Food Security: Animal Health

Below are example projects. Applicants are applying to the Programme and not for specific projects at this stage.

Parasitic nematode microRNAs and immuno-modulation 

Collette Britton Collette.Britton@glasgow.ac.uk Eileen Devaney Eileen.Devaney@glasgow.ac.uk

Helminth parasites have an extraordinary potential to modulate host immune responses. We have identified a microRNA from the parasitic nematode Haemonchus contortus that is only expressed in parasitic nematodes that live in the gastro-intestinal tract. A predicted target for this miRNA is CD69, a C type lectin receptor expressed on T cells. The aim of this project is to explore the interaction between the parasite miRNA and CD69. CD69 is an early marker of T cell activation, has roles in Th17 differentiation, may help control the balance between regulatory and pro-inflammatory responses and is required for the persistence of CD4 memory T cells. We will investigate the impact of parasite miRNAs on the expression of host immune molecules and on the outcome of infection using a range of molecular and immunological tools.

Insecticide-responsive nuclear receptor/transcription factors in xenobiotic resistance

Shireen Davies Shireen.Davies@glasgow.ac.uk Julian Dow Julian.Dow@glasgow.ac.uk

Insect control significantly impacts on the global economy and on food security, as insects are major pests of food crops, stored food and animal health. Insects are particularly successful in adaptation to environmental stress including routine xenobiotic exposure by having sophisticated detoxification mechanisms and increased insecticide resistance.  There is thus an urgent need to identify potential new insecticides and/or targets in key tissues; and to understand insect xenobiotic handling mechanisms at the cell and tissue level.

We focus on epithelial function in the genetic model Drosophila melanogaster using the Malpighian tubule. Insect tubules modulate stress resistance, detoxification and survival of the insect - and so are key tissues in insect defence.

Drosophila Hepatic Nuclear Factor 4 (dHNF4), a Nuclear Receptor and transcription factor, is highly expressed in tubules; and is associated with the cnc pathway, a regulatory pathway for response to xenobiotics.

We plan to elucidate dHNF4-associated mechanisms of detoxification and response to insecticide in vivo, using transcriptomics, ChIP analysis and in vivo bioassays using a novel dHNF4 reagent.

Chronotype as a constraint in response to novel environmental conditions

Barbara Helm Barbara.Helm@glasgow.ac.uk

Coping with novel environments is an emerging concept in assessing welfare and functioning of animals in a changing world. We know as humans that changes in scheduling of activities within the 24 hour day (e.g. due to shift work or jet lag) are associated with major deficits in functional ability, reduce well being and the ability to respond to novel conditions. The ability to respond to such changes in scheduling is related to the length of the body’s circadian rhythms or chronotype. This project will use a well studied model species (the great tit Parus major) to investigate how chronotype of individual constrains their ability to respond to changes in length of activity periods (of the type that might be brought about by changing environments). The project will use (and provide training in) cutting edge technology and methods to measure animals chronotype and investigate how chronotype influences ability to cope with environmental challenges. Field work will be carried out in the woodlands surrounding SCENE (the university’s state of the art research station on the shores of Loch Lomond). Work will involve tracking and studying wild birds fitted with tiny, externally fitted temperature sensors that can be used to non-invasively measure an chronotype (due to the body’s natural temperature cycle). The response of birds of different chronotypes to experimentally enlarged broods (that will extend the length of their working day) will be investigated to test the hypothesis that chronotype constrains the ability to respond successfully to novel environments.

Dissecting the polyclonal antibody response to foot-and-mouth disease virus in cattle and buffalo

Richard Reeve Richard.Reeve@glasgow.ac.uk Dan Haydon Daniel.Haydon@glasgow.ac.uk John Hammond  Nick Juleff 

This is a joint project with Institute of Animal Health

Foot-and-mouth disease (FMD) is a highly contagious, acute viral disease of cloven-hoofed, domesticated and wild animals and crucial within the global food security agenda. Despite this, very little is known of the transmission dynamics of the virus in natural hosts (buffalo in Africa), in particular, how FMDV persists in the individual host, and the factors leading to spillover events from wildlife reservoirs (buffalo) into livestock populations (cattle, pigs, and sheep).

This project will determine the genetics underlying the protective immune response to FMDV by exploiting the natural resistance to FMD of the African buffalo (Syncerus caffer). Buffalo and cattle are closely related species that show differential resistance to several diseases including FMD. In cattle and other domestic livestock FMD is characterized by fever, lameness and vesicular lesions of the feet, tongue, snout and teats. In contrast, FMDV infection of African buffalo only causes mild or subclinical disease. Consequently this species is an effective reservoir host of FMDV South African Territories (SAT) 1-3 serotypes and poses considerable problems to livestock farmers and to wildlife conservation. This proposal brings together world-leading expertise in immunology, immunogenetics, virology and epidemiology to examine the genetic basis underlying this species-specific differential disease resistance. As FMDV protection is largely mediated by antibody, we will test the hypothesis that differences in the antibody responses between cattle and buffalo creates differential disease resistance to FMD. This fundamental research will inform future epidemiological studies and direct future vaccination strategies.  Specifically, we will determine the differences between the cattle and buffalo immunoglobulin (Ig) heavy chain germline sequences; compare the natural antibody repertoire between cattle and buffalo; and compare the IgG antibody repertoire between cattle and buffalo after FMDV infection.

The role of E. coli siderophores as “vitaPAMPs” in reproductive disease

David E Smith David.G.Smith@glasgow.ac.uk

The concept of “vitaPAMPs” has been proposed recently as factors produced by replicating bacterial and a means for the immune system to distinguish between viable and non-viable pathogens to fine-tune immune responses.  This project will investigate the role of bacterial siderophores as vitaPAMPs at mucosal surfaces. 

Siderophores are released and re-acquired by viable bacteria to sequester iron which is at growth-limiting concentrations in vivo.  Some siderophores can themselves be bound by the mammalian protein Lipocalin-2 and there is evidence that binding of Lipocalin-2 to its receptor 24p3R is a crucial component in the modulation of innate responses to pathogens.  The aims of the project are to establish the contribution of the siderophore enterochelin and its ligand lipocalin-2 for establishing infection, evoking innate immune responses and modulating mucosal responses through interplay with other innate immune receptors such as TLRs which can detect viable and non-viable bacteria.  Experience in a range of microbiological and immunological approaches will be gained through this project from which outcomes address both translational and fundamental aspects of pathogen-host interaction. 

Development of transgenic plants as edible vaccines against bovine respiratory tract infections

Robert Davies Robert.Davies@glasgow.ac.uk Daniel Walker Daniel.Walker@glasgow.ac.uk

Bovine respiratory disease causes major economic losses to the cattle industry worldwide and Mannheimia haemolytica and Pasteurella multocida play important roles in this disease complex; P. multocida is also responsible for haemorrhagic septicaemia of cattle and water buffalo in Africa and Asia. Improved, cost-effective vaccines are required to help combat these infections particularly in developing countries where food security is becoming of increasing importance. The aim of this proof-of-concept project will be to demonstrate that autotransporters can be expressed in stable form in plants with an ultimate goal of developing edible vaccines to protect cattle against these infections. Autotransporters represent a large super-family of Gram-negative outer membrane proteins that play important roles in virulence and are being widely investigated for their potential use as vaccine antigens. Bioinformatic approaches will be employed to identify the autotransporters present in each bacterial species and our own extensive strain collections will be used to assess their diversity and select representative types. Segments of the genes corresponding to surface-exposed regions of the proteins will be cloned into Escherichia coli and the recombinant proteins expressed, purified and characterized in further detail. In the final step, recombinant proteins will be produced in the model plant Arabidopsis for further analysis.

Modes of action of veterinary drugs determined through metabolomics analysis

Michael Barrett Michael.Barrett@glasgow.ac.uk Rudi Marquez Rudi.Marquez@glasgow.ac.uk  Adrian Lapthorn Adrian.Lapthorn@glasgow.ac.uk

Drugs represent a major way of protecting livestock from microbial disease.  Anti-parasitic agents in particular have been important in sustaining livestock productivity in tropical Africa where diseases such as trypanosomiasis devastate domestic animal populations.  There is an urgent need to develop new drugs to treat animal trypanosomiasis.  Fundamental to new drug development is the identification of modes of action of drugs.  We have recently developed a platform to demonstrate how drugs work using comprehensive metabolomics analysis.  A drug that inhibits an enzyme will lead to the accumulation of the substrate of that enzyme as it is no longer consumed.  Conversely, the enzyme’s product will be diminished as it is no longer produced.  In this project we will systematically test drugs used against veterinary trypanosomiasis for their effects on the parasite’s metabolome in order to identify drug targets.  This will include drugs already in use against veterinary trypanosomiasis and also experimental compounds proceeding through clinical development.  We will move on then to investigate the structure of targets and new chemical inhibitors of those targets though interactions with co-supervisors in Chemistry.

Will marine biomineralisers survive under the threat of multiple-stressors? Global warming, marine hypoxia and ocean acidification

Nicholas Kamenos Nick.Kamenos@glasgow.ac.uk

Biogenic calcium carbonate is abundant in the marine environment where invertebrates such as corals and molluscs produce calcium carbonate structures, a process called biomineralisation. However, anthropogenic CO2 emissions are predicted to cause undesirable environmental effects which may compromise the stability of biomineralising marine organisms. These include global warming, marine deoxygenation (hypoxia) and ocean acidification. For example, the structural detrimental impacts of ocean acidification have been observed in field experiments, however, there is evidence that other sub-organism processes may provide adaptive capacity to environmental change (e.g. osmolyte production). It is likely that proteomic responses are underlying such adaptive responses. However, little information is available on the proteomic responses of marine organisms to global change. This research shall investigate the proteomic responses of marine biomineralisers (important in marine-derived food security) to multiple environmental stressors projected to change the oceans over the next century. This will enable us to determine the consequences of single and multiple environmental stressors on marine biomineralising systems important in food supply and food security over the next century.

Food Security: Crop Science

Below are example projects. Applicants are applying to the Programme and not for specific projects at this stage. 

Creation of disease resistant transgenic plants expressing species specific protein antibiotics

Daniel Walker Daniel.Walker@glasgow.ac.uk

Plant diseases cause annual worldwide crop losses valued at over £100 billion, a situation that is likely to be exacerbated as environmental change facilitates the establishment of new pathogens in previously unfavourable geographical areas. The aim of the project is to generate transgenic plants that express highly specific protein antibiotics targeted against specific bacterial plant pathogens. The first phase of the project will involve the discovery and characterisation of protein antibiotics with activity against major plant pathogens.  We will then express candidate bacteriocins in model plants such Nicotiana benthamiana and Arabidopsis thaliana to demonstrate individual bacteriocins can be produced in planta in an active form and are able to provide resistance to specific bacterial pathogens. Finally, we will use the best candidate bacteriocins to produce disease resistant crop plants.

Modelling guard cells for improved plant water use efficiency

Mike Blatt Michael.Blatt@glasgow.ac.uk

The MRB laboratory recently developed a quantitative systems dynamic approach to modelling guard cell homeostasis and stomatal dynamics, with demonstrated predictive power. Among others, this modeling approach uncovered a previously unrecognized homeostatic network that ameliorates the effects on water loss of an anion channel mutant in Arabidopsis. It is proposed now to translate the micro-macro link of this modelling strategy to incorporate gas exchange and transpiration, introducing feedback pathways from photosynthesis and water flux to stomatal control. Such translation is the essential next step for predictive analysis relevant to molecular breeding, such as might lead to designing new crop varieties with improved WUE at minimal cost to carbon assimilation. The project will  provide core training in key skills of mathematical and SYSTEMS BIOLOGY as well as expertise in related niche skills of PLANT PHYSIOLOGY, membrane biology and electrophysiology, all relevant to FOOD SECURITY and to OTHER WORLD-CLASS SCIENCE.

Regulation of responses to UV-B in oilseed rape

Gareth Jenkins Gareth.Jenkins@glasgow.ac.uk

UV-B wavelengths in sunlight provide an important environmental signal that regulates various responses in plants. These regulatory responses are mediated by the UV-B photoreceptor UVR8, which is the focus of research in the supervisor’s laboratory. Some UV-B responses, including differential gene expression determining the levels of secondary metabolites, are important in crop species such as oilseed rape (Brassica napus) because they impact on nutritional quality and deter insect herbivory. The aim of this project is to investigate the processes of UVR8 signaling in B. napus, in particular the relationship between UVR8 photoreception, interaction with key regulatory proteins, and the regulation of transcription, which is key to Plant physiology/Pathology understanding how UVR8 regulates responses in this crop species. The student will examine the expression of B. napus UVR8, identify positive and negative regulators of UVR8 signaling in B. napus, study their regulation and investigate how they interact with UVR8 to control transcriptional responses to UV-B.

Composition and function of histone-deacetylase complexes in plants

Anna Amtmann Anna.Amtmann@glasgow.ac.uk

Drought limits crop production in many areas of the world. Furthermore, irrigation represents a huge drain on ‘blue’ water reserves and hence contributes to worldwide water scarcity. Clearly, to secure future food and water supplies we will need to produce more food with less water (more ‘crop per drop’). This project contributes to our efforts to enhance the inherent potential of plants to cope with reduced water supply by manipulating their sensitivity to the stress hormone abcisic acid (ABA) using epigenetic regulators.

You will use a combination of biochemistry, molecular genetics and plant physiology to identify novel components of histone-deacetylation complexes in the model plant Arabidopsis thaliana, based on our recent discovery of a novel unique member of these multi-protein complexes. Supported by an in-house Proteomics Facility you will carry out a range of biochemical analyses (e.g. co-IP), as well as yeast-2-hybrid assays and bimolecular fluorescence complementation, with the aim to identify interacting protein partners. In the second part of the project you will functionally characterise mutant lines for the identified proteins using physiological and molecular methods (including survival assays, RNA sequencing and quantitative PCR).  You will be integrated into an active research group operating at the forefront of molecular plant science (http://www.psrg.org.uk/index.html), and you will receive training in a wide range of cutting-edge techniques.  The project falls into to Research Council priority area of Food and Water Security.

Molecular genetics and physiology of renal function in insects

Julian Dow Julian.Dow@glasgow.ac.uk and Shireen Davies Shireen.Davies@glasgow.ac.uk

Insects make up more than half of all living species; some are major vectors of human and animal disease, while others destroy 20% or the world’s crops. Part of the remarkable success of insects is their ability to osmoregulate in hostile environments.

This project will study osmoregulation in Drosophila and other insects, using a range of cutting-edge techniques in physiology, molecular biology, next-generation sequencing, informatics and genetics.

 

World Class Bioscience Projects

Below are example projects. Applicants are applying to the Programme and not for specific projects at this stage.

Testing for natural selection at the phenotypic and genomic level in divergent ecomorphs of Arctic charr (Salvelinus alpinus)  

 Kevin Parsons Kevin.Parsons@glasgow.ac.uk Colin Adams Colin.Adams@glasgow.ac.uk

 After over a century and a half natural selection remains a core concept in evolutionary biology, and a major focus of empirical research. However, while natural selection has a long history in research the means by which it can be investigated has been revolutionized over the past decade.

This project will take two approaches to examine natural selection in adaptively divergent populations of Arctic charr. Using cutting-edge method for 3d capture of shape the first approach will focus on relationships between morphological features and fitness within and between ecomorphs, while the second approach will take a population genomic approach using next-gene sequencing approaches to determine loci undergoing selection in charr.

Sensing G protein-coupled receptor activation: from in vitro to in vivo analysis

Graeme Milligan graeme.milligan@glasgow.ac.uk   Shireen Davies Shireen.Davies@glasgow.ac.uk

Intramolecular G protein-coupled receptor (GPCR) FRET sensors have been developed and used to detect conformational changes associated with the binding of agonist ligands and to explore the kinetics of ligand binding and de-binding in real time. These have particular attraction for poorly characterised GPCRs that have low affinity ligands or where traditional ligand binding studies cannot be performed. Such constructs also offer the potential to assess the activation state of a GPCR in vivo and how this may be modulated by ligands or by environmental conditions. However, to date such constructs have been utilised only within in vitro studies. The project will employ a multidisciplinary approach to (a) improve and optimise current mammalian GPCR FRET sensors, (b) develop the first such FRET sensor based on an insect GPCR and (c) transition current in vitro studies to in vivo analysis of GPCR activation via transgenic expression of both mammalian and insect receptors in Drosophila under both normal and environmental stress conditions.

Spinal cord neurons that inhibit itch

Andrew Todd Andrew.Todd@glasgow.ac.uk  John Riddell John.Riddell@glasgow.ac.uk

Itch is an unpleasant sensation associated with many chronic diseases, but the underlying mechanisms are still poorly understood and it remains difficult to treat. Stimuli that cause itch activate certain neurons in lamina I of the spinal cord that transmit sensory information to the brain. Scratching, which relieves acute itch, is thought to operate through inhibitory interneurons in the spinal dorsal horn that block transmission through this pathway. Insight into the neuronal circuits that mediate itch came from the recent demonstration that mice lacking a transcription factor (Bhlhb5) show severe itch, associated with loss of a set of inhibitory interneurons (B5-I cells) from the dorsal horn. Recent work in our laboratory has identified two potential candidates for the B5-I cells: GABAergic interneurons that express the neuropeptides galanin and dynorphin, and those that contain the neuronal form of nitric oxide synthase. This project will use combined immunocytochemical and electrophysiological techniques to reveal the synaptic targets of these two interneuron populations and thus to determine which type is responsible for the scratch-mediated inhibition of itch. Identifying receptors expressed by these cells should help to reveal potential targets for the treatment of chronic itch.

Dynamic imaging of acute adenovirus gene transfer in vivo

Andrew Baker Andrew.H.Baker@glasgow.ac.uk  Paul Garside Paul.Garside@glasgow.ac.uk

This application is focused on the development and optimisation of adenovirus vectors for application to human gene therapy. There is substantial potential in Ad5 and other human adenoviruses for application to human gene therapy. However, the properties of the vector have not been optimised for delivery and gene transfer. In this DTP application we will develop an innovative and exciting programme of work that will increase understanding of adenovirus virology, and host immunology, thereby informing vector development with a view to application in future clinical use to treat patients. The route of administration is critical for host-virus interactions. The breadth of use of adenovirus vectors for treatment of human disease necessitates an in-depth understanding of the mechanisms that govern cellular interactions and infectivity via each route – particularly bolus injections via the intravascular route, local delivery to the vasculature, subcutaneous and intramuscular injection. We will develop 2-photon microscopic studies to visualise acute adenovirus:host interactions in real time in vivo. These studies will use cell specific reporter mice in order to assess dynamically the early biodistribution of adenovirus within spleen and liver, as well the host response and impact of capsid modifications (mutation and coating).  These important interactions are complex and subtle and can only adequately be analysed by spatiotemporal analysis in vivo. We will employ a suite of state-of-the-art imaging and immunological approaches. Adenovirus research would therefore benefit from a new direction and enabling technology to visualize, in real time, the early phase cellular interactions with the immune system. This has never been performed before in the context of adenovirus vectors but is made possible through this DTP application and offers a novel, in depth and substantial training opportunity.

The use of novel optical techniques to study the effects of chronic electrical stimulation on cardiac myocytes.

Godfrey Smith Godfrey.Smith@glasgow.ac.uk Gail McConnell 

Biomedical and pharmaceutical research increasingly uses human stem-cell derived cardiac and neural tissue to test novel compounds and/or screen for toxic effects. There is a need for functional assays that can be applied to these cells which are grown under sterile specialised culture conditions. We have developed non-invasive techniques to measure electrical activity using optical dyes, but electrical stimulation normally requires solid-state electrodes that cannot be applied without disrupting the specialised culture conditions. This application will examine the efficacy of two novel methods for efficient non-invasive stimulation of electrically excitable cells, both culture-based stem-cell derived and acutely isolated human preparations. The first approach will involve the use of optics to create a specialised focussed light (Bessel beam) that can be used with a laser to transiently (5ms) destabilise biological membranes in discrete areas thereby providing the depolarising stimulus. A second approach will be to use a photo-active membrane-bound compound to release a transient burst of short-lived reactive oxygen that will locally interact with biological membranes to provide the membrane depolarisation. Both approaches can be used with existing optical systems in the supervisor’s labs using tissue from commercial sources to examine the effects of chronic stimulation on cardiac muscle phenotype.

Transcriptome and metabolome strategies to dissect cellular hypertrophy

Martin McBride Martin.McBride@glasgow.ac.uk Delyth Williams Delyth.Graham@glasgow.ac.uk

Elevated blood pressure is an important determinant of left ventricular hypertrophy (LVH) in humans, however the intensity of blood pressure load does not always correspond to the degree of hypertrophy suggesting independent genetic effects. Despite considerable advances in molecular analysis of the genetic contribution to LVH using large genome-wide association studies (GWAS) there has been little progress made towards understanding the mechanisms involved in hypertrophy at the cellular level.

In this proposal, our research aims are to investigate and characterise the functional effects of modulating levels of osteopontin in a cell based model of hypertrophy and primary cardiomyocyte cells isolated from strains that express different levels of osteopontin. As a single method of analysis will be unlikely to identify all key regulatory pathophysiological pathways we will generate large-scale multilevel transcriptome and metabolome datasets from H9c2 cells over expressing osteopontin and neonatal primary cardiomyocytes from our SHRSP_Gla, WKY_Gla, and WKY.SP_Gla14a strains that express low and high levels of osteopontin. A further key component of these comprehensive studies will be to integrate distinct data modalities (RNAseq data and metabolome profiles) using in-house software solutions and publically and commercially available software; Perseus and Ingenuity Pathway Analysis (Ingenuity® Systems, www.ingenuity.com) and xQTL (http://www.xqtl.org/). The analysis pipelines and data integration strategies to compare profiles from our cell model and isolated primary cardiomyocyte cells will provide valuable insights into the identification and prioritisation of biological networks and processes linked to hypertrophy.

Optimal band-separation of encephalographic brain signals to study brain (dys-)function: a neuroinformatics approach

Chistoph Kayser Christoph.Kayser@glasgow.ac.uk Stefano Panzeri Stefano.Panzeri@glasgow.ac.uk

Imaging brain function heavily relies on a mesoscopic assessment of neural activity using sensors distant from the tissue of interest. Signals such as encephalographic potentials (EEG/MEG) capture multiple neural processes, and to properly interpret these, sophisticated analytical and computational tools are required to separate the different components that make up the recorded signal. We have recently developed advanced statistical methods to identify regimes within the signal’s spectrum optimally tuned to specific external correlates (e.g. sensory stimuli) and that identify statistically optimal boundaries between bands.

This bioinformatics project aims to extend the previous approach to fully cover whole-brain recordings provided by EEG/MEG data and to provide the computational tools to identify objective and functionally meaningful components in such data. A first step will be to perform the Neuroinformatics work necessary to provide the analytical tools for an objective standardized spatio-temporal partition of aggregate neuroimaging signals into functionally relevant components. Subsequently we will apply this approach to paradigms involving sensory-cognitive tasks in healthy humans and selected clinical conditions. Thereby this work will enhance our understanding of the functional structure of neural signals and provide tools to derive objectively defined functional and clinical markers.

The project offers substantial training in Bioinformatics techniques, including the development and use of algorithms based on information theory, statistical methods of pattern classification, advanced spectral analysis, and their efficient software implementation in a highly competitive computer cluster. This entails both analytical skills, computer scientific knowledge and programming, key skills required for bioinformatics research.

Elucidating the role of PAR2 in the brain

Stuart Cobb Stuart.Cobb@glasgow.ac.uk Trevor Bushell Trevor.Bushell@strath.ac.uk

Proteinase-activated receptor 2 (PAR2) belongs to a novel and unusual family of G-protein coupled receptor traditionally implicated in inflammation-related pathogenesis. However, we have reported PAR2 expression in neurons and various non-neuronal cells of the CNS and have recently shown PAR2 to regulate neural excitability and synaptic transmission. Despite this, the role of PAR2 in the brain and the significance of PAR2 activation in normal brain function and in neuronal and glail homeostasis / control remain very poorly defined. The aim of the project is to shed light on PAR2 action in the nervous system by addressing three fundamental questions: 1. To determine when (under what behavioural / environmental conditions) and where in the brain (brain areas, cell types and subcellular loci) PAR2 are activated. 2. Obtaining mechanistic insight into the cellular and synaptic actions of PAR2 activation and in particular the role of PAR2 in neuronal-glial interactions and 3. Establishing the behavioural / systems consequences of brain PAR2 activation.

The project will provide training in a range of cell biological, anatomical and neurophysiological techniques and will be driven by two enabling technologies: the availability of novel brain permeable PAR2 activators which we have developed and optimised and the development of viral-delivered reporter assay for assessing and mapping the activation of PAR2 in the brain.

Understanding state-dependent information processing in the brain: a neuroinformatics systems-level approach

Stefano Panzeri Stefano.Panzeri@glasgow.ac.uk Shuzo Sakata 

Current understanding of brain functions is mostly based on mapping relationships between external stimuli and neural activity. Yet, this approach suffers from a fundamental limitation: neural activity is stirred not only by the current stimulus, but it is also governed by the internal state of the neural circuits. This state dependency results in high variability of neural responses to each stimulus. Many previous studies have neglected this variability, simply removing it by averaging neural responses over stimulus repetitions. However, this strategy is unsatisfactory, because this is not the one used by our brains, which perceive complex stimuli on a single trial basis. As a result, the impact of brain states on neural information processing is still poorly understood.

The aim of this neuroinformatics project is to develop the analytical methods for the information extraction from neuronal activity and the system-level mathematical models of neural network interactions that are needed to fully understand how the state dependence of neural responses fundamentally shapes brain information processing.

This projects offers training in advanced analytical methods of Bionformatics and Neuroinformatics, and in the mathematical modelling techniques of interacting biological systems that are relevant for Systems Biology, as well as offering training in systems level in-vivo neuroscience. 

The role of brain oscillations in rhythmic sensory sampling and audio-visual integration

Joachim Gross Joachim.Gross@glasgow.ac.uk Phillipe Schyns Philippe.Schyns@glasgow.ac.uk

Recent research has provided increasing evidence that the brain samples sensory information discretely instead of continuously. Measurements of brain activity at high temporal resolution point to brain oscillations as a likely mechanism. These oscillations in brain activity represent rhythmic changes in cortical excitability and have been shown to affect behavioural performance such as the probability to perceive a near-threshold target stimulus. In this project we want to study how brain oscillations affect the processing of naturalistic continuous audio-visual stimuli. Specifically, we will use Magnetoencephalography (MEG) to record brain activity at high temporal resolution while the participants observes audio-visual stimuli. First, the effect of short stimuli in one modality (e.g. auditory) on oscillations in the other modality (e.g. visual) will be studied. In a subsequent experiment naturalistic videos will be presented and the alignment of brain oscillations to regularities in the auditory and visual input will be studied. Finally, the role of brain oscillations in integrating auditory and visual information will be studied.

Serine Integrase Recombineering for Yeast Synthetic Biology

Marshall Stark Marshall.Stark@glasgow.ac.uk Joseph Gray Joseph.Gray@glasgow.ac.uk

Synthetic Biology is an emerging, interdisciplinary area focused on exploiting engineering principles to engineer and re-engineer living systems for scientific, technological and industrial benefit. Budding yeast, a eukaryote, is a key organism for developing synthetic biology approaches in eukaryotes. Here, we propose to engineer and exploit bacterial serine recombinases as tools for eukaryotic genome engineering and to create novel control and biocomputing devices Two bacterial serine integrasesystems, from bacteriophages φC31 and Bxb1, are characterized to date and have multiple advantages for recombineering in eukaryotes:

1) a single polypeptide is required for the site-specific recombination reaction.

2) each system has specific target sites.

3) the direction of each recombination reaction can be controlled by the expression of

a single dedicated accessory protein in each case.

4) these recombination systems can be transplanted into and function in eukaryotes.

This studentship will focus on four aims. First, the serine integrase directional recombination (SIDR) systems will be engineered into budding yeast. Second, these systems will be characterized and optimized. Third, SIDR systems will be exploited for tailored and novel genome engineering. Finally, novel Synthetic Biology applications of SIDR systems in yeast will be explored, including pilot experiments towards systematic programmed genome rearrangements and conditional gene knockout for creation of “zombie cells”.

Optogenetic tools for in vivo cell signalling, physiology and behavior

Shireen Davies Shireen.Davies@glasgow.ac.uk Julian Dow Julian.Dow@glasgow.ac.uk

Light-activatable genetically-encoded tools including enzymes, are currently being developed for many applications across biology and biomedicine. Such ‘Optogenetics’ is a novel technology powerfully utilised for in vivo studies, and already addressing a range of fundamental biological questions from neurobiology to plant growth.

Here, we are utilising such tools, based on blue-light activatable adenylate and guanylate cyclase enzymes to activate either cAMP signalling, or cGMP signalling (or

both) - in identified cells in the living organism. Using D. melanogaster, we can precisely target light - activatable constructs to particular cells and/or tissues in an otherwise normal organism. This approach allows specific in vivo cyclic nucleotide signals to be correlated to physiological function eg., epithelial, neuronal and metabolic function – and ultimately consequential effects on the whole organism using cutting-edge technology.

Ecological genomics of trophic divergence

Kathyrn Elmer Kathryn.Elmer@glasgow.ac.uk Colin Adams Colin.Adams@glasgow.ac.uk

Biodiversity research has direct implications for our understanding of the origins of species, their adaptation, and how they can respond to environmental change. Genomic factors that influence this organismal adaptation are a critical element in understanding the evolution of biodiversity. Two alternative viewpoints to study the genetic basis of adaptation are genome-wide patterns of genetic diversity and genome-wide patterns of gene expression. Recent advances in DNA sequencing technology make it possible to study the genomics of populations in nature, in order to understand the genetic bases of ecological diversity.

This doctoral research project seeks to address these two inter-connected aspects of the ‘omics of diversification in a non-model vertebrate populations in nature. Genomic and transcriptomic approaches will be used to investigate a) differential gene expression associated with rapidly evolving and phenotypically plastic trophic polymorphisms of lab-reared wild populations, and b) the extent and genomic location of genetic diversity between trophically divergent, incipient species. The study organisms are polymorphic species of salmonid fishes native to Europe. The experimental design will include replicates across populations and species, thereby increasing the power of inference via the repeated, parallel evolution of different ecologically relevant phenotypes. Research will be conducted in collaboration with SCENE and the Glasgow Polyomics Facility

Tracking the seasons: tissue-based memory for annual cycles?

Jane Robinson Jane.Robinson@glasgow.ac.uk Barbara Helm Barbara.Helm@glasgow.ac.uk

A major scientific challenge today is to understand the effects of global climate change on ecosystem health. This includes examining flexible responses to changing seasonality. Many animals time seasonal activities through physiological signalling in response to environmental cues, eg, photoperiod, but they also anticipate change by endogenous time-keeping mechanisms. Mismatches between seasonal activities and suitable environmental conditions can be detrimental. Thus, in response to changes in climate some species now perform activities like migration or breeding under altered timing cues. Current evidence that seasonal processes may thereby become desynchronized calls for better understanding of the underlying mechanisms. Birds provide an ideal model to address this because seasonal activities are striking in wild species and commercially relevant in domestic fowl. This proposal uses avian moult as an easily measurable trait that affects fitness and as a model system for regenerative, circannual processes. Circannual rhythms are poorly understood but appear to involve central regulation that interacts with local clocks in peripheral tissues such as skin. Moult can be driven by changes in photoperiod but is also locally sensitive to hormones including androgens, prolactin and thyroid hormones. The contributions of these factors will be determined following photoperiodic and hormone treatments at central and peripheral levels. The project is interdisciplinary and brings together physiological, ecological, and chronobiological approaches. Methods include local application of hormones, collection of skin biopsies, bioimaging, hormone assays, and quantification of clock genes and gene expression patterns.

Control of Leydig cell differentiation

Peter O’Shaughnessy Peter.O'Shaughnessy@glasgow.ac.uk Michelle Welsh Michelle.Welsh@glasgow.ac.uk

The Leydig cells (LC) in the testis secrete androgens which are essential for masculinisation and fertility in males. LC differentiation occurs before puberty but the process is poorly understood despite the critical role that it plays in normal development. This project will use an adult rat model in which the LCs are destroyed by a cytotoxic drug called EDS. After treatment with EDS a new, functional LC population emerges and it is this developmental phase that will be studied in detail. A comprehensive database of gene changes during LC differentiation will be established using RNAseq. Changes in transcript levels will be confirmed by real-time PCR and the role of pituitary hormones in the process established by inhibiting pituitary gonadotrophin release. Changes in gene expression following EDS will be compared to events that occur normally during LC development and a list of candidate genes that may be crucial to the differentiation process will be generated. To test the function of these candidate genes an in vitro model will be established which will allow the role of each gene in the differentiation process to be determined by knockout using siRNA.

 New Probes to Map lipids on Membrane Proteins

Pavel Kocovsky Pavel.Kocovsky@glasgow.ac.uk Richard Cogdell Richard.Cogdell@glasgow.ac.uk

It is often difficult to locate lipids on the surface of structures of membrane proteins. This project will synthesise lipids and detergent molecules labelled with heavy atoms, such as Hg and Te, so that in X-ray crystal structures the heavy atom tags can be used to unequivocally indentify lipid/detergent binding sites at the surface. We will use reaction centres and LH complexes as test membrane proteins that can be readily crystallised.

 Modelling, visualising and understanding host-biofilm interactions

Shauna Culshaw Shauna.Culshaw@glasgow.ac.uk Gordon Ramage Gordon.Ramage@glasgow.ac.uk Owain Millington  

Bacteria, in the majority of environments, will develop as biofilms. Biofilms are mixed populations of bacteria, enclosed within an exopolymetric matrix and attached to one another and/or to substrata. These biofilms exist on mucosal surfacjes in both health and disease and pose a curious relationship with the host. In health, the interactions between biofilm and the host immune system seemingly regulate both biofilm function/growth and the normal physiological function of the host. In disease, changes in the biofilm, or in how the host responds to the biofilm can result in inflammation and tissue destruction. Thus, resolving the paradox of how the steady state of both host and biofilm is maintained is paramount to health. The oral cavity represents a complex environment of mucosal and hard surfaces (teeth) all coated in biofilms in both health and disease states. Moreover, juxtaposed to these biofilms are free-floating bacteria in saliva. Thus this is arguably the perfect backdrop against which to pose the question as to why the immune system responds differently to biofilms or free-floating bacteria. This project will seek to explore the relationship between key immune cells and biofilms involved in both steady state and disease scenarios. Using established in vitro and in vivo models of bacteria-host interactions you will probe immune system activation using a combination of Bioimaging and Systems Biology. Finally, we will build on our strengths in in vivo mammalian biology and access to human samples to understand these interactions in their physiological, complex environment.

The function of atypical chemokine receptors on lymphatic endothelial cells.

Robert Nibbs Robert.Nibbs@glasgow.ac.uk Gerry Graham Gerard.Graham@glasgow.ac.uk

The migration and positioning of white blood cells (leukocytes) is of critical importance in immunology.  It is controlled by a family of secreted proteins called chemokines that tell leukocytes where to go by interacting with chemokine receptors on their surface.  This is particularly important in the biology of lymph nodes (LNs).  Protection from infection, vaccine efficiency, and the development of autoimmunity and other diseases are profoundly influenced by the cellular interactions that occur in these organs.  We study two ‘atypical’ chemokine receptors, called D6 and CCRL1, which bind distinct subsets of chemokines.  Rather than making cells move, these molecules appear to draw chemokines inside cells for destruction and thus suppress chemokine function.  Unexpectedly, we found that D6 and CCRL1 are also unified by the fact that they are only found on lymphatic endothelial cells (LECs).  These cells line lymph vessels in LNs.  The immunological roles of LECs are poorly understood, but we believe that D6 and CCRL1 are essential contributors to immune regulation by LECs.  Indeed, we already know that these molecules are important for the proper functioning of LNs, and ongoing studies aim to define their indispensable roles during immune responses in vivo. The studentship will complement and inform this work by using state-of-the-art approaches, including immunofluorescent imaging, in vivo mammalian biology and transcriptomics, to dissect the cellular and molecular functions of D6 and CCRL1 on LECs.  The project will provide excellent scientific and technological training in a large, vibrant, and dynamic group of experienced chemokine researchers.

Further details can be obtained from Prof Rob Nibbs (robert.nibbs@glasgow.ac.uk).

Development of Broad Spectrum Anti-Parasitic Agents

Rudi Marquez Rudi.Marquez@glasgow.ac.uk

The emergence of drug resistant strains of pathogens is a leading cause of mortality worldwide. There is an urgent need to develop new anti-parasitic and antibiotic agents that selectively target new molecular pathways. As part of this application, we propose an interdisplinary programme to develop new CoA biosynthesis inhibitors as broad spectrum anti-parasitic and antibiotic agents. Our inhibitors are based on a novel enamide framework, and will be developed as part of an international collaboration involving the two main applicants together with colleagues in Australia, South Africa, Germany, and Scotland.

 Metabolomic profiling of bacteria on nanostructured substrates for improved microbial fuel cells

Nikolaj Gadegaard Nikolaj.Gadegaard@glasgow.ac.uk Susan Rosser Susan.Rosser@glasgow.ac.uk Karl Burgess Karl.Burgess@glasgow.ac.uk

Over the years we have demonstrated that eukaryotic cells are profoundly influence by surface topography, especially at the nanoscale. Recently we discovered that bone marrow derived stem cells can be made to either differentiate to bone forming cells or retain multipotency in prolonged culture. This is driven by minute changes in the surface topography (<50 nm) and we have shown that the metabolic profile for the cells on the different surfaces are distinctly different.

With the discovery of the nanopattern inducing bone differentiation we are now working at implementing this in medical implants. Importantly, during a surgical procedure there is an increased risk of infection when implanting a device in the body, thus a reduction or prevention of bacterial adhesion and function at the same time

Linking genome to functional role in low-temperature anaerobic digestion communities using Raman micro-spectroscopy

Christopher Quince Christopher.Quince@glasgow.ac.uk Huabing Yin Huabing.Yin@glasgow.ac.uk Michael Barrett Michael.Barrett@glasgow.ac.uk

The direct sequencing of environmental DNA, or metagenomics, can generate unprecedented amounts of information on the genetic make-up of microbial communities, providing information on the organisms present and the proteins they may express. However, in diverse communities assembling significant fractions of genomes is difficult and we still lack direct evidence of the metabolic functions performed. Raman micro-spectroscopy coupled to microfluidics can address this. Substrates designed to be taken up by a particular functional group, are labelled with stable-isotopes and fed to the community. The organisms that uptake the substrate can then be identified by shifts in their Raman spectra and selected through microfluidics. This provides a small number of cells of known metabolic function for follow-on studies such as genomics. With the double advantage that we both know their metabolic function and the genomic diversity has decreased. The aim of this studentship will be to pioneer this technique specifically for low-temperature anaerobic digestion communities, developing methods for the identification of methanogens and their syntrophs through Raman spectroscopy. This will allow us to sequence the selected organisms and culture them with microfluidics. The result will be an improved understanding of the metabolism of these key groups allowing optimisation of biogas production.

Propagation of Aortic Dissections

Nicholas Hill Nicholas.Hill@glasgow.ac.uk Nik Tzemos Niko.Tzemos@glasgow.ac.uk

Aortic dissections originate with an intimal tear in the ascending aorta and/or aortic arch (65%). The risk of death is exceedingly high in untreated aortic dissection and this is particularly true in the first 24 hours of the event. 75% of those with this type dissection who are not treated die within two weeks. However surgery is a very major undertaking in these patients, must be performed as an emergency (often during the night) and carries itself a significant risk of death or major complication. The cost of treating acute aortic dissection is intuitively very high. Many patients require prolonged therapies typically delivered in a critical care environment costing £1500 per day.

Although Type A aortic dissection is a frequently occurring phenomenon and a challenging clinical entity, the underlying biomechanics remains largely unclear. There are few studies on aortic dissection from a biomechanical point of view.

The aim of this project is to develop computational models of patient-specific geometries, extending recent mathematical theories of simple models of dissections, to develop methods of predicting the propagation of arterial dissections to better guide clinical decisions.

Heart remodelling during aging

Xiaoyu Luo Xiaoyu.Luo@glasgow.ac.uk Colin Berry Colin.Berry@glasgow.ac.uk

Mathematical modelling combined with MR imaging had provided a powerful tool in quantitative understanding of the functioning of the heart in health and disease. However, despite intensive research, one of the most important, yet largely ignored, issues in the heart research community is heart remodelling. During disease or medical treatment, the heart continuously remodels itself to adapt to the changing environment. However, currently almost all available heart models do not take this into consideration, and are therefore powerless in predicting changes to the heart.

This PhD project will study the cut edge research of heart remodelling. In particular, it will apply and extend the novel mathematical approach for vascular growth and remodelling to the heart that has been developed in the group. The approach will be based on representing the mechanobiology of vascular cells and their maintenance of the extra cellular matrix (ECM) in homeostatic and pathological conditions. The PhD study will incorporate explicit representations of cardiac fibroblasts and their functionality into our recently electro-mechanical model of the heart, and developing vivo and in vitro tests and magnetic resonance imaging (MRI) imaging to tests the models. The study will explore the impact of altered environmental stimuli on fibroblast functionality, ECM maintenance and fibrosis. This research will guide fundamental understanding of cardiac fibroblast mechanobiology in pathological conditions. Such modelling will provide insight into novel therapies to improve outcomes in heart disease

Harnessing activity-dependent plasticity in combination with chondroitinase treatment to improve functional outcome after spinal cord injury

John Riddell John.Riddell@glasgow.ac.uk Bernd Porr Bernd.Porr@glasgow.ac.uk

Spinal cord injury (SCI) leads to permanent functional loss. However, where injuries are incomplete (approx 50%), there is the potential to improve functional outcome by promoting plastic changes that can compensate for lost or weakened nerve pathways. One approach to this is to use treatments that release the molecular “brakes” applied to mechanisms of plasticity during development to stabilize mature neuronal circuitry. For example, delivery of the bacterial enzyme chondroitinase ABC, promotes sprouting and plasticity which correlates with improved functional outcome in SCI models. However, there is increasing evidence that remodelling of circuits following release of plasticity is highly dependent on electrical activity occurring at connections within the spinal cord. The aim of this project is therefore to determine whether inducing such activity artificially, by electrical stimulation, can enhance the plastic changes that follow treatment with chondroitinase. The project will involve close co-operation with an engineering group to develop a miniaturised stimulation device which will be implanted in rodent models of incomplete SCI in order to activate “spared” pathways. This approach will be used to determine whether stimulation combined with chondroitinase treatment promotes greater improvement in functional outcome than chondroitinase treatment alone. Direct electrophysiological recording from the stimulated pathways will be used to assess improved function.

Does MKP-2 play a critical role in regulating CNS development and function?

Trevor Bushell Trevor.Bushell@strath.ac.uk Ben Pickard Benjamin.Pickard@strath.ac.uk

A role for mitogen-activated protein kinases (MAPKs) is well established in physiological cell function as well as in certain disease states. Recently, there has been growing interest in the signalling systems which control MAPK function, especially the attenuation of their activity. One family of proteins that contribute to this process is the mitogen-activated protein kinase phosphatases (MKPs). There is significant interest in MKPs especially in relation to their role in development, the immune system and cancer. However, there is a significant gap in our knowledge in relation to their function in the central nervous system (CNS). Currently, our limited knowledge is restricted to MKP-1 function in the brain; no evidence exists as yet with regard to the role of MKP-2. Utilising a novel mouse knockout of the Dusp4 gene encoding MKP-2, we have generated preliminary data showing reduced neurite growth and astrocyte proliferation in primary cultures and reduced MKP-2 expression in the brains of aged mice. Hence, we hypothesise that MKP-2 is important in CNS development and function. Based on our findings we propose to characterise its role in a range of biological processes that impact on brain function from birth to old age. Techniques well established in our laboratories will be used to further explore MKP-2 function in the CNS, specifically 1) to investigate the role of MKP-2 in CNS development and neurogenesis and 2) to determine the consequence of reduced MKP-2 expression in the aged brain. Overall this project will lead to a better understanding of the role of MKP-2 in the CNS and its function in healthy and ageing individuals.

Investigating biological interactions based on nanoparticle interactions

Duncan Graham Duncan.Graham@strath.ac.uk Karen Faulds Karen.Faulds@strath.ac.uk

This studentship will probe sites of interaction on proteins to understand complex binding events, allostery and ultimately intervention using specific disruptive approaches. The approach is based on an enhanced vibrational spectroscopy using functionalised nanoparticles to examine specific interactions between proteins and species that interact such as other proteins and over a longer distance than currently possible by existing approaches e.g. FRET. Multiple interactions measured in solution mean that there is potential for a very high impact in the BBSRC’s strategic priority area of ‘technology development for the biosciences’ and also in the wider bioscience community. There is a current technology gap in being able to measure

Coordination of chromosome segregation with growth and development in the antibiotic producing bacterium, Streptomyces coelicolor

Dr Paul Herron Paul.Herron@stratch.ac.uk Dr Paul A Hoskisson Paul.Hoskisson@strath.ac.uk The aim of this project is to characterise the coordination of chromosome segregation with hyphal growth and cytokinesis in the model bacterium, Streptomyces coelicolor. Not only are streptomycetes the most commercially important group of bacteria, producing over 70% of antibiotics, but they are also morphologically unusual: they have a linear chromosome and grow by means of multinucleate vegetative hyphae, before differentiating to form unigenomic spores. As a result, a comparison of streptomycete cell division mechanisms with those of other bacteria will shed light on the fundamental practices shared between all prokaryotes. We have generated a strain of S. coelicolor that carries a fluorescent marker at it’s origin of replication and during this project the student will generate movies of chromosome segregation during hyphal growth of this strain. In addition, the student will generate mutants in key streptomycete cell division strains so coordination of chromosome segregation with hyphal extension can be better characterised. As such the student will also receive sound training in bacterial genetics and molecular biology as well as the BBSRC skills priority areas of bioinformatics, bioimaging, and ‘omics that are essential for the next generation of world class bioscientists.   Defining the function of MAP kinase phosphatase-2 - novel interactions with cell cycle proteins and regulation of mitosis Robin Plevin R.Plevin@strath.ac.uk Gwyn Gould Gwyn.Gould@glasgow.ac.uk MAP kinase phosphatase -2 (MKP-2) is a member of the DUSP family of enzymes which shape the profile of MAP kinase activity in the cell and as a result play a key role in function. We have accumulated evidence to suggest that MKP-2 can have an additional function in the cell mediated by binding to a protein called VRK-1. This finding could have major implications for the understanding of this class of enzyme. However, this hypothesis needs to be examined in a defined project. Thus the student will make novel mutated forms MKP-2 that can selectively interact with VRK-1 and re-introduce them into MKP-2 “null” cells from both mouse and human to determine how this interaction defines the function of MKP-2. The student will also use proteomics to confirm this interaction in cells and to determine if other novel substrates can also interact with MKP-2. The student will learn numerous techniques including; cell culture, immunoprecipitation, kinase assay, FACS, real time imaging, peptide array and proteomics.

 Production of RD114-free veterinary vaccines

Margaret Hosie Margaret.Hosie@glasgow.ac.uk Brian Willett Brian.Willett@glasgow.ac.uk

Infectious feline endogenous retrovirus (RD114) has been isolated from a proportion of live attenuated vaccines for domestic animals, raising concerns regarding the cross-species transmission of an endogenous retrovirus during vaccination. In particular, significant concerns have been raised where feline cells are used for the propagation of viruses for canine vaccines. Moreover, as many companion animal vaccines are used off-label for the vaccination of non-domestic felids and other wildlife species, the presence of an adventitious agent such as RD114 may lead to the spread of a novel pathogen into a naïve host species. Ensuring that vaccines are free from extraneous viruses is of utmost importance to the vaccine industry.  The elimination of endogenous virus contamination of vaccines will impact the health of farm animals as well as wild and domestic animals.  In this project, we aim to eliminate RD114 from feline cell lines used widely in veterinary vaccine production. We will investigate the utility of two approaches, firstly by silencing RD114 gene expression by selective targeting using RD114-specific TALENs and secondly by introducing a genetically-modified feline tetherin cDNA optimised for antiviral activity. 

Ecology and behaviour of mosquito vectors of zoonotic malaria in southeast Asia and their implications for human disease risk

Heather Ferguson Heather.Ferguson@glasgow.ac.uk Rowland Kao Rowland.Kao@glasgow.ac.uk

Historically only 4 parasite species were known to cause malaria in humans. Recent investigations have now confirmed that a fifth species previously thought only to infect monkeys, Plasmodium knowlesi, is causing human epidemics in southeast Asia.

The cause of P. knowlesi upsurge in humans is unknown, but hypothesized to be linked to environmental changes (deforestation) that alter the ecology of the mosquitoes that transmit it. This project will be integrated within a new multidisciplinary consortium investigating the determinants of P. knowlesi emergence in Malaysia and the Philippines. The primary objective will be to conduct field studies investigating the ecology of mosquito vectors of P. knowlesi in Malaysian Borneo, and evaluate habitat-specific human exposure risk. The latter will involve rigorous statistical analysis of field data and the development of models to predict exposure.

The candidate should have a background in ecology, experience with fieldwork, and an aptitude for quantitative analysis. The candidate will have opportunity to work with an experienced team of insect vector ecologists, and work closely with a large interdisciplinary team consisting of researchers from the Boyd Orr Centre of Ecosystem and Population Health at UG, and other leading research institutes in the UK and P. knowlesi endemic countries.

Shedding light on ER oxidative stress

Tony Page Tony.Page@glasgow.ac.uk

The endoplasmic reticulum (ER) is the subcellular organelle where proteins are folded and modified prior to their secretion. A major event in this process is the formation of disulphide bonds, an event that is highly sensitive to the redox environment. Numerous enzymes, oxidases and peroxidases are predicted to be involved in the homeostasis of this redox balance to allow disulphide formation and to prevent oxidative stress. In this project we will combine expertise in a nematode model system, genetics and mammalian cell biochemistry to fully dissect how the redox balance is maintained in the ER of Caenorhabditis elegans. These studies will be used to inform and direct experiments in mammalian cells. The project will involve C. elegans mutagenesis and redox stress selection, as well as live organism imaging using a redox-sensitive variant of GFP (roGFP).

Predicting Behaviour from fMRI BOLD Signals

Martin Lages Martin.Lages@glasgow.ac.uk Lars Muckli Lars.Muckli@glasgow.ac.uk

 Recent advances in fMRI and decoding techniques have initiated discussions on possible implications on real-life domains, such as using brain imaging for lie detection in court and assessing consumer preferences in marketing research. However, before we can draw far-reaching conclusions from brain imaging studies, it is crucial to understand possible limitations in the analyses and pay close attention to specific experimental constraints. For example, we believe that research on the prediction of spontaneous decisions and hidden intentions may have methodological  flaws (Lages & Jaworska, 2012 Frontiers). Similarly, recently published research on predicting consumer choice and reward anticipation from brain activity may have confounding factors and we propose to address these issues through experimentation and improved data analyses. The purpose of this project is to identify contextual processes and sequential dependencies when predicting behavior from brain imaging data. More specifically, we aim to perform improved classification analyses that take into account context information and sequential dependencies

Chromosomal organisation during cellular senescence

Peter Adams Peter.Adams@glasgow.ac.uk Adam West Adam.West@glasgow.ac.uk

Cellular senescence is an irreversible growth arrest triggered by the genetic and epigenetic damage that accumulates with age or arises from oncogene activation. Senescence involves global gene expression changes that coincide with a gross change in nuclear organisation. Heterochromatin is a condensed structural form of chromatin that silences gene transcription. Many senescent cells display a striking redistribution of their heterochromatin to form specialised Senescence-Associated Heterochromatin Foci (SAHF). In this study, we will ask whether the gross changes in nuclear organisation that occur during the onset of cellular senescence correlate with a loss of insulator function. Insulators are DNA regulatory elements that play crucial roles in chromosomal organisation. Insulators employ epigenetic mechanisms and chromosomal looping interactions that can both set the boundaries of heterochromatin and influence the nuclear localisation of chromosomal regions. We have evidence that insulator proteins are inactivated during senescence. The project will use a robust culture system to study the senescence of primary human fibroblasts. Immunofluorescence will be combined with global gene expression analysis and epigenomic analyses using our high throughput sequencing facility. The student will join an environment of epigenetics and cancer researchers and will receive bioinformatics training.