0;*/ $_t4StyleInternal = $internal; if($_t4StyleInPreview){ $_t4StyleBaseServer = 'https://t4.gla.ac.uk'; } else { $_t4StyleBaseServer = '//www.gla.ac.uk'; } if($_SERVER['SERVER_NAME'] == 'udcf.gla.ac.uk') { $_t4StyleBaseServer = 'https://udcf.gla.ac.uk'; } elseif($_SERVER['SERVER_NAME'] == 'www2.gla.ac.uk') { $_t4StyleBaseServer = 'https://www2.gla.ac.uk'; } /*elseif(($_SERVER['SERVER_NAME'] == 'www.gla.ac.uk')&&($_SERVER['REQUEST_SCHEME'] == 'https')) { $_t4StyleBaseServer = 'https://www.gla.ac.uk'; }*/ ?> edit in t4', $internal); ?>

BBSRC Doctoral Training Partnerships

BBSRC Doctoral Training Partnerships

BBSRC Doctoral Training Partnerships
West Bio
University of Strathclyde

Overview & How to Apply

Become a future leader in academia and industry

This programme is not accepting applications at present

Stipend: £13,726 per annum (2013/14 rate)
Start date: 1 October 2014

The BBSRC has awarded funding to 14 Doctoral Training Partnerships across the UK to provide PhD training in areas of strategic relevance to the BBSRC. WestBio is a partnership between the University of Glasgow and the University of Strathclyde and has funding for 30-60 studentships over the next three years. This includes up to 30 studentships contributed by the institutions in the partnership. WestBio will provide students with excellent cross-disciplinary research training in line with the current BBSRC strategy. These fully-funded studentships commence in October 2014 and are available in a range of academic disciplines across the biosciences.                                

The DTP projects are designed to provide outstanding interdisciplinary training in a range of topics in food security, biofuels, ageing, animal health, crop science and ‘world-class bioscience’. We offer specialised training in bioimaging, ‘omics, synthetic biology, systems biology, bioinformatics, in vivo mammalian biology and plant physiology/pathology. The DTP studentships are designed to raise the aspirations of students by equipping them with the generic and employability skills needed to become future leaders in academia and industry.

WestBio will follow a 4-year PhD model. In their first six months, students will undertake two lab rotations, each designed to provide key skills and lab experience before finally choosing their PhD project. They will participate in the robust College skills training programme throughout their studies. Students will also spend three months undertaking a Professional Internship for PhD students (PIPS) in an area unrelated to their PhD project. Please follow URL for further information regarding the programme structure: BBSRC WestBio DTP

PLEASE NOTE THAT APPLICANTS ARE APPLYING TO THE PROGRAMME AND NOT FOR SPECIFIC PROJECTS AT THIS STAGE – THE PROJECTS LISTED ON THE SEPARATE TABS ARE EXAMPLE PROJECTS.

Eligibility

Qualifications criteria
Applicants applying for a BBSRC WestBio studentship must have obtained, or be about to obtain, a first or upper second class UK honours degree or the equivalent qualifications gained outside the UK, in an appropriate area of science or technology.

Residence criteria
The BBSRC DTP grant provides funding for tuition fees and stipend for UK and *EU nationals that meet all the required eligibility criteria.

*Note that EU nationals must be able to demonstrate that they have resided in the UK for three years prior to commencing the studentship. If not, EU nationals are still able to apply to the programme, but would be eligible to receive a ‘fees only’ award.

Full qualifications and residence eligibility details are available here: BBSRC Guide to Studentship Eligibility.


How to apply

You can apply here. Within the application, at the programme of study search field option, please select ‘MVLS – BBSRC (Biotechnology and Biological Sciences Research Council) DTP Studentship’.

Please note that, in step 6 within the online application process, you are asked to detail supervisor/project title information. This information is not available, because you are applying to the programme and not for specific projects at this stage. Within the research area text box area, please highlight your area of interest from the following (listed on tabs below this section):

  1. BBSRC DTP: Basic Biosciences Underpinning Health
  2. BBSRC DTP: Bioenergy and Industrial Biotechnology
  3. BBSRC DTP: Food Security
  4. BBSRC DTP: World Class Underpinning Bioscience


Please ensure that all supporting documents are uploaded at point of application:

  • Academic ability evidence
  • CV/Resume
  • Degree certificate (if you have graduated prior to 1 July 2014)
  • Language test (if relevant)
  • Passport
  • Personal statement
    (This should provide any other required information in support of the application, such as evidence of previous academic or professional experience that qualifies you for the programme (projects; placements; voluntary work etc). You should state the reasons why you selected this programme and what benefit you hope to achieve through successful completion of the programme. The statement should include information about lab techniques you have used and research projects in which you have been involved. The statement should not be longer than one A4 page).
  • Reference 1 (should be from an academic who has a knowledge of your academic ability from your most recent study/programme)
  • Reference 2 (should be from an academic who has a knowledge of your academic ability)
  • Transcript

General enquiries regarding the programme and application procedure should be directed to Alexis Merry: [Alexis.Merry@glasgow.ac.uk].

The tabs below will provide further information about example projects. Applicants are applying to the Programme and not for specific projects at this stage.


Basic Biosciences Underpinning Health

A new and developing area where the training programme focuses on the neuropsychology of ageing. The aims are to obtain a deeper understanding of the cognitive, structural and physiological correlates of healthy ageing, and underpinning tool development to allow development of novel cell engineered therapies for normal ageing. In addition, researchers study the influence of environmental conditions during growth and development on ageing in birds.

 

Identification and characterization of Wnt-dependent mechanisms regulating intestinal stem cell behaviour during ageing

Dr Julia B. Cordero, Institute of Cancer Sciences
Prof Peter Adams, Institute of Cancer Sciences

The ability to regenerate following stress is a hallmark of self-renewing tissues and it is achieved by the presence of dedicated stem cells. One characteristic of the ageing process is the decline in tissue homeostasis. A clear understanding of age-dependent cellular and molecular changes will contribute to the alleviation of tissue dysfunction and malignancies within the ageing population.

The intestinal epithelium is replenished by intestinal stem cells (ISCs) and represents a paradigm for the study of age-associated changes in stem cell function and tissue homeostasis. Our laboratory uses the adult Drosophila midgut as a model system to study the molecular and cellular mechanisms involved in the regulation of stem cell proliferation within a self-renewing epithelium. Our previous work has demonstrated that production of the ligand for the conserved signalling pathway Wnt/Wingless (Wg) within stem/progenitor cells is a key driver of age-induced intestinal hyperplasia. The mechanisms regulating Wg production and its role in the ageing intestine remain unknown. Using Drosophila as a model system this project aims to:

  1. Identify the mechanisms required for the induction of Wnt/Wg signalling in the ageing Drosophila intestine. Identify and functionally characterize age-dependent Wnt target genes in the intestine.


Development of nanoscale mechanotaxis arrays for stem cell engineering

Dr Nikolaj Gadegaard, School of Engineering
Prof Manuel Salmeron-Sanchez, School of Engineering

The fate of stem cells in vitro can be influence in several ways. For example the use of chemically defined media is today a gold standard for confirming the regenerative potential of a stem cell population. Alternatively, we have shown that by carefully controlling the topography at the nanoscale it is also possible to influence the fate of the stem cells. For example a controlled disordered nanopit pattern will induce osteogenic differentiation, whereas highly ordered nanotopographies can retain the multipotent properties of the stem cells. Moreover, the mechanical properties of the substrate on which the stem cells are cultured will also influence their fate. Engler et al. showed that a soft substrate promotes neurogenic differentiation whereas a harder substrate induces osteogenic differentiation. In this project, the main aim is to develop a nanofabrication platform that will combine the identified nanotopographies described above together a soft substrate. This will provide us with a new tool to explore synergistic effects on stem cell differentiation. One possibility of accurately controlling the mechanical properties in a high -throughput manner is the use on injection moulding to make substrate with high-aspect ratio structures. That approach enables use to make surfaces which to cells appear as soft as an elastomer but are made from hard engineering materials such as polystyrene or polycarbonate. It is intended that the developed sample format will be in an array style which will provide us with a high-content analysis platform.

The role of TRIB2 in Haematopoietic Stem Cell (HSC) function and ageing

Dr Karen Keeshan, Institute of Cancer Sciences
Dr Lisa Hopcroft, School of Computing Science

The ageing of tissue-specific stem cells is believed to be central to the pathophysiological conditions arising in aged individuals. Ageing degrades HSC functions, including HSC engraftment and maintenance, and importantly stress responses which accumulate as ageing takes place. The TRIB2 pseudokinase gene has recently emerged as having important roles in proliferation, survival, motility, and metabolism. Originally identified in drosophila (dTrib), it was shown to function in development, cell division and viability, and in mammals has been shown to function in th e dysregulation of haematopoietic cell development. Our hypothesis is that TRIB2 has a significant functional role in the HSC and the response of the HSC to the ageing process. This project will involve an in-depth transcriptomic analysis and  transplantation  approach  of  assessing  TRIB2  in  the  HSC,  with  respect  to  engraftment,  maintenance, development and proliferative stress modelling the physiological ageing process. This will be assessed in the context of TRIB deficiency to understand the physiological role TRIB2 has in HSC biology. This interdisciplinary approach will lend an insight into the molecular mechanisms of human and murine HSC biology in ageing/stress.
 

Labelled lines for transmitting pain and itch in the spinal cord

Prof Andrew Todd, Institute of Neuroscience and Psychology
Prof John Riddell, Institute of Neuroscience and Psychology

Somatosensory inputs activate projection neurons in the spinal dorsal horn that convey this information to the brain for conscious perception. Activity in nociceptors or prutitoceptors (itch receptors) is transmitted mainly by projection cells located in lamina I of the dorsal horn. There has been a long-standing controversy over whether these projection cells represent "labelled lines" that are specific for different types of stimulus, or whether multiple stimuli converge onto the same cells. In the latter case, the pattern of activity reaching the brain must be used to interpret the nature of the stimulus.  This project will use a recently developed mouse line, in which neuronal activation is converted into permanent expression of a fluorescent protein (e.g. tdTomato) to detect cells that have been activated by a particular stimulus (in this case, noxious or pruritic). After a suitable time interval a second (different) stimulus will be applied, and a tracer (cholera toxin B subunit) will be injected into the brain to label projection neurons. Subsequent immunocytochemistry and confocal microscopy will be used to assess whether projection neurons in lamina I respond to different types of noxious and pruritic stimulus, or whether there are labelled lines. The project will provide important information about the organisation of pathways within the spinal cord that are responsible for pain and itch.

Anatomical reservoir of parasites within the mammalian host

Dr Annette MacLeod, Institute of Biodiversity Animal Health and Comparative Medicine
Prof Paul Garside, Institute of Infection, Immunity and Inflammation
Prof James Brewer, Institute of Infection, Immunity and Inflammation
Dr Paul Capewell, Institute of Biodiversity Animal Health and Comparative Medicine

Somewhat surprisingly the importance of the skin in the transmission of parasites that have biting arthropods as intermediate hosts has been long overlooked. This is because the parasites have primarily been seen as blood dwellers. Indeed microscopic detection of trypanosomes in human blood is still the method of diagnosis for African sleeping sickness. Despite parasitaemia in many diseases being low or undetectable successful transmission still occurs via the small blood meal of vectors, suggesting that parasites may be present in the skin. In malaria infections it has recently become apparent that the skin may represent an important anatomical reservoir of infection that has previously been unappreciated. We have also recently shown that a significant population of parasites exists in the skin during Trypanosoma brucei infections. Thus the role of the skin, its immune components and how different protozoan parasites interact with this compartment may have important implications for disease control strategies. This studentship will investigate the common and distinct host immunological and parasite factors that interact to affect disease and transmission. The studentship offers training across a wide range of in vivo, immunological, bioinformatics and parasitological techniques that will uniquely equip the student for a successful future in biomedical research at the important and difficult to fill host-parasite interface.

Determining the mechanism of action of a novel lectin-like pyocin

Dr Daniel Walker, Institute of Infection, Immunity and Inflammation
Dr Andrew Roe, Institute of Infection, Immunity and Inflammation

The increasing prevalence of antibiotic resistant Gram-negative bacteria poses a catastrophic threat to the population and in order to avoid what is rapidly emerging as a health crisis, new classes of antibiotics are urgently required. In recent years few novel antibiotics have emerged on the market and it is generally accepted that there are few good candidate drugs in the developmental pipeline. The lack of novel classes of antibiotics in development is in part due to the relative failure of post-genomic target driven antibiotic discovery, which has yielded few novel antibiotic targets and consequently few candidate small molecule drugs for further development. An alternative and likely more successful route to identifying novel cellular targets or new ways of targeting known cellular targets is to determine the mechanisms through which potent novel classes of antibiotics of unknown function kill cells. One such class of antibiotics, are the lectin-like bacteriocins produced by strains of Pseudomonas, Burkholderia and Xanthomonas spp. The overall goal of this work is to identify the molecular target through which the lectin-like bacteriocins exert their cytotoxic activity and to define their interaction with the target. This will be achieved by using a combination of genomics, transcriptomics, biophysics and structural biology.
 

Using synthetic biology for the development of novel and safe vaccines for arbovirus infections

Dr Esther Schnettler, Institute of Infection, Immunity and Inflammation
Prof Massimo Palmarini, Institute of Infection, Immunity and Inflammation

Viruses transmitted by insects (arboviruses) are the cause of severe diseases of humans and animals. Historically, arboviruses were confined to tropical and sub-tropical geographical areas. However, increase in travelling, globalization and climate change have resulted in the emergence of several arbovirus infections in Europe and the UK. In this project, we aim to use a novel approach for the development of safe live attenuated vaccines for Bluetongue virus (BTV) and Schmallenberg virus (SBV), which are both transmitted by Culicoides midges. Live attenuated vaccines are cheap to produce and induce long lasting immunity. However, there is the possibility that vaccine strains could be maintained in the environment by the insect hosts and transmitted to unvaccinated animals leading eventually to reversion of virulence. Designing a virus that maintains its ability to replicate in the mammalian host but is unable to replicate in the midge vector would be the most cost effective and practical solution to control arboviral infections. This project aims to develop BTV and SBV vaccines that cannot replicate in the midge vectors, thus preventing environmental transmission, by the incorporation of target sequences, specifically recognized by midge specific miRNA molecules, in the vaccine strains. MicroRNAs are small RNA molecules expressed in a variety of organisms that regulate gene expression by inducing degradation (or translation inhibition) of complementary RNA molecules.

Genome-wide individual-specific and condition-specific effects in the analysis of omic data

Dr John McClure, Institute of Cardiovascular and Medical Sciences
Prof Darren Monckton, Institute of Molecular, Cell and Systems Biology
Dr Simon Rogers, Computing Science

The omics technologies such as transcriptomics, proteomics and metabolomics are providing vast amounts of data with which to investigate the molecular basis of variation and disease. Most commonly, studies using these technologies are designed on comparing two groups and much of the individuality of the process is masked, and the identification of condition-specific processes is confounded by underlying individual-specific differences in aspects of fundamental molecular physiology. In this project the student will develop novel analytical methods to account for individual-specific differences in cellular physiology in the analysis of transcriptomic and other high throughput data and to investigate the significance of their addition to the analysis of a wide range of datasets and disorders. In addition, the student will also investigate whether there are individual-specific condition-specific effects further modifying molecular phenotypes. The student will develop these methods using Generalized Linear Models and Bayesian methods and apply them to additional in-house and publicly available data sets. The training provided in this studentship will equip the student with an excellent platform from which to exploit the growing use of high throughput data in 21st century biology and medicine.

Mitochondrial regulation of energetic homeostasis through energetic switching

Dr John Mercer, Institute of Cardiovascular and Medical Sciences
Prof Kostas Tokatlidis, Institute of Molecular, Cell and Systems Biology

Basic metabolism is a requirement for all cells to maintain energetic homeostasis. Recent evidence suggests this process is not just a sequential series of enzymatic steps but a fluid and dynamic process that rapidly adapts to the cellular milieu. Indeed a multitude of cellular events beyond ATP generation are dependent on the orchestration of these processes including cell division and death, the ageing process, substrate synthesis, DNA replication and repair as well as organelle biogenesis and degradation.

Because of the spectrum of processes implicated, understanding the mechanism by which the cell augments these events have crucial implications for understanding fundamental biological processes, with implications for a number of human conditions; including cardiovascular disease, cancer and neurodegenerative disorders. Indeed the capacity of the cell to switch between oxidative phosphorylation and glycolysis is of fundamental importance to a number of these pathologies.

The successful candidate will use a variety of state of the art techniques to interrogate this biochemical switching mechanism. Novel modalities including polargraphic oxygen respiration, mitochondrial confocal microscopy, immunocytochemistry and fluorescent time-lapse microscopy. International training opportunities in Austria; http://www.oroboros.at/index.php?id=o2k-workshops_schroecken are also available. The successful candidate will be expected to publish and present their research at national and international meetings.

Establishment of a novel redox pathway in the apicoplast periphery as drug target for Malaria
 
Dr Lilach Sheiner, Institute of Infection, Immunity and Inflammation
Prof Neil Bulleid, Institute of Molecular, Cell and Systems Biology

The ancestor of the causative agents of malaria (Plasmodium spp.) and toxoplasmosis (Toxoplasma) was an alga. Consequently both parasites possess a chloroplast-like organelle called the apicoplast, an essential organelle with no equivalent in mammals, and a validated source of drug targets. This fascinating organelle originated from secondary endosymbiosis – a eukaryote engulfing a whole algal cell – and as a result is bound by four membranes, creating four sub-compartments. While the metabolic roles of the apicoplast lumen (inner-most compartment) are being rapidly unravelled, little is understood about the biology of its peripheral compartments. The emerging resistance to drugs targeting luminal pathways, as well as the unusual biological features of the peripheral environment drive our interest to study peripheral functions.
We recently discovered a novel peripheral-protein-import quality-control pathway in Toxoplasma and Plasmodium.

We identified the main component, ATrx2, an essential thioredoxin unique to parasites and divergent from thioredoxins found in the mammalian host. We developed in-vivo and in-vitro assays to analyze ATrx2 function and sensitivity to inhibitors.

This project will use these systems, first to dissect ATrx2 function via the identification and confirmation of its substrates, and second to develop a high throughput inhibitor screen to identify new leads for anti-malarials.


Dissection of the mitochondrial tRNA import translocon in Toxoplasma gondii

Prof Markus Meissner, Institute of Infection, Immunity and Inflammation
Dr Lilach Sheiner, Institute of Infection, Immunity and Inflammation
Prof Kostas Tokatlidis, Institute of Molecular, Cell and Systems Biology

We aim to dissect the divergent Toxoplasma mitochondrial tRNA import (MITI) translocon with a view to understanding its unique features and to identify novel drug targets for diseases like toxoplasmosis and malaria. Apicomplexan mitochondria are essential and a confirmed source for the anti malarial Atovaquone, nevertheless their biogenesis is entirely elusive. Our lab is among the first to recognize the unexpected level of divergence of the apicomplexan mitochondrion compared with mammalian mitochondria and we pioneers this field of research as part of the global search for new drug targets.

Our recent data suggests that the Apicomplexa MITI machinery has significant differences to the mammalian host:

  1. the mitochondrial genome encode no tRNAs
  2. amino acyl tRNA synthetases are absent from the T. gondii and Plasmodium mitochondria. We hypothesize that these extreme irregularities require a novel, specialized MITI translocon and our preliminary data support it.

This project will combine the following: mitochondrial isolation and proteomics to identify tRNA binding proteins; genetic manipulation and immunfluorescent microscopy (deconvolution and super resolution) to confirm hits localization; reverse genetics to characterize hits role within the MITI pathway.

This will solve the translocon composition resulting in high-impact publications and exposure of new routes to develop intervention.

Animal morbilliviruses: emerging viral pathogens in a measles-free world

Prof Margaret Hosie, Institute of Infection, Immunity & Inflammation
Prof Brian Willett, Institute of Infection, Immunity & Inflammation

In May 2011, the world was declared free from rinderpest virus (RPV), a morbillivirus which infects cattle and is closely related to measles virus (MV). Like RPV, MV is now being considered for global eradication by vaccination. However, there is increasing concern that, should vaccination against MV cease, the human population would no longer have cross-protection against zoonotic infections with related animal morbilliviruses. Concerns have been raised about the threat posed by morbilliviruses such as canine distemper virus (CDV). CDV infects diverse species including  dogs,  ferrets,  martens,  lions,  hyenas  and  seals,  potentially  threatening  many  endangered  species. Moreover, pathogenic CDV infections have been described in primates, raising the possibility of zoonotic transmissions to humans. What are the viral reservoirs of CDV? Can vaccination against MV guard against cross- species transmission of CDV? We will develop novel viral pseudotype-based assays to measure serological responses to diverse animal morbilliviruses; these will be rapid tests, highly sensitive and specific. We will test a simple methodology to measure neutralizing antibody responses against primary field strains of virus, novel emerging morbilliviruses and unique biotypes for which assays are currently unavailable.  Accordingly, we will identify the natural reservoirs of infection with morbilliviruses such as CDV by screening serum samples collected from diverse species for morbillivirus-specific antibodies. These studies will inform future strategies to prevent and control emerging threats to humans and animals alike.

 

Trancriptome and metabolome strategies to dissect cellular hypertrophy

Dr Martin McBride, Institute of Cardiovascular and Medical Sciences
Dr Stuart Nicklin, Institute of Cardiovascular and Medical Sciences
Dr John McClure, Institute of Cardiovascular and Medical Sciences

There are two main types of cardiac hypertrophy with diverse outcomes; physiological remodelling occurring in healthy individuals in response to exercise or pregnancy and pathological remodelling resulting in myocyte growth, reactivation of foetal programming and induction of fibrosis. Despite recent considerable advances in molecular analysis of the genetic contribution to left ventricular hypertrophy (LVH) using large genome-wide association studies (GWAS) there has been little progress made towards identification of the genes involved. Experimental models of cardiac hypertrophy can be used to facilitate the identification of causative genes identifying osteopontin as a gene that increases susceptibility to cardiac hypertrophy. We now wish to characterise the consequences of osteopontin over-expression in H9c2 cells and in our experimental models at the molecular level. As a single method of data generation and analysis will be unlikely to identify all key regulatory pathophysiological pathways, we will generate large-scale multilevel transcriptome (Total RNAseq - miRNA, mRNA and lncRNA) and metabolome datasets from H9c2 cells over expressing osteopontin and neonatal primary cardiomyocytes from our SHRSPGla, WKYGla, and WKY.SPGla14a strains. A key component of these comprehensive studies will be to integrate distinct data modalities and bioinformatic and systems analysis training will play a significant part in this project. 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.


Microvesicles: A novel therapeutic intervention for ageing

Prof Paul Shiels, Institute of Cancer Sciences
Prof Colin Selman, Institute of Biodiversity, Animal Health and Comparative Medicine

Currently our life-expectancy is increasing at a rate of nearly 4 years every decade. However, critically our health is not keeping pace with our longer life, resulting in more and more of us experiencing debilitating age -related disease. Consequently there is real need to identify interventions that can act to improve late-life health and vitality. We have shown that extracellular secretory vesicles (ESVs) derived from Pathfinder cells (a novel repair initiator cell type) effect the paracrine mediated regeneration of damaged tissue in various rodent models of disease, including streptozotocin-induced diabetes and renal ischaemic damage. Pilot studies have dissected out this effect as the property of a single class of non-exosomal microvesicles which modulate the action of tissue-specific stem and progenitor cells. In this PhD you will test the prediction that microvesicle treatment can act to retard the ageing process. Using a highly integrative approach you which will determine whether early or late -life treatment with microvesicles  in  mice  can  impact  on  a  range  of  functional  health  outputs  known  to  decline  dramatically  with advancing  age.  In  addition,  you  will  employ  a  range  of  molecular  biology  techniques  to  further  identify  the mechanisms through which microvesicles act to bring about these predicted improvements in health span.
 

Transcriptional control of inflammation

Dr Ruaidhri Carmody, Institute of Infection, Immunity & Inflammation
Dr Christine Wells, Institute of Infection, Immunity & Inflammation
Dr Carl Goodyear, Institute of Infection, Immunity & Inflammation

The transcription factor NF-κB is the master regulator of the immune response and is essential for the development and homeostasis of the immune system. NF-κB is a crucial component of responses downstream of key immunoreceptors such as Toll-like receptors, antigen receptors and members of the TNF receptor superfamily. NF-κB is a critical factor in human inflammatory disease: functional polymorphisms in NFKB1, which encodes the p50 subunit, are significant risk factors for the development of ulcerative colitis, acute respiratory distress syndrome, systemic lupus erythematosus, COPD, autoimmune syndromes, as well as a number of cancers. Whilst the importance of NF-κB in human health and disease is indisputable, we lack fundamental information on the biochemistry of NF-κB activity. The project will use a systems-scale analysis of NF-κB p50 phosphorylation to address this major knowledge gap, and to build a map of how the p50 subunit is targeted by upstream pathways to control NF-κB activity. The project will involve CRISPR genome editing techniques, transcriptomic analysis, and molecular and cellular biology techniques. The aims of this project are highly relevant to human inflammatory disease and will be used to identify novel therapeutic targets.

SUMOylation and the Control of the Inflammatory Transcriptome by EPAC1 in Vascular Endothelial Cells

Prof George Baillie, Institute of Cardiovascular and Medical Sciences
Dr Stephen Yarwood, Institute of Cardiovascular and Medical Sciences

This work aims to identify novel anti-inflammatory signalling mechanisms that are pertinent to the control of cytokine responses in vascular endothelial cells (VECs) and will form the basis for future drug development to combat damaging inflammation associated with deadly cardiovascular diseases (CVDs), such as atherosclerosis. This is important because CVDs remain a major cause of morbidity and mortality globally, despite significant academic and industrial focus. Clearly future therapies designed to “switch off” the enhanced cytokine signalling associated with endothelial inflammation will play a critical role in combating CVDs. In this respect, the ubiquitous second messenger, cyclic AMP, which is synthesised in VECs in response to G-protein coupled receptor (GPCR) activation, plays a key role in limiting pro-inflammatory cytokine action and reducing the inflammatory response associated with CVDs. Indeed, research from our laboratories has defined a central role for the cyclic AMP-regulated drug target, exchange protein activated by cyclic AMP (EPAC) 1, as a central controller of the anti-inflammatory processes in VECs. EPAC1 therefore represent an attractive new therapeutic target for the development of small molecule inhibitors of vascular inflammation underlying the development of serious CVDs.

AIM 1 Identification of the EPAC1-regulated Transcriptome - We will determine the mechanisms by which EPAC1 regulates anti-inflammatory gene activity and extend this to identify the full range of genes regulated by these protective pathways in VECs.

AIM 2 Nuclear Recruitment of EPAC1 and Transcriptional Control – Key to the regulation of anti-inflammatory gene expression is the recruitment of EPAC1 to the nuclear pore complex. We will determine the mechanisms controlling this engagement and the role that EPAC1 modification with SUMO proteins, which normally effect protein interactions, plays in this process.

 

The role of histone chaperones in healthy aging

Prof Peter Adams, Institute of Cancer Sciences
Prof Paul Shiels, Institute of Cancer Sciences

Healthy aging depends upon long-term maintenance of cellular gene expression programs and hence cell phenotype. Chromatin structure is critical for determination of cellular gene expression programs and, hence, cell phenotype. However, several lines of evidence indicate that chromatin structure and regulation is inherently dynamic. Given the dynamic nature of chromatin, maintenance of cell phenotype and healthy aging likely represents a challenge for the cell. In particular, long-lived post-mitotic, non-dividing cells must have DNA replication independent mechanisms to facilitate chromatin homeostasis. One good candidate for a role in such chromatin maintenance is the HIRA histone chaperone, which deposits the histone variant H3.3 into chromatin in a DNA replication independent manner in a so-called “gap filling” mechanism. Based on preliminary data, we hypothesize that HIRA promotes healthy aging of the pancreas by maintaining the normal epigenome of transcriptionally active pancreatic acinar cells and so long term maintenance of cell phenotype and viability and so healthy aging. This studentship will investigate the role of HIRA in chromatin homeostasis and healthy aging of the pancreas, in a novel HIRA conditional knock out mouse.

 


Bioenergy and Industrial Biotechnology

Our vision, based on strengths in photosynthesis, synthetic biology and process engineering, is to provide interdisciplinary training in artificial photosynthesis, aiming at making ‘solar fuels’, and microbial fuel cells.  Projects will be offered that examine biochemical structural biology, photosynthesis, biophysics, synthetic chemistry and electrochemical biology, microbial fuel cells, plant molecular biology and ion transport plant molecular biology and nanoengineering.

 

Developing a synthetic approach to manipulating stomatal guard cell membrane transport for enhanced water use and photosynthetic carbon capture
 
Prof Mike Blatt, Institute of Molecular, Cell and Systems Biology
Dr Simon Rogers, School of Computing Science

Synthetic methods offer a novel approach to physiologically enhancing stomatal function. Best estimates suggest very substantial gains in the efficiency of water use vs. photosynthetic carbon capture, and hence in biomass yield, would be achievable if stomata were better able to track light energy input. Synthetic methods present a novel approach to this problem of enhanced stomatal function. At the same time, they offer access to one of the most puzzling and fundamental  problems in cell biology, namely how  serial membranes of tonoplast and plasma membrane are able to coordinate transport during cell expansion. Targeted expression of light-driven ion pumps and channels – bacteriorhodopsins, halorhodopsins and channelrhodopsins – will be adapted to probe this coordination, at the same time exploring the potential for synthetic manipulation of transport to accelerate stomatal kinetics. The work will draw on quantitative dynamic modelling to guide experimental studies as an in silico testbed in validating competing hypotheses in transport coordination. The combination of modelling and experimental validation will be used to establish the properties emergent in the stomatal cell system and its capacity for synthetic enhancement.

Recombinase-based Synthetic Biology tools for bio-desalination

Dr Sean Colloms, Institute of Molecular, Cell and Systems Biology
Prof Anna Amtmann, Institute of Molecular, Cell and Systems Biology

Salt and brackish water is abundant in many areas where fresh water is a limited resource. While, conventional desalination processes are highly energy intensive, bio-desalination has the potential to produce drinking water and water for agriculture from abundant salt water with vastly reduced energy inputs. Photosynthetic bacteria grow to high density in salt water, and could be engineered to take up large concentrations of salt. Removal of salt enriched cells will produce water with reduced salt content. This requires the development of effective separation techniques to remove salt-filled bacterial cells from the water. Gas vesicles, flotation organelles produced by many species of bacteria, are an ideal candidate for this separation process. Salt filled cells will be engineered to produce gas vesicles, causing them to float to the surface where they could easily be removed. This will require new methods for regulation of gene expression in photosynthetic bacteria, and for genetic manipulation of these organisms. This project aims to re-engineer the gas vesicle production pathway, and to produce a recombinase-based genetic switch to regulate expression of salt uptake and flotation for bio-desalination and other industrial biotechnology processes. The project will also produce a set of site-specific recombination based SynBio tools for the genetic manipulation of photosynthetic bacteria.


Food Security (Crop Science and Animal Health)

Crop Science
The major research themes that we offer studentships in are: increasing crop production and efficiency in the face of the changing global environment; minimizing negative impacts on the environment and developing pre-competitive research for translation.

Animal Health
Our particular strengths in animal health are in endemic and exotic diseases, and zoonotic pathogens; and their epidemiology and evolutionary ecology is studied through integrated programs of field studies, advanced statistical analysis and mathematical modelling. The close and unusual alignment of research on biodiversity and animal health within the University of Glasgow also presents unique training opportunities in developing country food security and conservation. Our broad base of expertise in this area is strengthened by our collaborations with the Moredun Research Institute and the Pirbright Institute (formerly Institute of Animal Health).

Composition and function of histone-deacetylase complexes in plants
 
Prof Anna Amtmann, Institute of Molecular, Cell and Systems Biology
Prof Michael Blatt, Institute of Molecular, Cell and Systems Biology

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.

Manipulation of cell fate by minor groove DNA binders (MGBs) in Theileria infected and uninfected leukocytes

Prof Brian Shiels, Institute of Biodiversity Animal Health and Comparative Medicine
Dr Glenn Burley, Department of Pure and Applied Chemistry, University of Strathclyde
Prof Colin Suckling, Department of Pure and Applied Chemistry, University of Strathclyde

Compounds that bind to the minor groove of DNA (MGBs) are potential anti-parasitic, anti-cancer and anti- inflammatory drugs. This project aims to test the efficacy of MGBs against cells infected with the parasite Theileria (related to the malaria parasite) that has recently been shown to manipulate the expression of cellular genes that function in generation of cancer and the inflammatory response. Treatment with an MGB has generated profound effects on the phenotype of Theileria-infected white blood cells. The initial phase of the project will screen an available library for further MGBs with efficacy against proliferating infected and uninfected cells. A major aim of the project will be to define the binding sites of a selected MGB at the genome level using a bind and sequence approach. The systems biology approach will enable all genes that are potentially targeted by the drug to be identified combined with bioinformatic prediction of the molecular function of genes whose expression will be disrupted by the MGB compound. This will allow design of more specific inhibitors for selected disruption of gene function linked to parasite viability, cancer and the inflammatory response. The project provides training in systems biology, bioinformatics, drug design and molecular biology methodology.

Molecular genetics and physiology of renal function in insects

Prof Julian A T Dow, Institute of Molecular, Cell and Systems Biology
Prof Shireen A Davies, Institute of Molecular, Cell and Systems Biology

Insects destroy 20% of the world’s crops, and kill over a million people a year. With its sequenced genome, powerful genetic tools, mutant resources and large, active research community, Drosophila is an ideal model organism for insect studies. However, the small size of the fruit-fly means that our understanding of this important organism has been based around developmental biology much more than function. With recent advances in post-genomic technology, it is now possible to dissect function down to the level of individual cells and tissues, and study the interplay between the different parts of an organism at an unprecedented level. 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. Specifically, we will use transgenics to label specific cell types with tagged mRNA-binding proteins, allowing mRNAs to be purified from specific cells within the fly kidney. These will be subjected to microarray or RNA-seq analysis, providing the first gene-expression ‘directory’ of a single cell type in this mission-critical organ. The insights we obtain will be tested experimentally by RNAi, and selected candidate genes will be subjected to screening to try to identify novel insecticidal agents.

Novel screening tools for insecticide discovery

Prof Shireen A Davies, Institute of Molecular, Cell and Systems Biology
Prof Julian A T Dow, Institute of Molecular, Cell and Systems Biology
Mrs Carol Clements, Strathclyde Institute of Pharmacy and Biomedical Sciences

Numerically, insects are the dominant life-forms on earth, with more species than other animals, plants and microbes put  together.  Harmful insects incur enormous health and economic costs; crop damage or insect-borne plant diseases, and animal diseases, cause GDP loss of ~20% worldwide. Thus, insect control is critically important given the rapidly increasing pressures on food production. However, there is insect resistance to all known insecticides and new legislation against pesticide use. In order to overcome such problems, targeted strategies including identification of potential new targets in key tissues, screening new targets against insecticidal compounds, and mode of action studies,  can  together provide new avenues for insecticide development.  We have generated a novel in vivo biosensor, which shows differentiated responses to several insecticides and xenobiotics. We plan to exploit this biosensor to screen for insecticidal activity from novel plant compounds; and for xenobiotic/insecticide mode of action studies.

Small RNAs as potential control targets for parasitic nematodes of livestock

Dr Collette Britton, Institute of Biodiversity Animal Health and Comparative Medicine
Prof Eileen Devaney, Institute of Biodiversity Animal Health and Comparative Medicine

Parasitic nematodes cause significant economic and welfare problems in livestock and are a major threat to food production in the UK and globally. With nematode resistance to available anthelminitc drugs increasing, alternative control approaches are  urgently needed.  This project will investigate the roles of microRNAs (miRNAs) in development and survival of the ovine gastrointestinal nematode Haemonchus contortus. miRNAs play key roles in development of the related model nematode Caenorhabditis elegans by negatively regulating gene expression. miRNAs bind to specific sites, usually in the 3’UTR, leading to translational repression and mRNA degradation. We have identified 192 miRNAs from H. contortus and shown by microarray and quantitative real-time PCR (qRT-PCR) that the expression of some of these miRNAs changes significantly from the infective L3 to L4 stage, while others are highly upregulated in adult parasites. Possible functions of miRNAs in regulating larval arrest and activation will be investigated using bioinformatic prediction programs and qRT-PCR to identify potential target mRNAs. Effects of miRNA inhibitors and mimics on larval development will be examined in vitro and in vivo. Interestingly, a number of H. contortus miRNAs are, so far, unique to this species and are significantly enriched in adult parasites. We speculate that these may be involved in aiding parasite survival within the host and the potential for these miRNAs to regulate host immune responses will also be investigated.

The interactome of Rift Valley fever virus nucleocapsid- towards the identification of new intervention strategies

Dr Alain Kohl, MRC-University of Glasgow Centre for Virus Research
Prof Richard Elliott, MRC-University of Glasgow Centre for Virus Research

Rift Valley fever virus (RVFV) is an important animal pathogen which can also affect humans. The virus belongs to the Bunyaviridae (genus Phlebovirus), and its genome consists of three segments of negative stranded RNA called L (encoding the viral polymerase), M (encoding the glycoproteins) and S (encoding the nucleoprotein N and NSs). The N and L proteins transcribe and replicate the viral genome. There is presently no human vaccine and few veterinary vaccines. No specific therapies or drug treatments exist. RVFV is transmitted by a number of mosquitoes, and there is concern that RVFV may spread beyond currently affected areas and cause outbreaks that severely affect animal and human health elsewhere. Given the central role of the N protein in replication, it makes this protein an attractive target to understand replication and how these processes can be disrupted. In order to investigate replication in host cells derived from mosquito and vertebrate, we will aim to identify host proteins that interact with N, compare interactors in both hosts, and analyse the roles that these interactions play and how they can be disrupted. This will lead to further insights into RVFV biology and potentially also intervention strategies before or after transmission.

UV-B perception and gene regulation in oilseed rape

Prof Gareth I Jenkins, Institute of Molecular, Cell and Systems Biology
Prof John Christie, Institute of Molecular, Cell and Systems Biology

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 signalling in B. napus, in particular the relationship between UVR8 photoreception, interaction with key regulatory proteins, and the regulation of transcription, which is key to 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 signalling in B. napus, study their regulation and investigate how they interact with UVR8 to control transcriptional responses to UV-B.


Treating Nematode Infections with ICE: Inhibition of Cuticle Exsheathment

Prof Antony Page, Institute of Biodiversity Animal Health and Comparative Medicine
Dr David France, School of Chemistry
 
The trichostrongylid gastrointestinal (GI) nematodes of grazing livestock have a worldwide prevalence and cause morbidity and death with a consequential serious economic impact to farming. Teladorsagia circumcincta is the most important and widespread GI nematode of sheep in temperate areas, whereas on a global scale Haemonchus contortus is the most significant. In cattle the related species Ostertagi has a direct impact on meat production and milk yields. As a consequence of single and multiple drug resistance, there is an urgent need to develop new drugs against these important parasites. This studentship will characterize and target novel cuticle biosynthetic and moulting astacin enzymes that play essential nematode-specific roles. We have identified key enzymes in a model nematode Caenorhabditis elegans and we will now focus on these metalloproteinases in UK endemic trichostrongylid sheep and cattle parasites. This pathway has not previously been targeted in drug development schemes, and if successful, will provide an effective means of treating the existing anthelmintic resistant strains that are currently widespread worldwide. This project will involve the molecular identification and biochemical characterization of these drug targets and the testing and validation of synthesised inhibitors in vivo and in vitro.


Innate immunity to arboviruses at inoculation sites

Dr Clive S McKimmie, Institute of Infection, Immunity and Inflammation
Prof Gerry J Graham, Institute of Infection, Immunity and Inflammation

This project is an inter-disciplinary proposal that combines three related but rarely connected areas of research; in vivo immunobiology, molecular virology and arthropod vector biology. The project will gain fundamental knowledge on arthropod-mammalian interactions and how these processes affect the early stages of arthropod-borne virus (arbovirus) infection of mammals.  Europe, once confident in its isolation from substantial arbovirus epidemics is now at risk, as witnessed by the recent outbreaks of viruses such as Bluetongue and Schmallenberg, which infect economically important ruminants. Arthropod- borne viral diseases are highly heterogeneous and are caused by a wide variety of viruses, which makes the development of vaccines  and specific drugs for arboviral disease challenging. However, they all share a common life cycle in which an arthropod transmits the infectious agent into a bite site. New treatment modalities that target this common, shared aspect of their life cycle are a novel and potentially important strategy that may have wide applicability. Innate immune responses at bite sites to arbovirus infection are poorly understood. This project will determine the efficacy of post-exposure prophylactic intervention at bite sites by comparing the impact of innate immune modulation by agonists on inflammation pathways locally in the skin, and systemically in distal tissues. These studies aim to identify novel topical inflammatory innate immune modulators that are effective at suppressing viral replication and preventing spread/onset of clinical disease. The project will combine expertise from across the institute, utilizing both molecular and cellular approaches to determine the importance of innate immune responses at inoculation sites to arbovirus infection, and so characterize a fundamental and important aspect of arthropod-mammal-virus biology.

Defining the function of microRNAs in parasitic nematodes

Prof Eileen Devaney, Institute of Biodiversity Animal Health and Comparative Medicine
Dr Collette Britton, Institute of Biodiversity Animal Health and Comparative Medicine

Parasitic nematodes are incredibly successful organisms that have adapted to many different niches within their hosts. In this project, we aim to understand how parasites develop and survive, with a specific focus on the role of microRNAs in these processes. microRNAs are small non-coding RNAs that regulate gene expression. We have identified multiple miRNAs from the parasitic nematode Haemonchus contortus and, using microarray analysis, have identified miRNAs that are specifically expressed at defined points in the parasite life cycle. In addition we have identified a single miRNA that is significantly upregulated in an isolate of H. contortus resistant to anthelmintic drugs, implying that the molecule, or its mRNA targets, may aid the survival of the worm in the face of drug pressure. The project will focus on a small number of miRNAs involved in parasite development and drug resistance and will seek to understand their functions by identifying mRNA targets using a range of methods including ChIP-Seq, transfection of C. elegans and mammalian cell lines and a variety of bioinformatics tools.

The role of IgE in protection and pathology of nematode infection

Prof Michael Stear, Institute of Biodiversity Animal Health and Comparative Medicine
Prof Nicholas Jonsson, Institute of Biodiversity Animal Health and Comparative Medicine

IgE plays a key role in protection against parasitic infection but is also responsible for a variety of autoimmune diseases. The importance of IgE is clear in protection against nematode infection but it is also responsible for the relative protein deficiency that underlies the pathology. However, the IgE response is poorly understood. The aim of this project is to determine the kinetics of the IgE response, the relationship with Major Histocompatibility Complex (MHC) mediated protection and whether plasma IgE can serve as a marker for identifying animals that are resistant to infection. The study will focus on Scottish Blackface lambs, naturally infected predominantly with the nematode Teladorsagia circumcincta. You will measure IgE activity by ELISA, compare IgE activity against incoming infective larvae with the MHC haplotype, use proteomics to identify specific targets of the immune response, clone, sequence and express specific parasite targets, use phylogenetic analyses to study rates of host-parasite-coevolution, develop antigen-specific ELISA and relate recognition of specific molecules to MHC genotypes. Finally the research will determine whether plasma IgE can be used as a marker to identify resistant and susceptible sheep.


Towards a comprehensive theory of nematode-mediated immunosuppression

Prof Michael Stear, Institute of Biodiversity Animal Health and Comparative Medicine
Dr Louise Matthews, Institute of Biodiversity Animal Health and Comparative Medicine

The manipulation of host immune responses by nematodes is one of the most exciting areas of immunoparasitology. It helps to explain the wide variation in susceptibility to disease and may provide novel therapeutics to prevent or control autoimmune disease. Much research is focussed on identifying molecules and modes of action in a wide variety of different species from Acanthocheilonema viteae in jirds to members of the subfamily ostertaginiiae in livestock. The aim of this project is to solve two puzzling features of immunosuppression: why do different nematodes use such a wide diversity of molecules and why is immunosuppression not more effective.

The first part of the project will use bioinformatic methods to search nematode genomes for genes coding for immunosuppressive molecules and describe the evolution of immunosuppression in the phylum. In particular you will determine how often immunosuppression has evolved and how often immunosuppressive molecules are lost.

The second part of the project will explore the constraints on immunosuppression. There are no obvious resource limitations  on  the parasite; it could simply extract more food from the host.  Similarly, current fears that the effectiveness of immunosuppression is constrained by the need to prevent pathology appear simplistic given the fact that most individuals carry relatively few nematodes and even heavily infected individuals often show no clinical signs.  Here you will use adaptive dynamics to explore the possibility that some nematodes may free -ride by allowing contemporaries to immunosuppress the host.

Development and application of real-time surveillance tools for the investigation of FMD at the wildlife- livestock interface in Africa

Prof Sarah Cleaveland, Institute of Biodiversity Animal Health and Comparative Medicine
Dr Veronica Fowler, The Pirbright Institute
Dr Tiziana Lembo, Institute of Biodiversity Animal Health and Comparative Medicine

Foot-and-mouth disease (FMD) is one of the most important livestock diseases in the world, posing a threat to global livestock food security. However, little is still known about the epidemiology of FMD in endemic countries, particularly in Africa, where the disease has substantial impacts on rural livelihoods and where the complex epidemiology of FMD involves livestock and wildlife in mixed land-use systems. A newly-developed detection technology, reverse transcriptase loop-mediated amplification (RT-LAMP), has the potential to overcome limitations of existing laboratory detection methods, and, in combination with new field sampling techniques (e.g. tonsillar brushing) provides the opportunity to generate valuable new data for investigating FMD epidemiology at wildlife-livestock interfaces. This PhD project will apply RT-LAMP to determine FMDV infection patterns in (a) an extensive existing set of livestock and wildlife samples collected in a previous BBSRC-funded study of FMD in Tanzania; (b) new samples collected through on-going  FMD  outbreak  investigations  and  wildlife  sampling  in  Tanzania  and  (c)  new  samples  from  buffalo populations in the Kruger National Park, South Africa. The study will involve (a) validation and evaluation of the performance of the RT-LAMP for use in field settings in Tanzania; (b) application of the RT-LAMP to determine patterns of persistent FMDV infection, identify risk factors for infection and identify FMDV-positive samples for further molecular genetic characterisation; and (c) phylogenetic analyses of FMDV to investigate links between livestock and wildlife infection in northern Tanzania.


World Class Underpinning Bioscience

This theme seeks to promote strength in core, underpinning disciplines such as molecular, chemical, cellular and synthetic biology. Our aim is to develop researchers trained in both the rigorous methodologies of laboratory science and also the application of cutting edge mathematical and computational methods to help solve fundamental questions in the biosciences today. We offer training in metabolomics, transcriptomics, proteomics, cell signalling networks, synthetic biology, cell engineering, bionanotechnology, stem cell biology, novel gene in vivo transfer techniques and cellular processes. We also offer training in whole animal and human imaging as well as in whole animal research techniques.



Dissecting the function of USP7 in Inflammation
 
Dr Ruaidhri Carmody, Institute of Infection, Immunity and Inflammation
Dr Carl Goodyear, Institute of Infection, Immunity and Inflammation

NF-κB is the master regulator of cellular function and is an essential element in the development and homeostasis of the immune system. As such it is a critical controller of responses downstream of key immunoreceptors such as Toll- Like receptors (TLRs), antigen receptors, and members of the TNF receptor superfamily. The resulting activation of the NF-κB signaling cascade is critical for the appropriate transcriptional events required for the response to infection and the development of immunity. Importantly, approximately 500 genes are direct transcriptional targets of NF-κB including; cytokines, chemokines, regulators of antigen presentation and cell adhesion, as well as genes that control cell survival, proliferation and differentiation. However, uncontrolled expression of these genes can have devastating consequences including the development of fatal inflammatory disease and cancer. The ubiquitin-mediated proteasomal degradation of NF-κB is a critical step in the termination of the NF-κB transcriptional response and is a major limiting factor in the expression of pro-inflammatory genes. Our recent work has identified USP7 as a NF-κB deubiquitinase and established it as an indispensable factor in promoting the transcription of NF-κB target genes. The inhibition of USP7 deubiquitinase activity revealed that the ubiquitination of NF-κB occurs to a much greater extent than previously appreciated and showed that the balance between ubiquitination and deubiquitination of NF-κB is a fundamental determining factor in the level of gene transcription. This project will investigate the regulation of NF-κB by USP7 and the importance of USP7 in promoting the immune response. Defining how NF-κB is regulated in immune cells will provide fundamental insights into how the immune system works, and identify novel targets for therapeutic manipulation.

Metabolomics of neuroendocrine signalling in insects for food security

Prof Julian A T Dow, Institute of Molecular, Cell and Systems Biology
Prof Shireen A Davies, Institute of Molecular, Cell and Systems Biology

Insects destroy 20% of the world’s crops, and kill over a million people a year. Detrimental insects th us have severe consequences for global plant, animal and human health and productivity. With its sequenced genome, powerful genetic tools, mutant resources and large, active research community, Drosophila is an ideal model for insect studies. With recent advances in post-genomic technology, it is now possible to dissect function down to the level of individual tissues, and study the interplay between the different parts of an organism at an unprecedented level. Building on the success of FlyAtlas.org, a microarray atlas of gene expression in multiple tissues of Drosophila, we are developing FlyMet.org, a corresponding metabolomic resource. Metabolomics provides a wide-reaching ‘fingerprint’ of what a cell is doing at any moment. Whereas FlyMet will provide a baseline condition of metabolic activity, in this proposal we will look at the metabolomic signatures (across key tissues) of neuroendocrine stimulation with a insect hormones such as CAPA, AKH, bursicon and corazonin. This work will be performed on Drosophila Malpighian tubules (equivalent to mammalian kidney and liver), gut and fat body. Metabolomics will be performed on the tissue samples (Glasgow Polyomics) and the datasets analysed. The tissues in which the cognate neuropeptide receptors are predominantly expressed will be informatically assessed, using our FlyAtlas.org resource; and receptors will be genetically knocked down in particular subsets of cells using the Drosophila GAL4/UAS transgenic system. The impact of the changes on the metabolomic profiles across multiple tissues will then be assessed. This work will be performed not only in Drosophila, but in target pest insect species, e.g. dengue fever mosquito ; and the crop pest Manduca sexta, both of which we already have in the lab - so taking the important field of insect endocrinology to a new level.

Optogenetic tools for in vivo cell signalling, physiology and behaviour

Prof Shireen A Davies, Institute of Molecular, Cell and Systems Biology
Prof Julian A T Dow, Institute of Molecular, Cell and Systems Biology

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 invivo 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.


Regulating life and death through intracellular degradation

Dr Stephen Tait, Institute of Cancer Sciences
Prof Kevin Ryan, Institute of Cancer Sciences
 
Cell death is essential for life whereas its deregulation underpins many, particularly age-related, pathologies. Apoptosis, the major form of cell death, is a process that requires caspase protease activation. Mitochondria are often essential for activating caspases through an event called mitochondrial outer membrane permeabilisation. This leads to the release of mitochondrial, caspase-activating proteins into the cytoplasm. Although mitochondrial permeabilisation is often considered a point-of-no-return, we have found that cells can survive this catastrophic event – this has important implications in health and disease, for example by promoting life-long survival of post-mitotic cells or by enabling tumour cell survival. This project aims to understand two key mechanisms that allow cell survival following  mitochondrial  permeabilisation: 1) removal  of  permeabilised mitochondria and 2) degradation of pro - apoptotic mitochondrial proteins. Building on preliminary data, we aim to understand how permeabilised mitochondria are detected and removed from the cell, focusing upon the role of autophagy in this process. Secondly, we will investigate how pro-apoptotic molecules themselves are degraded upon their mitochondrial release, thereby limiting caspase activation. This project will employ a variety of approaches utilising live-cell bio-imaging techniques and proteomic analyses of mitochondrial proteins. Expected results will provide important new insights into the regulation cell death and mitochondrial quality control – two interlinked processes that play many important roles in health and disease.

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

Prof Graeme Milligan, Institute of Molecular, Cell and Systems Biology
Prof Shireen A Davies, Institute of Molecular, Cell and Systems Biology

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.

Synthetic Biology – providing high throughput screens for enzymes associated with site-specific gene manipulation

Prof Jonathan Cooper, School of Engineering
Prof Marshall Stark, Institute of Molecular, Cell and Systems Biology

Synthetic biology promises a modular approach to engineer products that allow new components to be discovered , tested and manufactured better, faster and cheaper than existing approaches and on a larger scale. Microfluidics offers the prospect of making compartmentalised reaction vessels of comparable size to single cells (picolitres). These “test-tubes” can be generated at astonishingly fast rates – upwards of 1000 per second – and can be simply imaged under a microscope. We have already demonstrated that we can perform cell- free expression of proteins in these pico-tubes – resulting in the production of new proteins. In this project, we now aim to combine these two technologies and build a high throughput platform, based on the use of microfluidics to produce libraries of variants of proteins (which can be done by performing an error prone isothermal DNA amplification within the picodrops). In order to screen these libraries for new activities we will seek to produce new sensitive fluorescent reporters – so that the 1000s of variants can be rapidly assessed by visual observation under a microscope. The technology has an enormous potential for use in a variety of applications – for example, in developing new enzymes to manipulate genes, in creating new diagnostic reagents or in developing new biologics based upon antibodies for therapeutics.

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

Dr Barbara Helm, Institute of Biodiversity Animal Health and Comparative Medicine
Dr Jane Robinson, Institute of Biodiversity Animal Health and Comparative Medicine

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.

Keeping pace with a 24/7 world: circadian clocks of birds in changing environments

Dr Barbara Helm, Institute of Biodiversity Animal Health and Comparative Medicine
Dr Jane Robinson, Institute of Biodiversity Animal Health and Comparative Medicine
Dr Peter O’Shaughnessy, Institute of Biodiversity Animal Health and Comparative Medicine

Humans were recently called an “arrogant species” for over-riding the biological clocks used by all organisms to keep track of time. In our breathless 24/society, obesity, cancer, cardio-vascular and mental health problems have all been linked to circadian disruption. These issues are current areas of intense research on humans, but they also concern the many species that share our environment, from wild animals in urban areas to companion and farm animals. Research on these species aids animal welfare and conservation but also offers new insights into the implications of current life-styles for human health. We, and others, have shown that exposure to nocturnal light pollution has massive effects on circadian clocks and reproductive biology of wild birds. This PhD project will use frontline molecular and polyomic tools in combination with field work to study the effects of urbanization on circadian clocks of Great tits. We have established a gradient of nestboxes running from Glasgow to the field station SCENE on Loch Lomond, and our pilot data indicate lower reproductive success in the city. The PhD will use cell culture to quantify individual circadian clocks, and will apply histology, gene expression and metabolomic approaches to identify target mechanisms by which urbanization affects wild birds. The studies will be complemented by collecting behavioural data using state-of-the-art remote recording methods. The wide range of approaches gives ample room for the innovative ideas of a motivated student.

Characterisation of intracellular ion channels through the creation of artificial cells

Dr Cheryl Woolhead, Institute of Molecular, Cell and Systems Biology
Dr Michele Zagnoni, Engineering, University of Strathclyde

Studies on ion channels are typically carried out using electrophysiology on whole cells. However this is not possible with intracellular ion channels, and hence the analysis of their structure/function relationship has not been elucidated to the same level as for extracellular channels. The CLIC1 protein is involved in the maintenance of cell homeostasis, acidification, proteolytic function and regulating the levels of reactive oxygen species. CLIC1 is structurally a very interesting protein, termed as “metamorphic” due to its ability to exist in two distinct stable soluble forms, before adapting its structure to a third state to enter the membrane. It is known that CLIC1 can auto-insert into a lipid bilayer to form functional ion channels, but how the soluble conformation transitions to the membrane integrated form is not known. With this project we will investigate the structural properties of integrated CLIC1. We will analyse the insertion of the transmembrane domains (TMD’s) and the oligomerisation of the protein in the membrane using a combination of biochemical and biophysical techniques. In addition the functionality of the protein will be investigated using microfluidic technology, where a fluorescent assay will be constructed to examine CLIC1 function in artificial cell membranes using a medium-throughput assay. The future application of this methodology will be in high-throughput metabolite screening, producing statistical experimental data within a single device, using reduced sample volumes and decreasing the costs with respect to the more established technologies. This project represents an academic collaboration between the Universities of Glasgow and Strathclyde in association with our industrial partner AstraZeneca.


The effects of expectation on spatial frequency tuning in primary visual cortex

Prof Lars Muckli, Institute of Neuroscience and Psychology
Prof Philippe Schyns, Institute of Neuroscience and Psychology
 
We are currently witnessing a paradigm shift in our understanding of human brain function. Sensory systems are no longer considered as 'passively recording' but rather as dynamically anticipating the rapidly changing environment. In this proposal, we aim to bridge between cognition and visual processing to understand the effects of spatial frequency tuning in V1 as a result of top-down expectation. We will use state-of-art methodology comprising hybrid spatial frequency (SF) images, functional brain imaging signals and multivariate pattern classifiers to test if early visual cortex can be sensitized to the specific spatial frequency content of images. Does sensitisation to either a high or low SF noise bandwidth selectively change preparatory filter functions in early visual areas, that is, before a stimulus is presented? If cueing affects the activity of specific SF channels then we should be able to read out the tuning before visual stimulation. Perceptual effects will be tested from trial to trial as a function of the read out of cortical filter functions. Does the brain prepare for the next stimulation by changing SF filter functions in V1? This project will link concepts of predictive coding to psychophysical paradigms of hybrid stimulation. Using brain reading, we will be able to measure at which level of cortical processing these top-down expectancy changes become effective.

Using EEG brain-computer interaction to improve performance

Dr Martin Lages, Institute of Neuroscience and Psychology
Dr Marios Philiastides, Institute of Neuroscience and Psychology

Recent advances in brain-computer interaction (BCI) and machine learning suggest possible applications in real-life domains, such as using neuro-feedback to improve memory and other cognitive abilities. In the context of reinforcement learning and memory BCI may be used as an assistive device to improve concentration and performance of individual participants. As advances in neuroscience provide a deeper understanding of the mechanisms involved in learning and comprehension, it is expected that new BCIs are developed that accelerate and improve learning by adapting to individual learning style and pace. It may be possible to determine the degree to which a student has learned a particular item directly from changes in brain signals, providing an elegant alternative to standardized tests for assessing learning rate.

The objective of this project is to establish BCI with neuro-feedback based on EEG recordings in an interactive paradigm with repeated trials. More specifically, we aim to perform classification analyses on EEG data recorded online during (a) (reinforcement) learning and (b) interactive gaming. We will employ state-of-the-art machine learning algorithms to achieve good prediction accuracies and advanced experimental designs to validate prediction rates. 

Variant Surface Glycoprotein diversity through antigenic variation in human- and animal infective African trypanosomes

Dr Richard McCulloch, Institute of Infection, Immunity and Inflammation
Dr Liam Morrison, Institute of Infection, Immunity and Inflammation

African trypanosomes survive in their mammalian hosts, which include humans and domestic animals, by continual changes in the composition of a protective surface coat, which is made of Variant Surface Glycoprotein (VSG). Changing the VSG coat is a pre-emptive process to thwart host immunity and belongs in a broad survival strategy termed antigenic variation, which is used in viruses, bacteria and eukaryotic pathogens. Antigenic variation in trypanosomes is remarkable for the mechanistic complexity of the process and for the huge genomic resources that the parasite devotes to it, since greater than 1000 VSG genes are found in the genome. In fact, trypanosomes are able to encode far greater than 1000 VSG coats, since they can use combinatorial recombination between multiple genes in the archive, generating novel ‘mosaic’ VSGs. It is now clear that mosaic VSG formation is central to trypanosome antigenic variation, generating huge levels of expressed VSG diversity. However, the true scale of the VSG diversity is poorly understood, and the underlying recombination reaction mechanisms and genomic locations of mosaic VSG formation have not been studied. Furthermore, whether VSG diversity arises by the same mechanism or to the same scale in exclusively animal-infective trypanosomes is unknown. This project will use next generation sequencing to address all the above questions regarding VSG diversity, shedding new light on how this feature of antigenic variation powers trypanosome persistence, transmission and survival.

Enzymes in a spin: single-molecule imaging of recombinase dynamics

Dr Steven Magennis, School of Chemistry
Prof Marshall Stark, Institute of Molecular, Cell and Systems Biology

A family of enzymes known as serine recombinases catalyses DNA site-specific recombination by cutting DNA strands and rejoining the ends in a new arrangement. It is proposed that these enzymes operate via a remarkable rotary mechanism, whereby the two halves of a recombinase tetramer, each carrying a pair of DNA ends, rotate relative to each other through 180° or multiples of 180°. In this project, we will use state-of-the-art single-molecule fluorescence  methods  (Magennis  lab)  to  observe  individual  serine  recombinase-DNA  intermediates  undergoing rotation. By labelling protein subunits and/or DNA strands with fluorescent dyes, we will monitor the conformational dynamics of these biological machines in real time, providing us with crucial information on mechanism and rates of rotation and the effects of the local environment. We will use our extensive collection (Stark lab) of purified natural serine recombinases, mutants with altered DNA exchange properties, and engineered variants with reconfigured DNA  sequence  recognition.  Our  overall  aim  will  be  to  achieve  a  full  understanding  of  the  rotary  mechanism
 
underpinning the biological function of this important class of enzymes. We speculate that this could lead to the
design and development of “components” in nanodevices for the fields of Synthetic Biology and Bionanotechnology.

Molecular dynamics of ion channel control by a vesicle trafficking protein

Prof M R Blatt, Institute of Molecular, Cell and Systems Biology
Dr Eirini Kaiserli, Institute of Molecular, Cell and Systems Biology

Control of volume and osmolarity lies at the core of cellular homeostatic networks in eukaryotes. Animal cells engage ion exchange for osmotic control and coordinate membrane traffic to ensure a balance of membrane delivery and removal. Plants and fungi use transport to generate turgor pressure for cell expansion and add membrane surface and cell wall material as the cell grows. In both systems, coordinating membrane traffic and ion transport is vital for survival, and its failure is associated with a number of physiopathologies (e.g. glaucoma) that reflect a loss in control of volume and osmotic homeostasis. This project explores the molecular dynamics coupling a membrane trafficking protein and its ion channel partner. The goal is to understand the kinetics of their interaction at the single-molecule level and its consequences for cellular physiology. The research will include (1) quantitative analysis o single-channel kinetics in association with the SNARE, (2) manipulating the interactions in order to understand their control of gating, and (3) analysis of ion transport and cell expansion. Training will cover a breadth of conceptual and technical approaches from molecular biology and patch clamping to single-cell imaging that are relevant to fundamental and applied research in cell biology and physiology.

Transcriptional regulation by light

Dr Eirini Kaiserli, Institute of Molecular, Cell and Systems Biology
Prof John Christie, Institute of Molecular, Cell and Systems Biology

Light is essential for plant growth and development. TZP (Tandem Zinc finger PLUS3 domain) is a key protein component that plays a major role in integrating light, hormone and clock signalling networks to promote plant growth in response to endogenous and environmental stimuli. To understand the molecule mechanism of its action, structure-function analysis of TZP is essential. More specifically, this project will investigate the transcriptional role of the evolutionary conserved Zinc Finger and the PLUS3 domains of TZP using in vivo and in vitro systems. The transcriptional activity of these domains, as well as their affinity to nucleic acids will be investigated by employing biochemical, genetic, cell biological, biophysical and bioinformatic approaches.

Photoregulation of plant hormone trafficking and signalling

Prof John Christie, Institute of Molecular, Cell and Systems Biology
Dr Eirini Kaiserli,, Institute of Molecular, Cell and Systems Biology

The phytohormone auxin (indoleacetic acid) is instrumental for directing and shaping plant growth and form. Understanding how this chemical growth regulator controls plant development will have important implications for manipulating plant growth for agronomic gain. Auxin trafficking is profoundly influenced by many abiotic factors, including light. For instance, phototropin receptor kinases (phot1 and phot2) function to redirect auxin fluxes that are required to reorientate plant growth toward or away from light. The phot1-interacting protein Non-Phototropic Hypocotyl 3 (NPH3) is essential for establishing these light-driven auxin movements. However, the mode of action of NPH3 and how it functions to regulate transporter activity remains poorly understood. This project aims to spatially dissect the site(s) of NPH3 action and how it impacts  the subcellular trafficking and function of known auxin transporter proteins implicated in phototropism. Work is also focussed on characterising a newly identified NPH3 protein (NPH3-like, NPH3L) that interacts directly with phot1. Functional characterisation of NPH3, NPH3L and its homologues will provide new insights into the photoregulation of auxin trafficking and signalling associated with phototropism and other phototropin-mediated responses.