is surrounded by a surface coat of 10^8 variable surface glycoproteins (VSGs), which protect against complement-mediated lysis,and the switching of VSG expression allows evasion of the adaptive immune system. Thisproject aims to understand how the trypanosome takes up both nutrients and human immune factors in the context of the VSG coat. The project will focus on the haptoglobin-hemoglobin receptor (HpHbR), and the transferrin receptor, which allow the parasite to scavenge heme and iron respectively, in complex with human ligands. HpHbR is also involved in uptake of trypanolytic factor 1 (TLF1), a human lipoprotein particle that protects the host from numerous trypanosome species.
Non-image forming responses to light are not a new phenomenon and have been known about for some time; however, it is only in the past decade or so that aphotoreceptive cell in the retinal ganglion cell layer, distinct from the classical rod and cone photoreceptors, was discovered that may be primarily responsible non-image forming responses to light. This type of cell, now named the intrinsically photoreceptive retinal ganglion cell (ipRGC), is maximally sensitive to wavelengths of light at approximately 480nm, in contrast to the classical photoreceptive system which is maximally sensitive to light at around 555nm. Hence, a new field of research has developed to investigate the effects ofvariably stimulating the classical and non-classical photoreceptive systems (equivalently the visual and non-visual systems). No single isolated measure of non-visual pathway stimulation exists, but there are several biological and psychological processes known to be affected by varying light spectra; including: circadian rhythms, sleepiness, alertness and cognitive function. These effects have until recently been studied primarily with narrow-band light. In In this project, we propose to investigate how modulations in the spectra of broad-band, polychromatic lights affect particular non-visual biological and psychological responses to light.
Hirschsprung's disease (HSCR) is a congenital disorder causing obstruction of the large intestine as partial or total innervation of the gut fails to occur in development. It is one of the most common causes of neonatal intestinal obstruction with incidence rates of up to 1.4/5000 live-births in China and 1/5000 in Caucasians. The most common form of the disease, short segment HSCR (S-HSCR), comprises 80% of HSCR cases and exhibits a strong sex bias with a 5:1 male to female ratio (Badner et al., 1990; Amiel et al., 2008; Garcia-Barcelo et al., 2009). This project aims to answer the disparity in HSCR incidence between males and females, and provides a tractable model to begin to investigate and understand sex bias in numerous diseases. We will focus on a number of mouse models with S-HSCR-like phenotypes for malebias and carry out genetic crosses utilising the "four core-genotype model" (De Vries et al., 2002). The two models showing the most robust sex bias will be chosen for further study. We will then investigate whether sex bias is sex chromosome-specific or gonad/hormone-specific, identifying HSCR-associated variants, genes and/or pathways that are significant in one gender and exploring differences in their activity and function.
Biomechanics of collective chemotaxis 15 Jul 2013
Collective chemotaxis (CCT), whereby groups of cells collectively migrate in response to chemotactic signals, is a fundamental mode of migration in development and metastatic cancers. The biomechanics of this process has been largely overlooked, with most work focusing on spontaneous migration of epithelial sheets despite evidence that strong cell-cell adhesions are not required for collective migration. Additionally, chemotactic signals are important for directional migration in vivo. We propose to use neural crest (NC) cells, a highly invasive mesenchymal cell population that extensively migrate throughout the embryo, to address the biomechanics of CCT. We will perform high-resolution time-lapse imaging of Xenopus NC to assess physical properties of CCT such as velocity and viscosity. Traction force microscopy, FRET tension sensors and atomic force microscopy shall be used to measure the physical forces required for CCT. Finally, the molecular mechanisms necessary for the biomechanics of this process shall be identified, in particular through chemical and mechanical manipulation of the actomyosin cytoskeleton tounderstand how it contributes to providing forces for CCT. Collectively, theseresults will provide a novel insight into the biomechanics of CCT which could have important implications for morphogenetic processes, regeneration and diseases like invasive tumours.
Genomic analysis to seek mechanisms of resistance to amphotericin B in Leishmania parasites responsible for leishmaniasis 24 Jun 2013
This project proposes to investigate the mechanisms underlying resistance to amphotericin B in parasitic protozoa of the genus Leishmania. The leishmaniases afflict millionsof people across the world and the threat of emerging resistance to current drugs could underlie a public health disaster. Parasites will be selected for resistance in the laboratory and other strains acquired from laboratories where selection has already been undertaken. Field derived isolates will also be acquired. A combination of metabolomic profiling and genome sequencing willidentify candidate genes responsible for resistance and these will be confirmed using genetic manipulation. Genome data available in public repositories will also be analysed to determine the status of any genes found to be associated with amphotericin B resistance in parasites present within the field.
Integration of epidemiological and genetic data to reconstruct disease outbreaks in host-viral systems. 24 Jun 2013
The recent history of a virus epidemic can be more accurately reconstructed when genetic and epidemiological data are integrated, compared to focusing on either data type alone. However, current reconstructive approaches are limited, being designed for outbreaks where most cases are identified. We lack a framework capable of powerful inference when more detailed epidemiological and viral genetic data are available, but when a smaller proportion of cases is sampled. I intend to resolve this by developing general Bayesian statistical methods and applying them to host-virus systems for which both viral genetic and host behavioural data are available: hepatitis C virus (HCV) in humans, and influenza in wild birds.Accessing data obtained from collaborators from four cohorts of HCV patients, I will apply improved methods to determine factors associated with increased risk of transmitting HCV. In tandem, I will study longitudinal viral genetic diversity in a resident mute swan colony (Abbotsbury, Dorset). This will test hypotheses that influenza dynamics in long-lived birds are unlike that in the short-lived species on which almost all research focuses. Combining epidemiological and genetic sequence data will increase understanding of the dynamic behaviour of these viruses, which can be translated to improving control and surveillance measures.
A putative lipase as a novel toxin/effector in the Pseudomonas aeruginosa typeVI secretion system 24 Jun 2013
The bacterial type VI secretion system (T6SS) is a macromolecular complex embedded in the cell envelope of most pathogenic Gram-negative bacteria. This secretion system is a major pathogenicity determinant and is required for Pseudomonas aeruginosa to establish chronic infections in cystic fibrosis patients. The T6SS is evolutionarily, structurally and mechanistically related to the bacteriophage tail, puncturing target cell membranes to deliver its cargo .The T6SS secretes toxins into both eukaryotic and prokaryotic cells in order to subvert host responses and to aid competition with other microorganisms. A limited number of T6SS effector proteins have been identified, with the majority displaying antimicrobial activities. The secretion system has no inherent mechanism of self-discrimination, therefore sister cells are only protected through the expression of immunity proteins cognate to the antibacterial effectors. Cognate antitoxins are unnecessary for antieukaryoticeffectors. The proposed research aims to characterise a putative T6SS effector from P. aeruginosa and to study its contribution to pathogenesis. Genetic and biochemical approaches along with cellular biology methods will further our understanding of the arsenal of toxins that this important bacterial pathogen has at its disposal.
Current problems with increasing antimicrobial resistance mean the discovery of novel antimicrobials is becoming increasingly important. Therefore, antimicrobial drug discovery has been selected as a model to investigate the feasibility of using synthetic biology to create azol(in)e modified peptide libraries and select mutants with biological activity. The library of azol(in)e modified peptides will be created by engineering Escherichia coli to express; heterocyclisation enzymes and a mutated array of substrate peptides. The library will undergo a selection methodology to detect mutants which show antimicrobial activity against a target bacterial overlay e.g. Mycobacterium tuberculosis. Once identified, the large scale biological production and potency optimisation of discovered antimicrobial compounds will be conducted.
This work will investigate the complex host-pathogen interactions occurring during Salmonella infection with a focus on innate immune modulation. Salmonella translocates approximately 30 effector proteins into the cytosol of host immune cells to modulate its intracellular environment. The precise function, biochemical activity, kinetics of translocation and hosttargets are poorly characterized for the majority of effectors. This project aims to identify further effectors that modulate host immune signaling with a focus on NFKB signaling. This is a key pathway involved in cytokine / chemokine induction and cell death via apoptosis modulation during Salmonella infection. By studying bacterial-mediated modulation of immune signaling we hope to assign function to uncharacterized effectors as well as understand more about the functions of the host immune response.
The aim of my project is to combine two lines of inquiry from the Newman Group: i) the effect of topology of gene networks on cellular robustness, and ii) the stochastic dynamics of chains of interactions linking biological states. The overlap between these two themes is a rich, untapped area concerning the selective pressures on biological networks due to intrinsic and/or extrinsic noise. The mathematical aspects are largely independent of the biological scale, and we intend to use theoretical results from intra-cellular systems to study higher-scale networks, such as those describing states of cellular differentiation. Key goals include: i) assessingthe role of fundamental biological properties, such as robustness, on network topologies, ii) using probability theory and rare event statistics to understand non-trivial and counter-intuitive aspects of network dynamics, and iii) uncovering the design principles that allow networks to filter stochasticsignals to produce deterministic outcomes. Our investigations will be coupled to experimental data, such as gene networks, and cell differentiation pathwaysto maximise potential impact on translational applications to human diseases, in particular cancer.