MVLS DTP - University of Glasgow – College of Medical, Veterinary and Life Sciences (CMVLS)

The College is home to world leading expertise across an impressive diversity of disciplines with research into processes at every biological level from genes, to cells, organs, individuals, populations, and ecosystems. It is through our research and teaching excellence that we make a sustained contribution to the understanding and resolution of national and global issues.

University of Glasgow example projects are detailed below by theme. 

Basic Bioscience Underpinning Health

Projects within this section fall under Basic Bioscience Underpinning Health research theme:

A novel approach for the diagnosis of Onchocerciasis

Supervisors:
Prof Annette MacLeod, Institute of Biodiversity, Animal Health and Comparative Health
Prof Duncan Graham, University of Strathclyde

PhD project summary:
Raman spectroscopy, which provides molecular information of biological samples, has recently advanced to the stage where it can be applied in clinical settings, but has not so far been applied to the detection of infectious diseases. The technique is non-invasive (can detect signals several millimetres in to skin), sensitive, user-friendly and cheap making it ideally suited to the diagnosis of diseases where the pathogen resides in the skin. Onchocerciasis, also known as river blindness, is an important health problem, with a particularly high prevalence in people in sub-Saharan Africa. The disease is caused by a parasitic worm, Onchocerca volvulus, which is transmitted via the bite of a black fly. The adult parasites reside in nodules in subcutaneous connective tissue and produce up to 10000 microfilaria a day that migrate through the blood to the skin, ready to be picked up by a black fly as it takes a bloodmeal. The disease is diagnosed using skin biopsies to detect the larvae that reside in the skin. This is invasive, not well tolerated, time consuming and of low sensitivity in early stage infections. There is an urgent need to develop more sensitive and non-invasive diagnostic tools.  This project aims to apply this Raman technology to the diagnosis of onchocerciasis, to develop a novel diagnostic tool to aid the elimination project for onchocerciasis and will be translated directly into control and elimination strategies.


A role for high density lipoprotein in protecting maternal blood vessel function in pregnancy that may fail in gestational diabetes mellitus & preeclampsia

Supervisors:
Prof Robert Lindsay, Institute of Cardiovascular and Medical Sciences
Dr Dilys Freeman, Institute of Cardiovascular and Medical Sciences
Dr Delyth Graham, Institute of Cardiovascular and Medical Sciences

PhD project summary:
Pre-eclampsia (high blood pressure and protein in the urine) is a leading cause of death, and short and long-term illness in mother and baby. Gestational diabetes mellitus (GDM), where there is maternal hyperglycaemia, is a risk factor for preeclampsia. We have evidence that there is a lipoprotein in maternal blood, high density lipoprotein (HDL), is able to protect the maternal blood vessels from damage arising from the metabolic and oxidative stresses of pregnancy. In preeclampsia and GDM maternal blood vessel function is impaired and we propose that this is because HDL does not protect the vessels properly. This project will test whether maternal HDL from GDM and preeclampsia pregnancy has reduced vascular protective properties. The student will learn to liaise with hospitals to collect clinical samples, to isolate plasma HDL and contaminating exosomes and to test the vascular protection properties of HDL using the BHF Centre of Excellence Core Wire Myography facility. The student will spend time with collaborators in Sweden and the Netherlands analyzing the HDL proteome and lipid composition. The student will also develop their own assays to test the anti-oxidative and anti-inflammatory functions of HDL.


Causal inference, clinical translation and novel mechanisms underpinning uromodulin associated hypertension and renal function

Supervisors:
Prof Sandosh Padmanabhan, Institute of Cardiovascular and Medical Sciences
Dr Tom van Agtmael, Institute of Cardiovascular and Medical Sciences

PhD project summary:
Genome wide association identified a novel pathway for hypertension and renal function involving uromodulin. Uromodulin is exclusively expressed in the Thick Ascending limb of Henle (TAL) and Distal Convoluted tubule (DCT1) in the kidney. The main sodium transporter in TAL is NKCC2, and the potential UMOD-NKCC2 interaction on salt-sensitivity is now the basis of a BHF funded clinical trial (www.clinicaltrials.gov NCT03354897). There are currently large gaps in our understanding of the underpinning mechanisms by which uromodulin affects sodium balance, glomerular filtration and blood pressure. This collaborative translational PhD project will bring together our extensive experience in hypertension genomics, clinical trials and molecular genetics with world leading experts in uromodulin biology and in-vivo renal studies. We will assess causal relationships between uromodulin and blood pressure and renal function. We will study the incremental value of serum/urine uromodulin and serum hepsin levels through studies of a UMOD genotype directed clinical trial. Finally, through a combination of molecular and in-vivo experiments we will dissect the role of salt-exposure and ER stress on uromodulin function. This project will provide crucial information in accelerating the next phase of clinical translation through new drug discovery and interventions for both hypertension and CKD.


Deciphering the role of ubiquitination in the process of inter-strand crosslink repair in trypanosomatids

Supervisors:
Prof Richard McCulloch, Institute of Infection, Immunity and Inflammation
Dr Richard Burchmore, Institute of Infection, Immunity and Inflammation

PhD project summary:
Many cellular processes are controlled by cycles of ubiquitination and deubiquitination, where the addition and removal of a 76 amino acid polypeptide to lysine residues of target proteins controls their degradation, localisation and activity. One notable genome repair reaction that is controlled by ubquitination is inter-strand crosslink repair, which tackles a particularly pernicious form of genome lesion that can block both DNA replication and transcription. In mammals inter-strand crosslinks are repaired by the multiprotein Fanconi Aneamia pathway, in which ubiquitination and deubiquitination is central to the activity. However, this pathway is poorly conserved in single celled eukaryotes, including trypanosomatid parasites, which have been shown to be highly susceptible to ICL agents and where ICL damage has been shown to be repaired. This project will use existing mutants, and generate new mutants, that alter ubiqitination in trypanosomatid parasites to identify unknown factors that act in inter-strand crosslink repair. The role of ubiquitination in controlling the repair machinery, and how the reaction operates during the growth of the parasites will then be dissected. 


Decoding the synovial glycome: on the road to personalized glycan-based therapeutics in Rheumatoid Arthritis

Supervisors:
Dr Miguel Pineda, Institute of Infection, Immunity & Inflammation and Prof Iain McInnes, Institute of Infection, Immunity & Inflammation

Additional Collaborators:

- Biopolymer Mass Spectrometry, Imperial College London. http://www.imperial.ac.uk/life-sciences/research/mass-spec/

- Professor Christopher Buckley and Dr. Andrew Filer, University of Birmingham.
http://www.birmingham.ac.uk/staff/profiles/inflammation-ageing/buckley-christopher.aspx

PhD Project Summary:
Rheumatoid Arthritis (RA) is chronic inflammatory condition of the joint affecting 0.5M people in the UK for which current treatment consists primarily of immunosuppressive drugs with substantial side-effects. Moreover, even gold standard biologic regimens such as TNF blockers still present 30-40% of non-responders, reflecting that key events underpinning pathogenesis remain elusive.

In health, synovial fibroblasts (SFs) provide the required stromal support within the joint, but are recognized to adopt a pathological role in inflammatory RA, delivering region-specific signals to infiltrating cells that perpetuate the local inflammatory microenvironment. Therefore, interventions targeting SFs may modify disease progression and offer safer therapeutics simply by not suppressing systemic inflammation. However, there is an alarming lack of therapeutics targeting SFs.

This project will investigate the transformation of SFs into aggressive pro-inflammatory cells in RA that is associated with aberrant changes of cell glycosylation induced by pro-inflammatory mediators. We will aim to define the glycosylation circuits underpinning SFs-dependent immunomodulation integrating in vivo and in vitro studies with mass spectrometry structural analysis. This should provide further insight into the mechanisms underlying SF-dependent inflammation and its resolution and also, given the susceptibility of cell and tissue specific glycome to environmental changes, will provide crucial information for development of personalized medicine and patient stratification and discovery of novel disease biomarkers.

 


Defective adipocyte differentiation in pre-eclampsia: a potential mechanism underlying obesity as a risk factor

Supervisors:
Dr Dilys Freeman, Institute of Cardiovascular and Medical Sciences
Dr Ian Salt, Institute of Cardiovascular and Medical Sciences

PhD project summary:
Pre-eclampsia is of major concern to obstetricians due to its sudden onset and increased morbidity and mortality for mother and baby. There are no effective predictive or preventative strategies for pre-eclampsia and therefore there is an urgent need to understand the pathophysiology of the disease. Obesity is a risk factor for pre-eclampsia and we have published data showing that pre-eclampsia is associated with adipocyte dysfunction i.e. reduced insulin sensitivity, reduced suppression of lipolysis, and increased inflammation. We hypothesise that the cause of adipocyte dysfunction is a reduced ability to differentiate pre-adipocytes to make mature adipocytes in which to safely store gestationally-acquired fat. This project will test whether this occurs only in obese women with pre-eclampsia or also in non-obese pregnant women with the disease. The student will assess the mechanisms for adipocyte dysfunction and relate adipocyte differentiation potential to adipose tissue inflammation and placental ectopic fat accumulation.


Defining the biological effects of good vs bad fats on -cells in order to develop better drugs for type 2 diabetes

Supervisors:
Dr Brian Hudson, Institute of Molecular Cell and Systems Biology
Prof Graeme Milligan, Institute of Molecular Cell and Systems Biology

PhD project summary:
There are established links between different types of fat and our health. For example, poly unsaturated and omega-3 fats are thought to be beneficial, while saturated and trans fats are detrimental. In the body, fats are broken down into long chain fatty acids (LCFAs), that serve as important signalling molecules. FFA1 is a cell surface receptor activated by LCFAs, expressed in pancreatic-cells, and receiving interest for the treatment of type 2 diabetes (T2D). However, it is unclear whether FFA1 is involved in the effects of both beneficial and determinantal LCFAs. This project will use advance pharmacological approaches to define how different types of fat produce unique responses through FFA1 in pancreatic-cells to regulate key functions like insulin secretion. This information will then be used to determine the ideal signaling profile for potential FFA1 therapeutics, and through collaborations with chemists, allow for the identification of novel FFA1 drugs with both improved efficacy and reduced side effects. Overall, the project will help us understand how different types of fats impact our health, aiming to use this information to improve the treatment of T2D.


Defining the contribution of the integrin LFA-1 to tissue γδ T cell function in infection and cancer

Supervisors:
Dr Vicky Morrison, Institute of Infection, Immunity & Inflammation
Dr Seth Coffelt, Institute of Cancer Sciences
Prof Tom Evans, Institute of Infection, Immunity & Inflammation

PhD project summary:
γδ T cells are innate-like cells that reside predominantly at mucosal sites and have essential roles in immune protection against infection and cancer. Despite recent interest in the development of therapeutic strategies to enhance γδ T cell function, our understanding of the basic biology of these cells remains poor. One key unanswered question is what controls their turnover and survival in tissues. We have identified the adhesion molecule, LFA-1 (integrin alphaL/beta2; CD11a/CD18), as a novel regulator of γδ T cells. In the absence of LFA-1 (in CD11a or CD18 knockout mice), γδ T cells were significantly expanded in a tissue-specific manner: 50-fold in the lungs and spleen; 8.5-fold in the uterus; as a result of enhanced survival. The expanded cells expressed the Vγ6+ T cell receptor and secreted IL-17. This proposal aims to determine the functional relevance of Vγ6+ cell expansion in the lungs and genital tract of LFA-1-deficient mice. Specifically, we will demonstrate the functional importance of this cell population in tissue homeostasis, in relevant infection models and in cancer. Together, the outcomes of this study will advance our understanding of this elusive immune cell type, and provide new targets for the therapeutic manipulation of γδ T cells in infectious disease and cancer.


Defining the molecular interactions during the initial folding of proteins entering the secretory pathway

Supervisors:
Prof Neil Bulleid, Institute of Molecular Cells and Systems Biology
Dr Cheryl Woolhead, Institute of Molecular Cells and Systems Biology

PhD project summary:
The temporal relationship between protein synthesis, folding and modification within early stages of the secretory pathway is poorly understood. We have previously developed techniques to address questions related to these very early stages of secretory protein biogenesis in experimental systems that mimic the process as they occur in intact cells. In particular we are interested in how the folding of individual domains is co-ordinated with post-translational modifications such as glycosylation and disulfide formation. Recent discoveries in our laboratories have highlighted the role of specific folding enzymes and chaperones in facilitating the correct folding of secretory proteins. The main aims of this project are to define the cellular machinery required to fold a nascent polypeptide chain as it is translocated across the membrane of the endoplasmic reticulum and to determine the extent of substrate specificity during the maturation of protein in the early stages of the secretory pathway. As well as being trained in all the modern molecular biology and biochemical techniques required to complete the project, the student will be encouraged to gain experience in cutting-edge techniques that are available in the Bulleid and Woolhead laboratories. The project will impact on fundamental aspects of protein biogenesis as well as providing the opportunity to optimise recombinant protein expression.


Delivering stratified medicine approaches to the CML clinic through inhibition of EZH2

Supervisors:
Dr Mary Scott, Institute of Cancer Sciences
Dr David Vetrie, Institute of Cancer Sciences

PhD project summary:
Targeting of drug-resistant leukaemic stem cells (LSC) in chronic myeloid leukaemia (CML) is required to cure the disease. Using pioneering systems biology approaches, we recently identified EZH2, a catalytic component of the epigenetic Polycomb Repressive Complex 2 (PRC2) as a novel drug target and have shown that EZH2 inhibitors (EZH2i) are effective at targeting LSC (Cancer Discov. 6:1248-1257,2016). In order to identify patients who would most benefit from EZH2i through our CR-UK funded TASTER clinical trial, the molecular hallmarks and heterogeneity of the clones that are sensitive and resistant to EZH2i must be characterised. To this end, the inter-disciplinary PhD project will combine powerful experimental and computational approaches to characterise the LSC that are targeted by EZH2i. The candidate will use state-of-the art phenotypic and genetic assays, clinically-relevant mouse models and ‘omics’ technologies (DNA-barcoding and single cell RNA-sequencing) in the wet-lab. He/she will then analyse and integrate these datasets in the dry-lab to define the molecular hallmarks of LSC clones, and then incorporate these data into existing CML computational models to simulate and predict which LSC clones will be eradicated by EZH2i. The candidate will be trained and based at the Wolfson Wohl Cancer Research Centre – a centre of excellence for cancer translational research at the University of Glasgow.

 

 


Determinants of HIV-1 Transmission and Replication

Supervisors:
Dr Suzannah Rihn, Institute of Infection, Immunity and Inflammation
Prof David Robertson, Institute of Infection, Immunity and Inflammation

PhD Project Summary:
Within infected individuals, HIV-1 displays enormous genetic diversity and can be present at high viral loads (in excess of a million virus particles per ml of blood). Yet most new HIV-1 infections (~60-90% of heterosexual transmissions) are initiated by just a single HIV-1 virus particle that is successfully transmitted to a new host. Thus, the transmission of the single transmitted/founder (TF) virus particle represents a uniquely vulnerable stage in the HIV-1 lifecycle, and interventions targeting TF virus particles could prevent lifelong infection. However, creation of such critically important interventions requires a better understanding of the very earliest events during HIV-1 acute infections. This studentship seeks to dramatically advance upon recent research in order to determine which of the distinct biological properties of HIV-1 TF virus particles enable their successful transmission and replication. In particular, the project aims to use a longitudinally sampled cohort of HIV-1 viruses from patients from diverse geographic origins, in order to map specific determinants within the TF viruses that either increase replicative fitness or increase the virus’ capacity to evade immune responses. By comparing these determinants with other diverse cohorts of patient sequences, the project ultimately aims to map a comprehensive HIV-1 transmission fitness landscape.


Determining the role of NADPH oxidase 5 (NOX5) in ischaemic stroke, cerebral small vessel disease (cSVD) and vascular cognitive impairment (VCI)

Supervisors:
Dr Lorraine M. Work, Institute of Cardiovascular & Medical Sciences
Dr Augusto Montezano, Institute of Cardiovascular & Medical Sciences
Prof Rhian Touyz, Institute of Cardiovascular & Medical Sciences
Dr Jozien Goense, Institute of Neurosciences & Psychology 

PhD project summary:
Neurological disorders (including stroke) are the 2nd leading cause of death worldwide and the leading cause of physical disability and cognitive issues.  Stroke doubles the risk of developing dementia and 30% of stroke patients will develop dementia.  Novel treatments to address both the acute and chronic sequelae of cerebrovascular disease are needed.  The NADPH oxidases (NOXs) are a primary source of reactive oxygen species (ROS) – one of the key pathophysiological processes contributing to lesion progression after stroke.  NOX5 is a calcium-activated isoform and, given the central role calcium excess plays in vascular function, excitotoxicity, initiation of inflammation and apoptosis in stroke this makes this isoform particularly worthy of further study.  We have produced a vascular smooth muscle cell (VSMC)-specific NOX5 expressing mouse which has systemic and vascular oxidative stress, vascular hypercontractility and cardiac fibrosis.  However, in the setting of stroke, the cerebrovascular effect of this genotype is unknown and will be the primary focus of this studentship.  In addition, no studies have determined the role of NOX5 in vascular cognitive impairment (VCI).  We will address this using the bilateral carotid artery stenosis model in VSMC-expressing NOX5 mice (vs wildtype controls) to induce a VCI phenotype. 


Development of lipoprotein-based nanomaterials for vascular immunomodulatory drug delivery in atherosclerosis

Supervisors:
Dr Pasquale Maffia, Institute of Infection, Immunity & Inflammation and Prof Jonathan Cooper, College of Science and Engineering

(Additional Collaborators: Prof Iain McInnes, Institute of Infection, Immunity and Inflammation and Prof Paul Garside, Institute of Infection, Immunity and Inflammation)

PhD Project Summary:
Atherosclerosis comprises progressive occlusion of arteries, via plaque formation, leading ultimately to myocardial infarction and stroke. Immune responses play a critical role in atheroma development; however, immunomodulatory therapies are not used routinely to treat atherosclerosis, reflecting in part, concerns about systemic immune suppression given the necessity for chronic therapeutics. Nanotechnology can potentially deliver drugs selectively to atherosclerotic plaques avoiding systemic exposure. Recently, high-density lipoproteins, natural nanoparticles that transport cholesterol to the liver, have been used for targeted drug delivery to atheroma. Herein we will employ a novel microfluidics-based method to produce lipoprotein-mimicking nanoparticle carrier vehicles to selectively deliver immunomodulatory drugs to atheromatous plaques. We will incorporate appropriate detection moieties e.g. fluorochromes into nanoparticles, to enable their localisation by various imaging modalities. Thereafter, we will evaluate the anti-inflammatory impact of locally delivered immunomodulators in vitro in complex vascular cell culture and in vivo in validated murine models of atherosclerosis.


Developing and validating risk prediction and prognostic tools for head and neck cancer

Supervisors:
Prof David Conway, School of Medicine, Dentistry, and Nursing / Institute of Health and Wellbeing
Dr Alex McMahon, School of Medicine, Dentistry, and Nursing / Institute of Health and Wellbeing
Dr Peter Bailey, Institute of Cancer Sciences

PhD project summary:
Incidence of head and neck cancer is on the rise globally and across the UK, and survival has not significantly improved in recent decades. Stratified and precision medicine approaches have the potential to target high risk populations and individuals to better target prevention, early detection, and treatment interventions. While risk factors associated with head and neck cancer are well established, the translation of this information into validated risk prediction and prognostic tools has yet to be realized. This PhD uniquely combines training and research projects in cancer epidemiology and cancer biomarker sciences.  Research studies will: i) develop head and neck risk prediction and prognostic models using a large INHANCE pooled international dataset; ii) validate these models in the UK Biobank cohort; and iii) explore the identification of prognostic biomarkers in head and neck cancer.  Research training will be in areas of advanced epidemiological and statistical analyses; and laboratory biomarker / bioinformatics analyses.  The proposed studies have international collaborators, and support of the local head and neck cancer managed clinical network which will enable rapid translation.

 


Disease mechanisms of vascular disease: Investigating the role of endoplasmic reticulum stress

Supervisors:
Dr Tom Van Agtmael, Institute of Cardiovascular and Medical Sciences
Prof Christian Delles, Cardiovascular and Medical Sciences

PhD project summary:
Vascular diseases including haemorrhagic stroke are a major health problem for which there is an urgent need for treatments. Increasing our understanding of the underlying molecular disease mechanisms will aid in the development treatment strategies. We have previously identified that mutations in the genes Col4a1 and Col4a2 cause stroke and vascular disease. These mutations cause defects to the extracellular matrix and a cell stress response called endoplasmic reticulum (ER) stress, caused by misfolding of the mutant collagen protein. Interestingly ER stress has also been observed in other vascular diseases in the general population including high blood pressure and heart failure. However, the actual role of ER stress to these diseases including Col4a1 disease remains unclear. To address this gap in our knowledge, you will employ novel mouse models to determine in vivo the role of ER stress in disease. Combined with cell culture models, imaging and proteomics/next generation sequencing you will investigate the molecular mechanisms by which ER stress affects the vasculature. In so doing this project, will increase our fundamental understanding of ER stress and may help the development of novel disease-mechanism based treatments for vascular disease.


Double Trouble: Concurrent Infections and Conflicting Instructions in the Immune System

Supervisors:
Dr Georgia Perona-Wright, Institute of Infection, Immunity & Inflammation
Prof Simon Milling, Institute of Infection, Immunity & Inflammation
Dr Donal Wall, Institute of Infection, Immunity & Inflammation

PhD project summary:
Infections rarely occur in isolation. An ongoing immune response can change the reaction of the immune system to a different challenge, and such immune interference frequently results in increased susceptibility to infection-induced disease. Intestinal infections are the 2nd highest cause of death in children under 5 worldwide: helminth infections currently affect over 2 billion people, and diarrhoea kills over 520,000 children each year. Our aim here is to understand how and why chronic worm infections predispose their hosts to other intestinal infections, and how we can break this pattern of susceptibility.

Concurrent helminth infections are known to compromise the type of immune response that is necessary for rapid defeat of Salmonella bacteria. In this project, we are seeking to understand the mechanisms behind such interference between infections. Our hypothesis is that cytokine signals initiated by the helminth infection activate both innate and adaptive immune cells in a way that prevents their useful function in an immune response against Salmonella. 

We will use experimental approaches in vitro and in vivo, dissecting the process of cytokine signalling in molecular detail and testing its therapeutic potential in the physiological context of a complete immune system. Our focus will be on the ability of helminth-induced cytokine signals to alter gene expression in target cells, particularly through epigenetic regulation. Our plan is that new insight into the mechanisms of co-infection will fuel the identification of new approaches to reduce susceptibility.
 


Drosophila as a model to study metabolic and immune implications of stem cell-driven intestinal tumourigenesis

Supervisors:
Dr Julia B. Cordero, Institute of Cancer Sciences
Dr Oliver Maddocks, Institute of Cancer Sciences
Dr Seth Coffelt, Institute of Cancer Sciences

PhD Project Summary:
Due to its role as a metabolic, immune and endocrine organ, the intestine is considered a central coordinator of multiple physiological functions and disruptions to intestinal homeostasis are expected to have profound organismal implications.We have developed Drosophila models of intestinal stem cell (ISC) hyperproliferation, which mimic multiple tissue-intrinsic aspects of colorectal cancer (CRC) and provided novel conserved mechanistic insights into the disease [1][2]. Current work from our laboratory has revealed that deregulation of metabolic and immune/inflammatory pathways are predominant features of fly hyperproliferative intestines. The role and regulation of immune and metabolic processes in cancer is a current major focus of research. Understanding how these processes are regulated and contribute to the development of the disease in the context of genetically defined tumours is extremely challenging to achieve using mammalian models.

Taking advantage of the power of Drosophila genetics and the extensive conservation between fly and mammalian intestinal biology we will combine whole genome and metabolomics analysis with functional genetic experiments to study the regulation of immune/inflammatory and metabolic processes in genetically defined models of intestinal hyperplasia and assess their functional role at the local and organismal level. Our work will provide a powerful and integrative approach to address issues of major impact to human health and disease.

1- Cordero, J.B., et al., Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut. Development, 2012. 139(24): p. 4524-35.
2- Cordero, J.B., et al., c-Src drives intestinal regeneration and transformation. EMBO J, 2014. 33(13): p. 1474-91.


Engineering protein antibiotics for the treatment of antibiotic resistant Pseudomonas aeruginosa infection

Supervisors:
Professor Daniel Walker, Institute of Infection, Immunity and Inflammation
Dr Donal Wall, Institute of Infection, Immunity and Inflammation

PhD Project Summary:
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. An alternative approach to the discovery of new antibiotics is use of bacteriocins, which are potent species-specific protein antibiotics made by Gram-negative bacteria during environmental stress. We recently discovered that pyocins, deployed by P. aeruginosa to kill neighbouring Pseudomonad species, are more effective at protecting mice infected with an acute P. aeruginosa lung infection than the leading antibiotic used clinically for the treatment of lung infections. In this project, we will use structural biology and protein engineering to design and produce protein antibiotics with enhanced killing activity against clinical isolates of P. aeruginosa.


Exploring how developmental mitochondrial ROS signalling determines lifespan

Supervisors:
Dr Alberto Sanz, Institute of Molecular, Cell and Systems Biology
Prof Kostas Tokatlidis, Institute of Molecular, Cell and Systems Biology

PhD project summary:
Ageing is one of the foremost challenges facing modern biomedicine. This project will dissect the role of developmental mitochondrial Reactive Oxygen Species (mtROS) in ageing and age-related diseases.  mtROS are essential in determining longevity in animals. ROS in high concentrations cause oxidative damage and shortens lifespan. In contrast, experimentally boosting moderate amounts of mtROS increases longevity in animal models. This is an extraordinary finding, as increasing mtROS levels could be used to increase health-span. To achieve this, we need to understand where and when ROS levels need to be stimulated to induce the pro-survival pathways that protect the cell and extend lifespan.
Preliminary evidence indicates that moderate to high levels of mtROS during development extend healthy lifespan. This project aims to determine how developmental mtROS signalling regulates adult lifespan by: (1) studying how mtROS levels change during the development of Drosophila melanogaster; (2) identifying the mitochondrial ROS generator(s); and (3) determining the consequences of increasing and decreasing the levels of developmental mtROS on adult lifespan . During their studies, the student will be trained in various techniques from the fields of molecular and cell biology, biochemistry, genetics, physiology and bioinformatics. 


Exploring the disease gateway of Psoriasis arthritis with single cell RNA-seq

Supervisors:
Dr Thomas Otto, Institute of Infection, Immunity and Inflammation
Dr Mariola Kurowska-Stolarska, Institute of Infection, Immunity and Inflammation

PhD project summary:
Psoriatic arthritis (PsA) is a debilitating condition that develops in some people with psoriasis and can’t be cured. However, some patients stay in remission upon successful treatment although the mechanisms are unknown. In this PhD we want to explore
the disease trajectory of PsA at the single cell level in synovial joint tissues to understand PsA pathogenesis and return to homeostasis: Why do some PsA patients stay in remission, but others flare? The student will perform single cell sequencing and analyse the data to
characterise and then test in the lab cellular and molecular mechanisms of inflammation and homeostasis. The novel data will be compared computationally to similar data of synovial joints from RA patients. A major focus will be put on computational tools to detect proteins involved in cell-cell communication between different cell populations. These proteins present potential new drug targets and will be follow up in the laboratory.


Identification of cis- and trans-acting genetic modifiers of somatic expansion as novel therapeutic targets in the repeat expansion disorders

Supervisors:
Prof Darren Monckton, Institute of Molecular, Cell and Systems Biology
Dr Graham Hamilton, Glasgow Polyomics

PhD project summary:
Many human disorders, including Huntington disease and myotonic dystrophy, are caused by the expansion of simple sequence repeats. Disease-associated alleles expand during intergenerational transmission accounting for anticipation. Disease-associated alleles also expand in the soma, driving the tissue specificity and progressive nature of symptoms. Genetic modifiers of somatic expansion thus present as novel therapeutic targets and could be identified using genome wide association studies. However, the application of genome wide association studies in these disorders is limited by the rarity of the conditions. Nonetheless, the ERDA1 locus presents with a high frequency of expanded alleles (~20%) in the general population. It is our hypothesis that we can use high-throughput ultra-deep sequencing to derive individual-specific measures of mutational dynamics that act as biomarkers of genetic instability and can be used as molecular phenotypes in genome wide association studies. To this end, the student will: 1) develop a high-throughput ultra-deep sequencing assay for the ERDA1 locus; 2) sequence large numbers of alleles in the general population; 3) quantify the degree of somatic mosaicism; and 4) use residual variation in somatic mosaicism as a molecular phenotype in a genome wide association study. The results will identify novel therapeutic targets for the repeat expansion disorders.

 


Identifying the mechanisms controlling the fate of skill memories

Supervisors:
Prof Edwin M. Robertson, Institute of Neuroscience & Psychology
Prof Gregor Thut, Institute of Neuroscience & Psychology

PhD project summary:
Long after reading this summary, or playing a game of squash your brain continues to process the knowledge and skills acquired. These offline processes continue for hours and days after reading, or after your game. They improve your understanding of this summary, and enhance the grace and power of your game. Some skill memories are enhanced by as much as 20-30% in the hours immediately after their formation whereas, other skills are simply retained. Identifying the mechanisms that control the development of these different fates (enhanced vs. retained), will open a new area of research, and provide novel insights into how the offline brain operates. We hypothesize that these different fates are controlled by an interaction between the primary motor cortex (M1) and the dorsolateral prefrontal cortex (DLPFC). We will use a combination of EEG and TMS, to test not only the functional connection between DLPFC and M1, but determine the direction of that connectivity, and its critical importance to memory fate. Overall, this project will provide a wonderful training opportunity equipping a student with a contemporary understanding of brain stimulation, important neuroimaging techniques, behavioural analysis, and an appreciation for how the offline brain operates.


Investigating how gene – environment interactions cause schizophrenia

Supervisors:
Prof Brian Morris, Institute of Neuroscience and Psychology
Prof Judith Pratt, SIPBS, University of Strathclyde

PhD project summary:
Existing drugs to treat schizophrenia, a common and severely debilitating disease with enormous societal costs, are only effective against some of the symptoms, and can have serious side-effects. Understanding the causes of the disease should lead to improved treatment strategies. Schizophrenia is caused by a combination of genetic and environmental risk factors, the latter including prenatal infection. Evidence suggests that four genes clearly associated with schizophrenia risk (VIPR2, VRK2, DOCK8, TIPRL) may contribute to the response of the immune system to infection, suggesting a possible link to environmental risk, but their function in the brain remains mysterious.

The project will combine molecular, cellular and rodent behavioural studies to explore the function of these genes in the brain. 1) Do they interact genetically or functionally with each other or with other known schizophrenia risk genes? 2) Do they regulate neurobiological processes that are impaired in schizophrenia (eg GABAergic interneurone maturation, NMDA receptor function) ? 3) Does deficiency in these genes produce cognitive deficits characteristic of schizophrenia (deficits in working memory)?

The results should provide new insight into the causes of schizophrenia. In addition, the project will provide training in a range of specialized techniques currently central to neuroscience research, and also in generic laboratory and research skills such as experimental design and planning, and image and statistical analysis techniques.

 


Investigating the mechanisms of resolution of joint inflammation

Supervisors:
Dr Mariola Kurowska-Stolarska, Institute of Infection, Immunity and Inflammation
Dr Thomas Otto, Institute of Infection, Immunity and Inflammation
Prof Iain B McInnes, Institute of Infection, Immunity and Inflammation

PhD project summary:
Psoriatic Arthritis (PsA) affects 0.3% of the population and only a small proportion of patients achieve sustained remission of joint disease1; thus, there is substantial clinical need to find novel treatments. Recently, using cutting-edge single cell transcriptomics we have described sub-populations of joint synovial tissue macrophages (clusters) with potential distinct functions2. Two of the clusters occur uniquely in patients with sustained resolution of inflammation as compared to active arthritis. The transcriptomic profile of these clusters is enriched in regulatory pathways suggesting that these cells and their functional pathways may have an active role in restraining inflammation and maintaining joints inflammation-free. Our hypothesis is that reduced expression/activation of pathways that restrain joint inflammation contributes to disease, and that activation of these pathways will prevent inflammation and reinstate joint homeostasis in PsA. Thus, the aim of this PhD program is to dissect the role of candidate pathways in maintaining joint inflammation-free. We propose that such pathways offer rich potential as novel curative therapeutic targets for PsA. Training outcomes: The student will be embedded in the internationally recognized ARUK Rheumatoid Arthritis Centre of Excellence and will be trained by an established collaborative group of clinician, scientist and bio-informatician with a focus on research and the principles of precision medicine. Training will include the most cutting-edge techniques in cell and molecular biology, analysis of scRNAseq transcriptomics and its integration with experimental data and clinical patient information.


Investigating the potential for MSC-derived microvesicles to induce breast cancer cell dormancy within a tissue engineered bone marrow microenvironment

Supervisors:
Dr Catherine Berry, Institute of Molecular Cell and Systems Biology
Prof Matthew Dalby, Institute of Molecular Cell and Systems Biology

PhD project summary:
Epithelial tumours, such as breast cancer, suffer from skeletal metastasis, whereby cancer cells leave the primary tumour and migrate to the bone marrow. It is now evident that, in the early stages of metastatic spread, these disseminated tumour cells in the marrow undergo an extended period of growth arrest in response to the quiescent, resident mesenchymal stem cell (MSC) microenvironment within the marrow, a phenomenon known as dormancy. Understanding the process involved in the onset of dormancy is the subject of much research. In this project, we will use an established three-dimensional co-culture model of MSCs and breast cancer cells (BCCs) in order to study the recently reported link between MSC-derived microvesicles and cancer cell dormancy. Initial pilot studies in our lab have shown that BCCs reduce proliferation and migration when cultured with MSC-derived microvesicles; key identifiers of BCC dormancy. This project will therefore further investigate the effect of MSC microvesicles on BCC behaviour and subsequently analyse potential candidates packed within the vesicles that may be responsible for the onset of dormancy. In this regard we will focus on metabolites, identifying which ones are found in increased concentration in vesicles and their isolated effect on BCC cell cycle.


Investigating the temporal extent of cortical prediction in humans using functional brain imaging

Supervisors:
Prof Lars Muckli, Institute of Neuroscience and Psychology
Dr Alessio Fracasso, Institute of Neuroscience and Psychology

PhD project summary:
With the proposal of predictive processing as a unifying theory of brain function, the cognitive neurosciences are experiencing a paradigm shift. The predictive processing framework is also redefining fields of philosophy of mind, psychological disorders and artificial intelligence. This redefinition demands new neuroscientific experiments. We propose that one such domain of experimentation must test how the brain predicts its inputs over time. The temporal expansion of cortical prediction is not as well understood as the prediction of moment-to-moment sensory inputs, but will inform conceptual models for mental simulation such as mind-wandering and counterfactual thinking. We will use high-resolution functional brain imaging of the human visual cortex with multivoxel pattern analysis (MVPA) to read out cortical prediction mechanisms expanding over stretches of time. Participants will engage in tasks designed to probe cortical feedback contributions to perception and cognition over time. For example, how does the brain perceive when a child’s tower of building blocks will fall? How does the brain predict the ending sequence of a movie? Data will contribute to evolving frontiers in predictive coding research.


Investigation of KDM and BET inhibitors as a candidate novel combination therapy for AML

Supervisors:
Dr Xu Huang, Institute of Cancer Sciences
Dr Helen Wheadon, Institute of Cancer Sciences
Prof Robert Liskamp, Institute of Cancer Sciences

PhD project summary:
There is a significant unmet need for novel therapeutic approaches in blood cancer. Current treatment has evolved little since several decades ago especially for Acute Myeloid Leukaemia (AML). The recent development of several pharmacological inhibitors targeting BRD4 and Dot1L, highlights that such epigenetic regulators could be promising anti-tumour targets. Based on our previous shRNA screen results, we have identified a histone demethylase, depletion of which in human AML cells promoted AML cancer stem cells terminal myeloid differentiation and rapid cell death but spared normal haemopoietic stem cell function. This suggests that this protein could represent rational target for therapeutic intervention. However, it lacks in-depth understanding of the cellular mechanisms through which this demethylase and its inhibitors selectively target leukaemic cancer stem cells. In this project we will focus on identifying its specific downstream targets in AML, and validate the results in primary AML patient samples and in our established human AML xenograft mouse model. The proposed study will utilise combined systems biology approaches and expects to provide a fundamental scientific understanding to be used to initiate the next stage of drug discovery and propose the effective combination treatments with other standard AML therapies.


Investigation of the multi-genic basis of artemisinin resistance in malaria parasites

Supervisors:
Prof Andy Waters, Institute of Infection, Immunity & Inflammation
Prof Mike Barrett, Institute of Infection, Immunity & Inflammation 

PhD project summary:
Drug resistance in malaria parasites is a continual and increasing problem.  The front-line drug, Artemisinin is a partner in all effective antimalarial treatments in South-East Asia.  Unfortunately, such formulations are becoming increasingly ineffective and there is precedence for drug resistant parasites spreading world-wide from these regions.  Mutations in a Kelch propeller protein have been validated in human parasites and in a ubiquitin hydrolase in rodent parasites.  The programme will look at combinations of these mutations in both genes in rodent malaria parasites to understand the potential of these mutations to increase artemisinin resistance and to confer resistance on other fast acting drugs such as chloroquine and its derivatives. Furthermore, similar validated, anti-malarial drugs will be tested for their metabolic impact on malaria parasites in order to understand their mode of action.  The student will work at the interface of modern metabolomics and cutting-edge molecular parasitology.


Labelled lines for transmitting pain and itch in the spinal cord

Supervisors:
Prof Andrew Todd, Neuroscience and Psychology, University of Glasgow
Dr David I Hughes, Neuroscience and Psychology, University of Glasgow

PhD Project Summary:
Injury to peripheral nerves often results in neuropathic pain, which is very difficult to treat and represents a major unmet clinical need. The mechanisms underlying neuropathic pain are poorly understood, but it is thought that loss of inhibition in the spinal cord is a contributory factor. We have recently identified a novel population of interneurons in the spinal dorsal horn that presynaptically inhibit nociceptive primary afferents, and have found that these cells are lost following nerve injury. This suggests that the resulting reduction of inhibition contributes to neuropathic pain. This project will use a mouse line in which these interneurons can be identified, to investigate their involvement in neuropathic pain. Initially the extent and timecourse of cell death will be determined in two different nerve injury models that result in different forms of neuropathic pain. It is likely that cell death results from loss of synaptic input from damaged nociceptors, and this can be prevented by treatment with glial-derived neurotrophic factor (GDNF), which also reduces neuropathic pain. The hypothesis that application of GDNF protects these neurons will therefore be tested. The hyperalgesia and allodynia after nerve injury result from activity in nearby undamaged primary afferents and the extent to which axons of these cells cross nerve territories will therefore be assessed. The project will provide important information about the roles of spinal inhibitory interneurons in neuropathic pain. 

 

 


Mapping the neutralising antibody determinants of morbilliviruses to determine their zoonotic potential and to predict vaccine efficacy

Supervisors:
Prof Margaret Hosie, Institute of Infection, Immunity and Inflammation
Prof Brian Willett, Institute of Infection, Immunity and Inflammation

PhD project summary:
The student will measure serological responses to diverse morbilliviruses with a highly sensitive and specific pseudotype-based neutralisation assay. Firstly, broadly cross neutralising sera will be tested for neutralisation against Turkish PPRV pseudotypes and titres will be compared against those measured against the PPRV vaccine strain Nigeria 75 on cells expressing the dog SLAM receptor. Secondly, sera with high neutralising antibody titres against wild-type PPRV (Nigeria 75 and/or Turkish PPRV) will be tested for the ability to neutralise PPRV-R191P, a mutated virus that displays a switch in receptor usage so that it utilises the human receptor molecule for infection. Finally, sera from humans vaccinated against measles will be tested for the cross neutralisation of PPRV-R191P on cells expressing human SLAM.


Molecular Epidemiology and Virulence Characteristics of Streptococcus pyogenes in Scotland

Supervisors:
Dr Katarina Oravcova, Institute of Biodiversity, Animal Health and Comparative Medicine
Dr Andrew Smith, MVLS/Dental School & Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory (SHLMPRL)
Prof Ruth N Zadoks, Institute of Biodiversity, Animal Health and Comparative Medicine
Prof J Musser, Center for Molecular & Translational Human Infectious Diseases Research, Houston Methodist, Weill Cornell Medical College

Collaborator: Dr Arlene J Reynolds, Health Protection Scotland

PhD project summary:
Streptococcus pyogenes (Lancefield Group A streptococcus- GAS commonly known as “flesh eating bacteria”) is a human commensal associated with a wide range of infections ranging from sore throats to blood stream poisoning and severe skin and muscle infections. Worldwide invasive GAS (iGAS) are responsible for over 700 million new cases annually with incidence rates in Scotland ranging of 2.8-3.8 per 100,000 and case fatality rate of 15%. The aim of this project is to determine an understanding between the ability of GAS to cause disease, its genomic composition and clinical outcomes in the Scottish population. This project will provide a unique training experience that will balance laboratory work at Glasgow University, clinical microbiology and whole genome sequencing at the NHS Scottish Reference Laboratory at Glasgow Royal Infirmary, interaction with Health Protection Scotland teams to understand links with disease in the population and international (USA) collaboration with Professor J Musser to understand international genomic interactions between GAS and their epidemic spread.


Neurocognition of social versus non-social decision making

Supervisors:
Dr Marios Philiastides, Institute of Neuroscience and Psychology 
Prof Philippe Schyns, Institute of Neuroscience and Psychology 

PhD Project Summary:
Most strategic decisions occur under considerable uncertainty. For example, the decision to undergo a risky surgical operation may use online statistics regarding overall success rates or the advice of a person who has undergone a similar operation. Similarly, deciding on an important investment may depend on the probabilistic nature of the stock market or on the strategy that other traders are adopting during a bargain. Though the source of uncertainty varies across scenarios (social-vs-non-social), long-standing models of choice behaviour predict that the same rules would govern your decision (i.e. regardless of uncertainty source). Here, we will use computational modelling and state-of-the-art brain imaging (EEG & fMRI) to understand the computational and neurobiological principles governing the interplay of social vs. non-social uncertainty during decision-making and their implementation in the human brain. To this end we use theoretical frameworks and advanced statistical data analysis applied to neuroimaging data. Overall this project involves psychophysical studies of human precepts, cognitive neuroimaging studies and statistical analysis, providing training in key skills for systems neurobiology and bioinformatics for working on the frontiers in the neurobiology of decision making.


Novel Therapeutic Targets for the Treatment of Heart Failure

Supervisors:
Prof Christopher Loughrey, Institute of Cardiovascular and Medical Sciences 
Prof Stuart Nicklin, Institute of Cardiovascular and Medical Sciences 

PhD Project Summary:
Research-led improvements in healthcare mean that more people survive a heart attack (myocardial infarction; MI). However, the damaged heart muscle following MI can predispose these patients to develop heart failure (HF) – a debilitating condition in which the heart cannot pump blood as well as it should. We have discovered that shortly after MI the expression of a protein called RUNX1 increases in heart muscle cells. Until now its role in the heart was unknown. Our mice studies demonstrate that reducing the levels of RUNX1 in these cells can prevent hearts becoming dilated and markedly preserves pump function following a MI. Our most recent preclinical studies in mice demonstrate that RUNX1 can be therapeutically targeted to improve the ability of the heart to pump. Furthermore, increased RUNX1 expression is not confined to MI but also occurs in response to multiple HF aetiologies. RUNX1 therefore represents a common target with far-reaching therapeutic potential. This project aims to further our understanding of the mechanisms underlying these discoveries and enable a step-change in translational potential of RUNX1 targeted therapies to prevent progression from MI to HF. You will have the opportunity to work within an interactive team of people who will provide you with all the necessary training in techniques including confocal microscopy, rtPCR, Western blots, Langendorff whole heart perfusion techniques and calcium imaging with the option to learn echocardiography and microsurgery.

 


Precision Oncology Therapeutic Development

Supervisors:
Prof Andrew Biankin, Institute of Cancer Sciences
Dr Susanna Cooke, Institute of Cancer Sciences
Dr David Chang, Institute of Cancer Sciences

PhD project summary:
Pancreatic cancer is the fourth leading cause of cancer related death in Western society, and predicted to become the second within a decade. Few treatments are effective and most succumb within a year of diagnosis with only 5% surviving 5 years. A key goal of our laboratory is to improve outcomes for people with pancreatic cancer by applying molecular phenotyping to enhance our understanding of disease biology, improve detection, and to identify novel therapeutic strategies that can be applied through the Precision-Panc Therapeutic Development Platform (www.precisionpanc.org). The Glasgow Precision Oncology Laboratory (GPOL) leads Precision-Panc and is Headquarters to the International Cancer Genome Consortium (www.icgc.org), leading its new initiative “ARGO” (www.icgcargo.org). GPOL is a fully resourced, cutting edge laboratory of over 20 scientists and clinicians focused on therapeutic development for cancer, particularly pancreatic cancer. It emulates the 3 pillars of Precision-Panc (Discovery, Preclinical, and Clinical Development) through a cutting edge Genomics Lab, with world class preclinical and translational programmes. Opportunities for students exist along the spectrum of therapeutic development from genomics, systems biology, informatics, tumour biology, preclinical therapeutics, translational research in clinical trials including biomarker discovery, clinical trial development.


Realistic models of animal movement and its impact on disease transmission

Supervisors:
Prof Jason Matthiopoulos, Institute of Biodiversity, Animal Health & Comparative Medicine
Dr Katie Hampson, Biodiversity, Animal Health & Comparative Medicine
Prof Dan Haydon, Biodiversity, Animal Health & Comparative Medicine

PhD project summary:
Host movement is integral to the contact process and the dynamics of infectious diseases. Using detailed contact tracing data, this project will quantify the impact of individual level and environmental influences on the movement and biting behavior of rabid dogs. The student will develop statistical models of infected animal movement that will be examined and applied within individual-based models of disease transmission. The process of model fitting will used to quantify individual and environmental heterogeneities that influence infected animal movement and contract. The resulting transmission models will be used for simulating rabies spread and persistence and to evaluate whether heterogeneities can be exploited for more effective disease control. The project is supervised by a team with considerable expertise in statistical approaches for examining animal movement and predicting disease dynamics, and draws from a rich individual-level dataset. Using a movement ecology approach should allow dissection of the underlying behavioral mechanisms that lead to the spread and persistence of disease in different populations, and directly generate guidance to inform control and elimination strategies for canine rabies.


Revealing the role of fibrosis in autoimmunity

Supervisors:
Prof Paul Garside, Institute of Infection, Immunology and Inflammation
Dr Robert Benson, Institute of Infection, Immunology and Inflammation
Prof James Brewer, Institute of Infection, Immunology and Inflammation

PhD project summary:
This project will employ the latest imaging and transcriptomic techniques to define how stromal cell changes in autoimmune and inflammatory disease may modulate the behaviour and function of immune cells to exacerbate pathology. Cellular and molecular approaches defining key time points and interactions will provide potential biomarkers for disease progression as well as targets for generalised and/or tissue specific therapeutic intervention.


Selectivity of red blood cell invasion by human malaria parasites

Supervisors:
Dr Lisa Ranford-Cartwright, Institute of Biodiversity, Animal Health and Comparative Medicine
Prof Matthias Marti, Institute of Infection, Immunity and Inflammation

PhD project summary:
Malaria is a major global public health problem causing over 200 million cases each year. The disease is caused when Plasmodium parasites invade human red blood cells. The most serious form of malaria is caused by Plasmodium falciparum; infections range from mild or symptomless infection to severe disease and death. There is currently no good predictor of disease severity.
Red blood cells in P. falciparum infections are often seen to have more than one parasite present, and the extent of this multiple invasion is correlated with disease severity. Parasites which are highly selective (high selectivity index), and invade only a subset of red blood cells, result in high levels of multiply-invaded cells. Parasites which lack selectivity (low selectivity index) are associated with increased severity of disease. Previous work in our laboratory has identified a region of the parasite genome which controls the selectivity of the parasite for red cells. The region has been narrowed to 19 genes, of which 4 are stronger candidates. This PhD project will examine these genes using genetic modification technology (CRISPR/Cas 9) to alter the parasite genes and characterise any resulting changes in selectivity of invasion. In addition, a population level analysis will be performed to examine the extent of linkage of selectivity to the genes identified.
 


Target Autophagy and Aberrant Mitochondrial Folate Metabolism in Leukaemic Stem Cells

Supervisors:
Dr Vignir Helgason, Institute of Cancer Sciences
Dr Alexei Vazquez, Institute of Cancer Sciences

Summary of PhD project:
Chronic myeloid leukaemia (CML) develops following a specific mutation in a single blood stem cell. Therefore, these cells serve as crucial target for therapeutic intervention. We have shown that patient-derived CML stem cells are not eradicated with currently available drugs. Therefore, drug combination therapy is required to cure CML patients.
Our previous work has illustrated that autophagy (“self-eating”), a recycling process that maintains cell integrity, is an attractive target for CML stem cell eradication. We have also shown that CML stem cells rely on mitochondria metabolism for survival. This is an area of great importance in CML, and other stem cell driven cancer types where inhibition of autophagy/metabolism might also improve therapy. The overall aim of this project is to further understand how leukaemic stem cells use autophagy/mitochondrial metabolism to escape drug treatment and to test a newly developed pre-clinical inhibitors.
Techniques: Isolate normal and CML stem cell populations (FACS), survival assays following in vivo and in vitro drug treatments, measurement of autophagy (immunofluorescence/Western), mitochondria, DNA damage (FACS) and metabolism (Seahorse/mass spectrometry). This innovative project will also provide the student with opportunities to work with basic researchers/clinicians and interact with patients and sponsors through various public engagement and fundraising events.

 


The secret life of malaria parasites – analysis of the early development of Plasmodium parasites inside the mosquito vector

Supervisors:
Dr Katarzyna Modrzynska, Institute of Infection, Immunity & Inflammation
Dr Lisa Ranford-Cartwright, Institute of Biodiversity, Animal Health and Comparative Medicine
Prof Matthias Marti, Institute of Infection, Immunity & Inflammation

PhD project summary:
To pass from one patient to another, the malaria parasite (Plasmodium) needs to be transmitted by a mosquito. The initial stages of this process are the biggest bottleneck of the parasite’s complex life cycle and, in theory, the ideal moment to target the disease. Unfortunately our poor understanding of the parasite biology at this stage and inability to produce a large number of the early transmission forms of the human Plasmodium species, are significant obstacles on the way to developing such treatments. We have previously shown that understanding the transcriptional regulation between the life stages can both supply valuable information regarding parasite biology and potentially open the way to transform one stage into another by manipulating the levels of expression of key transcription factors. We, therefore, propose to combine the expertise of three different parasitology teams from the Glasgow University to 1) systematically analyze the dynamics of transcription regulation within the first 24h of the parasite development inside of the mosquito using the latest next-generation sequencing and bioinformatics tools, 2) identify the key factors regulating it and 3) manipulate their expression levels and study the effect it has on the parasite development.
   


Towards an Atomic Level Description of the DNA Packaging Machinery of the Important Human Pathogen, Herpes Simplex Virus

Supervisors:
Dr David Bhella, Institute of Infection, Immunity & Inflammation
Dr Christopher Boutell, Institute of Infection, Immunity & Inflammation

PhD project summary:
Herpes viruses are a family of highly-infectious viruses causing a range of important diseases and cancers in humans. Herpes Simplex Virus type 1 is the prototype species of the alpha-herpesvirus group that also includes Varicella-Zoster Virus, the cause of Chicken Pox and Shingles. Herpes viruses package their genomes in a complex icosahedral capsid. The capsid assembles first, and the genome is pumped into the shell through a unique structure called the portal. When they infect a new host, the genome is injected into the nucleus of the infected cell through the same assembly. Despite its importance, little is known about the structure or function of the herpes virus portal.

This project will use cryo-electron microscopy (cryoEM) to resolve the structure of the DNA packing machinery (portal). This work has previously proven very challenging because the portal components are asymmetric features in an otherwise highly symmetrical virus capsid. Recently established methods for determining the structures of small asymmetric features will be employed to elucidate the atomic-resolution structure of the portal. Recent investment in the cryoEM facilities at the CVR has led to the establishment of a world-class centre equipped with cutting edge facilities that will support this study.

 


Transcriptional and epigenetic regulation of long-term inflammatory gene expression by lung stromal cells following influenza virus infection

Supervisors:
Dr Megan MacLeod, Institute of Infection, Immunity and Inflammation
Dr Carol Leitch, Institute of Infection, Immunity and Inflammation

PhD project summary:
Lung stromal cells, including epithelial cells and fibroblasts, are known to play important roles in initial responses to local viral infections such as influenza virus. They call in adaptive immune cells that clear the infection and which are through to provide a faster “memory” response to re-infection. Our data suggest, however, that lung epithelial cells and fibroblasts maintain an imprint of the initial infection allowing them to respond more quickly to re-infection. We hypothesize that these altered lung stromal cells collaborate with adaptive immune cells to provide enhanced memory responses. This project will follow on from our current research using a mouse influenza virus infection model. The project will investigate the transcription factors and epigenetic changes responsible for altered gene expression and will probe the heterogeneity of altered lung stromal cells. A range of cutting-edge cellular and molecular techniques will be involved including multiparameter flow cytometry, RNA-scope, microdissection and epigenetic analysis. The project’s overarching aim is to understand how lung stromal cells contribute to altered secondary immune responses. This knowledge will help us understand how pathogens induce long term changes to our bodies and ultimately could help us design more effective vaccines that drive protective stromal cell responses.

 


Transcriptional control of inflammation

Supervisors:
Dr Ruaidhrí Carmody, Institute of Infection, Immunity and Inflammation
Dr Karen Keeshan, Institute of Cancer Sciences

PhD Project Summary:
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/Cas9 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.


Understanding and improving the antiviral response to rabies virus

Supervisors:
Dr Marieke Pingen, Institute of Infection, Immunity & Inflmmation
Dr Sam Wilson, Institute of Infection, Immunity & Inflmmation 
Dr Daniel Streicker, Institute of Biodversity, Animal Health & Comparative Medicine  

PhD project summary:
Rabies kills over 55,000 people yearly and is a large burden on livestock in resource-limited settings. Rabies virus is transmitted by bites from infected animals such as dogs and bats.
After being bitten by a rabid animal, early vaccination can still prevent development of disease. As rabies is most common in rural Africa and Asia, such vaccinations are often too expensive or not available fast enough. However, this tells us there is a short window where spread of the virus from the bite site to the brain can still be stopped. Surprisingly though, we know very little about what is actually happening at the bite site. During this PhD project we will study these very early moments after rabies transmission in mice. We use rabies virus-like particles (rabVLPs) that are designed to infect cells as normal virus would, but cannot spread any further and are thus a safe and versatile alternative to study early events during infection. rabVLPs will be mixed with saliva from bats or dogs to model natural transmission. Using this model, we will study the early virus-host interactions using techniques such as qPCR, microscopy, and flow cytometry and determine whether we can therapeutically target the bite site.


Wolbachia-arbovirus interactions in mosquito cells

Supervisors:
Prof Steven Sinkins, Institute of Infection, Immunity and Inflammation
Prof Alain Kohl, Institute of Infection, Immunity and Inflammation

PhD project summary:
Wolbachia are common maternally inherited bacterial symbionts found in insects. The mosquito Aedes aegypti is naturally Wolbachia-free, while Ae. albopictus carries two Wolbachia co-infecting strains. It has been shown in both species that some artificially introduced Wolbachia strains can completely block or strongly inhibit the transmission of arboviruses and several other pathogens. Wolbachia also induce cytoplasmic incompatibility (CI), a crossing sterility mechanism that allows it to rapidly invade insect populations. For these reasons Wolbachia are becoming important biocontrol agents for the prevention of transmission of arboviruses by mosquitoes. The mechanisms of viral inhibition remain incompletely understood, however. The studentship project will examine interactions between Wolbachia, mosquito cells and viruses. It will examine promising leads arising from recent proteomic studies, and use molecular biology, cell biology and virology techniques to better understand this important phenotype.

 


Food Security

Projects within this section fall under Food Security research theme:

Dietary Selection of Bacterial Pathotypes Capable of Multi-Site Zoonotic Disease

Supervisors:
Prof Andrew Roe, Institute of Infection, Immunity and Inflmmation
Dr Gillian Douce, Institute of Infection, Immunity and Inflmmation

PhD project summary:
Our lab is focused on how and why different pathotypes of E. coli cause site specific disease. ExPEC strains such as those that cause urinary tract infections often carry a utilisation system (encoded by the dsd genes) that allows the strain to grow on the rare amino acid, D-serine (D-ser), as the sole carbon source. In these strains, D-ser acts as both a carbon source and is considered to act as a positive signal for expression of colonization factors. This capacity to metabolise D-ser is consistent with the presence of up to 1 mM of this amino aicd in the urine of humans. In contrast, InPEC pathotypes associated with hemorrhagic and diarrheal disease rarely metabolise D-ser and cannot grow on it as a sole carbon source.


Functional analysis of Trypanosoma congolense protein kinome

Supervisors:
Prof Mike Barrett, Institute of Infection, Immunity and Inflammation
Dr Tansy Hammarton, Institute of Infection, Immunity and Inflammation

PhD project summary:
Trypanosoma congolense is the main cause of African animal trypanosomiasis (AAT) in sub-Saharan Africa, which severely impacts livestock productivity and agricultural development in ~40 countries. T. congolense has two hosts – the mammal and the tsetse fly, which transmits the parasite during a bloodmeal. T. congolense has been under-studied, and nothing is known about how it replicates in its mammalian host or of the protein kinases that control cell division. Recently, in a related parasite, Trypanosoma brucei, an RNAi kinome (189 kinases) screen identified >40 protein kinases essential for proliferation, and showed that 24 of these potentially regulated the cell cycle (Jones et al 2014). Here, bioinformatics analysis will be used to determine the T. congolense kinome. A CRISPR/Cas9 approach will then be taken to inducibly knock out each kinase in the bloodstream form of T. congolense. Cell lines will be analysed for growth rate, morphology and cell cycle defects (via DAPI staining and immunofluorescence of cytoskeletal structures) to identify essential viability and cell division kinases. Knockout cell lines with no growth phenotype will be further examined for other potential phenotypes e.g. defects in differentiation or attachment to endothelial cells, which is key in pathogenesis. This will provide the first functional analysis of any protein kinase in T. congolense, and will potentially identify novel AAT drug targets urgently required.

Jones, N.G., Thomas, E.B., Brown, E., Dickens, N.J., Hammarton, T.C., and Mottram, J.C. (2014). Regulators of Trypanosoma brucei cell cycle progression and differentiation identified using a kinome-wide RNAi screen. PLoS Pathog 10, e1003886.

 


Genetic and cellular mechanisms of reproductive mode: laying eggs vs pregnancy

Supervisors:
Dr Kathryn R Elmer, Institute of Biodiversity, Animal Health & Comparative
Prof Maureen Bain, Institute of Biodiversity, Animal Health & Comparative
Dr Mark McLaughlin, School of Veterinary Medicine

PhD project summary:
Laying eggs or having live birth is one of the most fundamental biological traits and is usually genetically fixed over long evolutionary times. The biological pathways of reproduction are deeply homologous across amniotes yet because of this evolutionary distance between different modes – for example birds vs therian mammals – the genetic mechanisms that define and determine reproductive mode are not known. This research will leverage a powerful new model for reproductive mode evolutionary genetics: the reproductively bimodal common lizard. Previous work has demonstrated key candidate genes for traits such as eggshell composition and gestation duration within the mother. These valuable new candidate genes now require experimental validation to determine their effects at molecular, cellular, and organismal levels.

This project will leverage in vivo and in vitro models to determine the functional genetics and cellular activity of egg-laying vs live-bearing in key reproductive tissues; validate candidate genes experimentally; and reconstruct the evolutionary history of alternative reproductive mode genes across biological scales.

The student will gain a wealth of translatable skills in state of the art biomedical sciences. This includes tissue culture, molecular biology of gene expression, protein dynamics, visualization of molecular activity in cells, genome-editing with CRISPR-Cas, and evolutionary genetic reconstructions. A wealth of material is already in hand but there will be additional opportunity for field research to collect new samples. The student will join an active and well-resourced research team working on contemporary questions in the rapid convergent evolution of complex adaptive traits.
  


Genome-Encoded Barriers that Prevent Viral Emergence

Supervisors:
Prof Massimo Palmarini, Institute of Infection, Immunity and Inflammation 
Dr Sam Wilson, Institute of Infection, Immunity and Inflammation 
Dr Dalan Bailey, The Pirbright Institute 

PhD Project Summary:
The most effective way to remove disease burden is to eradicate the pathogen entirely. To date, targeted vaccine strategies have eradicated two viral pathogens (smallpox and rinderpest). It is hoped that in the 21st century more viruses will be eradicated and strategic eradication of polio and measles is already underway.

Rinderpest and measles are both morbilliviruses and because vaccination/infection with one morbillivirus can induce immunity to multiple morbilliviruses (so called crossprotection), many have hypothesized that eliminating one morbillivirus creates a ‘vacant niche’ that could promote the cross-species transmission and emergence of morbilliviruses in novel species.

Only minor changes (sometimes single amino acid substitutions) in morbillivirus glycoproteins are required to infect the cells of a new species. Thus, there is an urgent need to understand the factors that block the cross-species transmission of these pathogens.

The student will use libraries of interferon stimulated genes from a variety of species (humans, rhesus macaques and cows) to screen fluorescently-labeled viruses and identify host genome-encoded defences that block morbilliviruses. Once identified, the student will use a variety of molecular virology techniques to unravel how these defences work and illuminate the role these defences might play in constraining cross species transmission.


Genomic Surveillance for the Elimination of Dog-Mediated Rabies

Supervisors:
Dr Katie Hampson, Institute of Biodiversity, Animal Health & Comparative Medicine
Prof David L Robertson, Institute of Infection, Immunity and Inflammation
Dr Roman Biek, Institute of Biodiversity, Animal Health & Comparative Medicine

PhD project summary:
Rabies kills thousands of people around the world every year but a global target has now been set to eliminate human deaths from dog-mediated rabies by 2030 and large-scale mass dog vaccination programmes are being undertaken around the world working towards this aim. Extensive genomics and bioinformatics research has generated valuable insights into the diversity, emergence and spread of rabies viruses. Building on this background, this PhD will investigate how genomic data can be incorporated into surveillance to inform rabies elimination programmes. Field and laboratory approaches will be investigated for improving the quality and reducing the cost of whole genome sequencing of rabies viruses. These approaches will be applied across settings in sub-Saharan Africa and Southeast Asia through an extended collaborative network to improve the geographic coverage of rabies sequences. Circulating viral diversity will be quantified and the distribution of viruses characterized, to identify gaps where improved surveillance would be valuable and to measure the progress made towards rabies elimination. The project will focus on developing tools to support the endgame including variant discrimination, revealing undetected transmission, identifying sources of incursions and visualizing and communicating insights from genomic surveillance to policymakers, practitioners and the general public to inform control.


Innovative ubiquitous radio frequency sensing to improve the welfare of farm animals

Supervisors:
Prof Nicholas Jonsson, Institute of Biodiversity, Animal Health and Comparative Medicine
Dr Francesco Fioranelli, School of Engineering

Dr Lorenzo Viora, Institute of Biodiversity, Animal Health and Comparative Medicine 

Dr Qammer Abbasi,  School of Engineering

PhD project summary:
Lameness is a very significant problem for farmed animals and performance horses and is usually detected by animal-care workers – stable hands, farmers, veterinarians. This requires regular direct observation, but not all livestock can be examined by a skilled person every day. Sheep on hill farms provide a particular challenge in this respect. Livestock are increasingly required to be tagged individually with radio-frequency identification (RFID) tags. All sheep in the UK must be tagged by law and it is expected that all cattle will be similarly tagged in the near future. Robotic devices for managing livestock have been developed to exploit RFID and enable automation of basic procedures including weighing and drafting (separating groups of animals for specific management treatments). These devices could house systems for the detection of lameness. RF sensor methods such as the micro-Doppler radar system that we have prototyped offer cost and operational advantages over systems based on accelerometers or gyroscopes, in which each animal must be fitted with its own sensor. This project will develop an effective micro-Doppler radar system for lameness detection in sheep, cattle and horses. The project will involve the examination of animals and classification of their locomotion as normal or abnormal, applying appropriate machine-learning methods of analysis.

 


Leveraging pathogen genomics and phylodynamics to control endemic anthrax

Supervisors:
Dr Roman Biek, Institute of Biodiversity, Animal Health & Comparative Medicine
Dr Taya Forde, Institute of Biodiversity, Animal Health & Comparative Medicine
Dr Tiziana Lembo, Institute of Biodiversity, Animal Health & Comparative Medicine

PhD project summary:
Anthrax is a neglected zoonotic disease that causes major yet underrecognised impacts on the health and livelihoods of rural farmers throughout the world, particularly in sub-Saharan Africa. Livestock vaccination is a key tool for anthrax control, and has great potential for reducing the disease burden. This project aims to create the necessary framework for guiding anthrax control programmes in endemic settings through the use of pathogen genomics and phylodynamic modelling.

This project builds on robust partnerships and research platforms established in northern Tanzania by the Glasgow supervisors, as well as existing whole genome sequence data. The DTP student will extend current analytical tools and molecular clock models to accommodate the alternation between long periods of environmental persistence punctuated by rapid replication typical for Bacillus anthracis, the causal agent. They will also develop a simulation model combining genomic, spatial, temporal and epidemiological information to examine the effect of vaccination on B. anthracis genetic diversity and transmission in silico. Finally, there will be opportunities to validate this model by generating genomic data obtained during government-driven livestock vaccination programs.

Applicants should have an interest in developing computational skills, in infectious disease genomics, and in practical issues around disease control in natural systems.


Molecular dynamics of ion channel control by a vesicle trafficking protein

Supervisors:
Prof Michael Blatt, Molecular, Cell and Systems Biology, University of Glasgow
Dr Eirini Kaiserli, Molecular, Cell and Systems Biology, University of Glasgow

PhD Project Summary:
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 of 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.


Molecular epidemiology of Coxiella burnetii

Supervisors:
Dr Jo Halliday, Institute of Biodiversity Animal Health and Comparative Medicine
Dr Kathryn Allan, School of Veterinary Medicine
Dr Nick Wheelhouse, School of Applied Sciences, Edinburgh Napier University

PhD project summary:
Coxiella burnetii is a globally important zoonosis that causes febrile disease in people and significant production losses in economically crucial livestock species including cattle, sheep and goats.  Despite its importance as a leading cause of human and livestock disease, awareness of C. burnetii is low in many regions and key gaps in our knowledge persist about multiple facets of the epidemiology, impacts and scope for control of C. burnetii.  This project focuses on the application of genotyping schemes and integration of molecular data with serological and epidemiological data from human and animal populations to advance our understanding of the epidemiology of C. burnetii in Tanzania. The project aims to adapt and apply multiple genotyping approaches to characterise the diversity of C. burnetii genotypes in human and animal populations; to determine the relationship between genotypes and clinical impact in people and livestock; to use epidemiological, serological and genetic data to infer key transmission processes and to evaluate the potential effectiveness of livestock-targeted interventions such as vaccination to reduce the burden of human and animal disease.
 


Novel screening platforms for insect GPCRs

Supervisors
Prof Shireen Davies, Molecular, Cell and Systems Biology
Prof Graeme Milligan, Molecular, Cell and Systems Biology

PhD Project Summary
In insects, hormonal neuropeptides regulate many aspects of physiology, behaviour, development, and environmental stress tolerance by binding to cognate receptors (GPCRs) and eliciting changes in cellular chemistry and physiological output. GPCRs may thus provide novel targets for development of pest insect control strategies, so identification of ligands using a novel screening system for the first time in insects is an exciting prospect. The project will develop such novel screening techniques using Bioluminescence resonance energy transfer (BRET). BRET is used to study protein-protein interactions, and also for detection of drug concentrations using fluorescent sensors. BRET can now be used to assess ligand binding to mammalian GPCRs (Stoddart et al., Nature Methods, 12, 7, 661; and Hudson et al., in prep). The project will employ a multidisciplinary approach to (a) construct and express fluorescent GPCRs for insect neuropeptides (b) develop the first high throughput ligand screening assays for insect GPCRs and (c) screen for novel ligands which can modulate insect physiology and/or environmental stress responses.


Proteome-level diversity in RNA viruses

Supervisors:
Dr Edward Hutchison, Institute of Infection, Immunity and Inflammation
Dr Richard Burchmore, Institute of Infection, Immunity and Inflammation

PhD project summary:
RNA viruses are major threats to human and animal health and account for the majority of emerging infectious diseases. This is in large part due to the highly error-prone polymerases which replicate RNA virus genomes, resulting in rapid evolution. The same error-prone polymerases will also mutate mRNA, affecting viral gene transcription. However, the diversity of protein products that result, and how these could affect infection and immunity, is unclear.

This project will consider influenza viruses, a genus which includes both endemic and emerging threats to human and animal health. The student will develop novel data analysis tools to identify signatures of mutation and variant post-translational modification in viral proteins, using mass spectra collected from purified viruses by the Hutchinson group. They will generate and compare maps of protein-level diversity and next-generation sequencing maps of the viral genome and transcriptome, in order to identify sites in viral proteins which can tolerate variation and sites which select against it.

The project will provide the first indication of how the high levels of mutation in the genome of any virus actually relate to protein polymorphisms. In doing so it may provide a wider insight into the effects of the lower but non-negligible error rates of cellular transcription mechanisms. By mapping sites of viral protein conservation and plasticity it will expand our understanding of targets for the immune response, including by ‘universal’ vaccines, and provide a rational basis for viral protein engineering.


The discovery of phage-inducible chromosomal islands in Gram-negative bacteria

Supervisors:
Prof Jose R Penades, Institute of Infection, Immunity and Inflammation
Dr Pablo R Murcia, Institute of Infection, Immunity and Inflammation

PhD project summary:
The development of novel multiresistant hypervirulent strains from formerly avirulent or only weakly virulent strains is dramatically fuelled by the acquisition of mobile genetic elements (MGEs) carrying virulence factors. In spite of its relevance, the mechanisms underlying gene transfer among bacteria remain, in most cases, unidentified. We have recently discovered and extensively characterised a family of pathogenicity islands in Gram-positive cocci, the phage-inducible chromosomal islands (PICIs), which contribute substantively to horizontal gene transfer, host adaptation and virulence. We now propose that similar elements also occur widely in Gram-negative bacteria. As with the PICIs from Gram-positive cocci, their uniqueness is defined by a constellation of features: unique and specific attachment sites, exclusive PICI genes, a phage-dependent mechanism of induction, conserved replication origin organisation, convergent mechanisms of phage interference, and specific packaging of PICI DNA into phage-like infectious particles, resulting in very high transfer frequencies. Overall, these findings represent the discovery of a universal class of mobile genetic elements, which have had a broad impact on lateral gene transfer in the bacterial world. In this project we will extend the relevance of the PICIs by characterising their presence in Gram-negative bacteria. By achieving this objective we will establish new paradigms involving pathogenicity islands in bacterial evolution and virulence, and will provide strategies to block pathogenicity island dissemination and the emergence of novel bacterial virulent clones.


The role of nuclear hubs in regulating plant development

Supervisors:
Dr Eirini Kaiserli, Institute of Molecular Cells and Systems Biology
Prof John Christie, Institute of Molecular Cells and Systems Biology

PhD project summary:
Light is essential for plant growth, development and photoprotection. Plants have evolved sophisticated photoreceptor systems to sense light quality, quantity, duration and direction as a means of optimizing light capture and adaptation. Light triggers major transcriptional re-programming events with over 60% of genes regulated. The majority of plant photoreceptors act in the nucleus, where they interact with downstream signaling components and transcription factors to regulate gene expression and shape plant development. This project aims to investigate the formation, dynamics, content and function of light-induced subnuclear protein complexes that act as integrating hubs regulating gene expression and plant development.


World Class Underpinning Bioscience

Projects within this section fall under World Class Underpinning Bioscience research theme:

Arrival of the fittest: examining the underlying mechanisms of morphological plasticity in an adaptive radiation

Supervisors:
Dr Kevin Parsons, Institute of Biodiversity, Animal Health and Comparative Medicine
Prof Matthew Dalby, Institute of Molecular, Cell, and Systems Biology

PhD project summary:
Phenotypic plasticity has become a central topic in evolutionary biology which is studied for its role in generating adaptive variation. Yet, despite a rapidly growing interest there is still little known about the underlying mechanisms of plasticity. This project will focus on uncovering some of these mechanisms using adaptive radiation in African cichlids. Cichlids are an exemplar system for evolution because they are derived from a recent common ancestor but exhibit vast amounts of adaptive skeletal variation controlled by few mutations on a common genetic background. We have previously uncovered candidate ‘plasticity genes’ that act within the craniofacial region. These genes have been implicated in bone development but also as potential role players in alternative mechanisms for mechanosensory function. The student would take these results forward  to develop a project with a series of exciting investigations in the lab and field aimed at understanding the molecular and cellular mechanisms involved in plasticity. Students with an interest in evolutionary biology, molecular biology, or developmental biology are encouraged to apply.

 


BH3 profiling of acute myeloid leukaemia to develop a biomarker assay that can predict response to BH3 mimetics

Supervisors:
Dr Karen Keeshan, Institute of Cancer Sciences
Prof Mhairi Copland, Institute of Cancer Sciences

PhD project summary:
Acute Myeloid Leukaemia (AML) is a common blood disease that has seen a 30% increase in incidence rates since the early 1990s and 70% of patients diagnosed with the disease still die from this disorder. The current overall 5-year survival rate falls progressively with age to 5% in those aged over 65 years and highlights the critical need for improved therapies. The current standard treatment for AML dates back to the 1970s. In the past two years we have seen new therapies emerge with potential for improving AML standard of care, but because AML is such a complex disease, the use of these therapies is often limited to specific subgroups of patients. We will test a new class of drugs called “BH3 mimetics” across the different subgroups of AML to develop a test that will allow us to predict which patients are likely to benefit (or not) from these new drugs.


Characterisation of cell fate decisions that are critical for skeletal health

Supervisors:
Prof Carl Goodyear, Institute of Infection, Immunity & Inflammation
Prof Iain McInnes, Institute of Infection, Immunity & Inflammation

PhD project summary:
In health, to maintain skeletal integrity the balance between osteoclasts and osteoblasts is a dynamic process, which is under tight regulation. Osteoclasts are derived from the haemopoietic stem cell lineage, and in diseases such as rheumatoid arthritis or multiple myeloma, regulation is uncontrolled, and increased numbers of osteoclasts can lead to overt bone loss. This project will focus on the investigation of a newly identified osteoclast pre-cursor. The overall objective will therefore be to understand how this new osteoclast pre-cursor contributes to skeletal health and disease pathology. This will require the characterisation of this pre-cursor and related pre-cursors, to see how they interact and how they contribute to disease pathology i.e., osteolytic lesions. We anticipate that the results obtained by the student will reveal transcriptional signatures that can be used to identify the source of osteoclasts in lytic lesions and uncover new pathways that can use to therapeutically target specific osteoclast subpopulations. In summation, this project will provide essential information on a crucial aspect of disease pathology associated with a number of inflammatory-mediated and neoplastic diseases, and help in the development of innovative drugs.


Clinical, genetic, and environmental factors associated with cardiac outcomes within families affected by hypertrophic cardiomyopathy

Supervisors:
Prof Alex McConnachie, Institute of Health and Wellbeing
Dr Caroline Coats, Institute of Cardiovascular and Medical Sciences
Dr Robin Young, Institute of Health and Wellbeing 
Prof John Cleland, Institute of Health and Wellbeing

PhD project summary:
Hypertrophic cardiomyopathy (HCM) is a genetic disease that causes the muscle wall of the heart to become abnormally thick, which may lead to heart failure or sudden death. Family screening and genetic testing offer the possibility of early diagnosis and treatment to prevent sudden death, but it is difficult to predict. Accurately selecting those afflicted who do (or do not) need treatments that can have major adverse consequences and may be expensive, remains problematic. Genetic tests are offered to relatives when one member of the family is diagnosed with the condition. However, there are big gaps in our knowledge about how often gene carriers will develop HCM, at what time in life, and the associated risk of sudden death. The West of Scotland hypertrophic cardiomyopathy cohort will provide the data for this research. Routinely collected health data will be combined with genetic information to look at the natural history of the disease using a family study design. The project aim is to develop tools that improve decision making (e.g.:- lifestyle, medicines, need for an implanted device, genetic testing of offspring) for patients with HCM and their relatives. This project will help clinicians to communicate information about prognosis and risk to patients. The student will learn about genetics and statistics and their role in managing inherited heart disease.


Determinants of vector tropism of an emerging haemorrhagic fever virus

Supervisors:
Dr Benjamin Brennan, Institute of Infection, Immunity and Inflammation
Prof Alain Kohl, Institute of Infection, Immunity and Inflammation

PhD project summary:
In recent years several new viruses have been isolated from ticks that are capable of causing severe disease in man. One such virus, named SFTS phlebovirus (SFTSV) has caused disease and death in over 8000 individuals from in China, South Korea and Japan. Following extensive environmental testing, viral RNA was only isolated from a handful of tick species, despite high numbers of mosquitoes in endemic areas feeding off of the same infected hosts.  This goal of this project is two-fold: one to understand the molecular mechanisms behind this observation and determine how this virus is vectored by ticks. Secondly, to examine the role of the virally-encoded proteins in the virus lifecycle within the arthropod cell. The answers to these important questions will help us predict the potential for these medically important arboviruses to switch vectors and change the global distribution of SFTS disease.


Development of a novel MRI based metabolic Imaging method

Supervisors:
Dr William Holmes, Institute of Neuroscience and Psychology and Dr Rosario Lopez Gonzalez, Institute of Neuroscience and Psychology

PhD Project Summary:
Metabolism is vital to life, abnormalities in metabolism are important indicators in several medical conditions, for example cancers are characterized by hyper-metabolism and stroke hypo-metabolism. Currently, the only clinical option for the non-invasive imaging of metabolism is Positron Emission Tomography (PET)1. The major disadvantage of PET is the expense, both in terms of capital equipment and running costs, which severely limits its application and geographic availability. We believe an MRI based approach to imaging metabolism would have the advantages of lower costs, use of non-ionising radiation and a much wider NHS availability (>350 NHS MRI scanners). We hypothesise MRI metabolic imaging, based on 17O2 gas delivered via intravenous injection, can be a viable alternative. This research and development will take place at on the 7Tesla MRI systems at the Glasgow Experimental MRI Centre and will be validated in various pre-clinical in-vivo models of disease. This proposal comes under MRC theme “Biomedical Imaging”, working at the junction of MRI physics and in-vivo biomedical research.


Development of gene and molecular therapies for X-linked neurodevelopmental disorders

Supervisors:
Dr Mark Bailey, School of Life Sciences
Dr Stuart Cobb, University of Edinburgh

PhD project summary:
A number of severe neurological disorders exist that mainly affect females and result from mutations in X-linked genes, such as Rett syndrome (RTT; MECP2), CDKL5 disorder and DDX3X disorder. Disruption in these genes result in a variety of molecular and cellular phenotype, often involving altered gene regulation on a large scale, leading to altered synaptic signalling and neuronal network activity in the brain. Most patients with these disorders show mosaic expression of the mutant allele meaning that half of the cells in the brain are faulty and half of the cells function normally. We have shown previously that reactivation of a silenced MECP2 gene in mice modelling Rett syndrome can reverse established Rett-like symptoms, and we have had considerable success in applying gene therapy approaches to fix the RTT phenotype in pre-clinical models. In the current project we aim to develop novel gene-based therapies that can replace dysfunctional MECP2, CDKL5 and DDX3X in the brain to treat their respective neurological phenotypes. The approach is to develop molecular agents that efficiently deliver a functional copy of the respective gene to the brain (gene transfer) as well as agents that can correct or by-pass disease causing mutations. A major goal of the work is to develop effective therapeutic agents that can restore function to cells previously deficient in MeCP2/CDKL5/DDX3X without disrupting function in cells expressing the wild-type copy of the gene. It is hoped that the technologies developed will be applicable to other genetic brain disorders characterised by intellectual disability.


Diarrhoeal dilemma: understanding the contribution of the S layer in Clostridium difficile disease severity

Supervisors:
Dr Gillian Douce, Institute of Infection, Immunity and Inflammation 
Prof Andrew Roe, Institute of Infection, Immunity and Inflammation

PhD project summary:
Clostridium difficile is the most frequent cause of hospital acquired diarrhoeal disease globally. This highly antibiotic resistant pathogen relies on antibiotic-mediated disruption of the gut microbiota in order to cause disease. Consequently, we urgently need new species-specific antimicrobials that kill C. difficile that do not further disrupt the gut microbiota.

One target for drug therapy is the crystalline protein surface layer (S-layer) that coats the organism’s surface.  This structure is believed to mediate contact between the bacterium and its host, activating inflammation.  We now have the tools necessary to study variants of this critical surface structure and to establish the contribution made to host cell signalling and disease severity.  Recent work suggests the S layer may contribute to disease severity through enhancement of Toxin A and Toxin B activity.  The aim of this project is to investigate this link and identify the host cell signalling pathways that re involved in this process.

This project will form part of a larger ongoing collaborative project with the University of Sheffield and Newcastle.
 


Drug treatment failure in Leishmania?

Supervisors:
Dr Richard Burchmore, Institute of Infection, Immunity & Inflammation; Dr Richard McCulloch, Institute of Infection, Immunity & Inflammation; and Prof Michael Barrett, Institute of Infection, Immunity & Inflammation

PhD Project Summary:
Leishmania are obligate intracellular protozoan parasites that are transmitted by sand flies. They cause a spectrum of diseases ranging from the self-healing cutaneous to the visceral form, the latter being the most severe and fatal if left untreated. 350 million people are at risk from Leishmaniasis disease, which is second to malaria in worldwide human parasite fatalities. No vaccines exist and current chemotherapy is toxic, difficult to administer and is becoming less effective. Whether reduced drug effectiveness is due to resistance or relapse is little understood, though there are reports that parasites isolated from relapse patients are still susceptible to the previously administered drug. For bacteria and Plasmodium, differences in the replication rate of parasite subsets within the population have been reported. In addition, drugs affect these subsets differently. Recent reports have shown such replication dynamics also exist in vitro in intracellular L. donovani. The project proposed here aims to unravel the in vivo replication dynamics of Leishmania, asking if fast replicating, slow replicating and quiescent populations exist in vivo. These dynamics will be compared between a visceralising and a cutaneous Leishmania spp. Isolation of the different replicating subsets will enable their comparison at the transcriptomic and proteomic level, identifying molecular differences between the subsets and species. This accumulated data will then be used to investigate whether the different replication dynamics contribute to treatment failure.


Establishing a therapy-responsive FOXO1 gene signature in chronic lymphocytic leukaemia

Supervisors:
Dr Alison M. Michie, Institute of Cancer Sciences
Dr Xu Huang, Institute of Cancer Sciences
Dr Michael T. Leach, School of Medicine, Dentistry and Nursing

PhD project summary:
Chronic lymphocytic leukaemia (CLL) is the most common blood cancer in the UK, with ~3,500 new UK diagnoses/year, and remains incurable. Although the majority of patients initially respond to current treatments, all eventually relapse due to re-emergence of leukaemic cells that escaped treatment. There is a critical need to establish biomarkers that enable discrimination between treatment-responsive and non-responsive CLL patients. CLL cells interact with the lymphoid organ microenvironment, which provides survival and growth prompts to the leukaemic cells, resulting in disease progression. Healthy cells have checkpoints that prevent over-expansion of cells, however these checkpoints are disrupted in cancer cells. Forkhead box, class O (FOXO) proteins can behave as molecular brakes in cells, regulating processes responsible for cell cycle arrest and promoting apoptosis. We show that FOXOs are inactivated in CLL cells through interaction with the tumour microenvironment, resulting in a reduction of the FOXO-mediated transcription programme. Furthermore, drug treatment can re-activate FOXO and induce CLL cell death. We hypothesise that CLL cells isolated from treatment-responsive patients will display active FOXO-mediated biomarkers, which will be lost in patients exhibiting resistance to treatment. Taking an ‘omics’ approach, we aim to elucidate the biomarker signature that accompanies FOXO activation thus providing an important clinical tool to enable clinicians to follow patient responsiveness to treatment, and generate a research tool for identifying novel treatments that target CLL cells, thus assisting in the generation of new treatments for CLL patients.


Exploring the role secondary senescence for cancer and ageing

Supervisors:
Dr Kristina Kirschner, Institute of Cardivascular and Medical Sciences
Dr Thomas Otto, Institute of Infection, Immunity and Inflammation
Prof Owen Sansom, Institute of Cancer Sciences

PhD project summary:
We recently identified Notch mediated cell-to-cell communication as a major, alternative pathway to secondary senescence induction, with implication in cancer and ageing. Senescence is a tumour suppressor response where cells secrete cytokines, mediating clearance by immune cells and propagating secondary senescence to neighboring cells (paracrine senescence). Uncleared senescent cells create a pro-inflammatory, pro-tumorigenic environment and their accumulation during ageing leads to organ dysfunction. Interplay between primary and secondary senescence are poorly understood. We recently identified Notch mediated cell-to-cell as a major, alternative pathway to secondary senescence induction. We hypothesise that Notch-mediated secondary senescence is a major driver of pathological mechanisms in cancer and

ageing. If we better understand the mechanisms behind Notch-mediated senescence, we could exploit these findings to improve therapies aimed at rejuvenation or improved clearance of residual tumour cells after treatment.
Therefore this PhD will aim:

1. Using single cell RNA-Seq to Identify triggers for Notch secondary senescence in vitro and in vivo
2. Using in vitro systems and in vivo mouse models to perform senolytics screens to test the difference / similarities between primary and secondary senescence in terms of response to drug targeting
3. Follow up positive hits in human samples.

This study will have an impact on cancer patients and individuals with age- associated disease (e.g. dementia) as we will address the importance of Notch mediated secondary senescence (a pathway we recently discovered), providing mechanistic insights into elimination of subsets of senescent cells for healthy ageing and improved cancer therapy.

 


Integrated analyses of metabolomic-epigenomic axes for stratified medicine in myeloid leukaemia.

Supervisors:
Prof David Vetrie, Institute of Cancer Sciences
Dr Vignir Helgason, Institute of Cancer Sciences
Dr Oliver Maddocks, Institute of Cancer Sciences

PhD project summary:
In chronic myeloid leukaemia (CML) the disease is initiated and driven by leukaemic stem cell (LSCs). Current therapies do not target the LSC, therefore novel approaches must be developed to eradicate them and cure the disease. One key area with immense therapeutic potential is the relationship between metabolism and methylation/demethylation of DNA, RNA and histones - as intermediates of cellular metabolism are substrates or co-factors for the requisite epigenetic modifiers. In CML, the Vetrie and Helgason laboratories have recently demonstrated that LSCs have dependencies on the histone mark H3K27me3 and oxidative mitochondrial metabolism and we hypothesize that these and other metabolic-epigenomic dependencies are linked in CML LSC. First, we will use a combination of the state-of-the-art metabolic and epigenetic approaches to understand metabolomics-epigenetic relationships globally in CML cell lines and primary patient material that have been drug-treated, starved of amino acids or genetically engineered using CRISPR-Cas9 gene editing technology. Candidate genes predicted to mediate these relationships will be further evaluated in CML mouse models by gene editing. By discovering novel metabolic-epigenetic dependencies and computationally comparing them with publically-available CML ‘omics’ datasets, completely novel mechanisms of leukaemic transformation will be revealed. We will harness this knowledge to identify and explore new therapeutic targets for LSC eradication.

 


Investigation of plasticity of cortical networks after nerve injury using laminar fMRI

Supervisors:
Dr Jozien Goense, Institute of Neuroscience and Psychology; Dr John Riddell, Institute of Neuroscience and Psychology; and Prof Andrew Hart, NHS GGC Plastics and Institute of Molecular Cell and systems Biology

Project Summary:
Peripheral nerve injuries are common and intensely painful. Complex microsurgical reconstruction helps, but recovery is slow (1–5 years) and very incomplete. Major injuries (e.g. brachial plexus injuries, at birth or after road traffic accidents) can be as devastating as spinal cord injury. Almost nothing is known about how the brain adapts after these injuries and nerve repair, but a better understanding of this could facilitate new treatments. Ultra-high-resolution laminar fMRI (a very new technique that will be further developed in this project) lets scientists see individual layers of the cerebral cortex, and will be developed to understand cortical reorganization after nerve injury, with the aims of reducing pain and improving recovery of sensorimotor function. The first steps are to refine and validate the methods in rats after controlled nerve and spinal cord injuries, and follow brain reorganization as nerves regrow and function returns. Subsequently, we will use laminar fMRI and functional connectivity measures in rats and humans to follow how the brain circuits change after peripheral nerve injury. Understanding how cortical reorganization occurs in animal models, in parallel to studies in humans after peripheral nerve injury, can be used to help patients with various injuries to the peripheral and central nervous system.


Investigating the role of RNA Polymerase III in metabolic health

Supervisors:
Prof Colin Selman, Institute of Biodiversity, Animal Health and Comparative Medicine
Prof James Leiper, Institute of Cariovascular and Medical Sciences
Prof John Speakman, University of Aberdeen

PhD Project Summary:
RNA polymerase III (Pol III) is one of three eukaryotic, nuclear RNA polymerases that generates short, non-coding RNA, including the transfer RNAs (tRNAs) and the 5S ribosomal RNA (rRNA). Pol III plays a pivotal role in protein synthesis and ribosomal biogenesis, and excitingly it has been shown that Pol III plays an evolutionary conserved role in organismal longevity; partial inhibition of Pol III extends lifespan in yeast, C. elegans and Drosophila. We are currently extending these studies to determine the role of Pol III in mammalian longevity.

Protein synthesis accounts for a high proportion of the metabolic costs of an organism at rest. Given the central role of Pol III in protein synthesis, we predict that modulating Pol III is likely to have major implications to the metabolic phenotype of mice (e.g. mitochondrial function, ROS production, lipolysis), that is likely to be exacerbated during the ageing process. This project will combine whole-animal metabolic approaches, alongside primary cell culture, mitochondrial functional analysis, ribosomal profiling and general molecular biology approaches to better understand the role of Pol III in age-associated metabolic health

 


Mass spectrometry imaging of the gut-brain axis to find novel microbiome metabolites that cross the blood brain barrier

Supervisors:
Dr Donal Wall, Institute of Infection, Immunity & Inflammation
Dr Richard Burchmore, Institute of Infection, Immunity & Inflammation

PhD Project Summary:
The microbiome is now understood to hold the key to many diseases previously thought not to have a microbial input. Determining the impact of the microbiome in these diseases and harnessing this knowledge may offer new intervention strategies across a variety of diseases.

Using mass spectrometry imaging (MSI) we have for the first time mapped the gut-brain axis in a mouse model, determining the presence and distribution of both neurotransmitters and novel, potentially microbiome-derived, molecules alike. MSI is a unique technique that works independently of tagging and allows the building of 2D and 3D maps of tissue sections. Using this data, and through training at state of the art MSI facilities at AstraZeneca in Cambridge, this PhD seeks to exploit the molecular information contained within this dataset to identify novel microbiome derived compounds that cross the blood brain barrier. These compounds will then have their structures solved and where possible through further analysis, have a function ascribed to them. As a proof of principle one such microbiome derived compound is already identified and its functionality currently being tested. This interdisciplinary PhD will provide training in MSI, microbiology and cell biology techniques.


Mitochondrial protein export and dynamics underpinning cellular protein quality control in aging and neurodegeneration

Supervisors:
Prof Kostas Tokatlidis, Institute of Molecular Cells and Systems Biology
Prof Richard Hartley, Chemistry
Prof Neil Bulleid, Institute of Molecular Cells and Systems Biology
Prof Stephen Tait, Institute of Cancer Sciences

PhD project summary:
Maintenance of functional mitochondria is essential for life and an important therapeutic target in several diseases. Mitochondria biogenesis and function relies on accurate protein import mechanisms to the organelle that have discovered and studied in detail. On the other hand, misfolding of mitochondrial proteins and aggregation poses a threat to cell homeostasis. We have discovered that maintaining the redox state in the intermembrane space of mitochondria requires a protein machinery that is crucial for mitochondrial dynamics and for the capacity of mitochondria to export misfolded proteins for degradation in the cytosol. In this project we will study this novel mechanism of mitochondrial unfolded protein response which functions as a mitochondria-localised quality control mechanism. We will use an interdisciplinary approach combining biochemical, cell biology and chemical biology approaches to develop new knowledge. This mechanism has important ramifications in the maintenance of a healthy protein balance in the cell and the cell’s response to stress, particularly in age-related diseases.


Modelling kidney disease in Drosophila

Supervisors:
Prof Julian Dow, Molecular, Cell and Systems Biology, University of Glasgow
Prof Shireen Davies, Molecular, Cell and Systems Biology, University of Glasgow

PhD Project Summary:
Kidney stones (nephrolithiasis) are a major cause of pain and morbidity, resulting in 250 000 emergency room admissions annually in the USA alone, and the incidence is increasing. Understanding the causes of, and developing treatments for, this major problem is hindered by the lack of an animal model. In NIH-funded work, we have shown that stone disease is quickly and conveniently modelled in Drosophila melanogaster, so bringing all the powerful genetic tools and technologies of this potent model organism to bear on the problem. The project will investigate the roles of key transport genes in the formation of kidney stones, by identifying candidates from NGS and transcriptomic datasets, generating and validating RNAi transgenics, and imaging renal tubules to look for changes in stone formation. As well as generating a new understanding of the formation and growth of stones, this simple model will allow screens for new therapies to be trialled for the first time, so offering new hope for both prevention and therapy.


Omics based strategies for Precision Medicine in hypertension and cardiovascular disease

Supervisors:
Prof Eleanor Davies, Institute of Cardiovascular and Medical Sciences
Dr Scott Mackenzie, Institute of Cardiovascular and Medical Sciences

PhD project summary:
This project will utilize a systems biology "-omics" approach to improve diagnosis of endocrine forms of hypertension while also investigating the role of microRNAs in the development of these conditions. Up to 15% of hypertension has an endocrine cause resulting from excessive hormone production and leading to a range of co-morbidities that include stroke, heart failure, atrial fibrillation, left ventricular hypertrophy and obesity. While endocrine hypertension is readily treatable, its accurate diagnosis is time-consuming and costly, which delays the administration of appropriate treatment. We are currently part of a large international study tasked with using circulating microRNA profiles to improve diagnosis of endocrine hypertension by analyzing a large cohort of carefully-phenotyped human subjects with endocrine hypertension (www.ensat-ht.eu). MicroRNAs are regulatory non-coding RNAs that are also released by tissues into the bloodstream where they circulate in a stable, cell-free form, and can act as relatively stable and accessible biomarkers for specific disease states. Circulating microRNAs that associate with forms of endocrine hypertension are also likely to provide insights into the underlying pathophysiological mechanisms of these conditions. The identification and investigation of these microRNAs will form the core of this highly important and timely research project.


Palmitoylation and the regulation of the transient outward current Ito

Supervisors:
Dr William Fuller, Institute of Cardiovascular and Medical Sciences
Prof Godfrey Smith, Institute of Cardiovascular and Medical Sciences

PhD project summary:
The ‘transient outward’ current (Ito), phase 1 of the cardiac action potential, transiently repolarizes ventricular myocytes early in the action potential, and is thought to control action potential duration. The main charge carrier for this current is potassium, and the molecular identity of the channel is Kv4.3, also known as KCND3, which forms a voltage sensitive potassium channel. The aim of this investigation is to determine how palmitoylation influences KCND3 trafficking and function, and whether palmitoylation modifies the regulatory effect of the KCND3 regulatory protein KChIP 2.1, which binds to the KCND3 N terminus and is also palmitoylated. We will first identify the KCND3 palmitoylating and depalmitoylating enzymes by gene silencing with siRNAs directed against candidate enzymes and using pharmacological agents. We will determine the function of wild type and palmitoylation deficient KCND3 in transfected HEK cells and myocytes using whole-cell voltage clamp, and the impact of KChIP 2.1 on the function (voltage clamp), oligomerisation (partial fixation) and trafficking (microscopy) of wild type and unpalmitoylatable KCND3. We will also evaluate KCND3 palmitoylation in models of cardiac hypertrophy and failure.


New approaches to diseases of ageing using novel senotherapies

Supervisors:
Prof Paul G Shiels, Institute of Cancer Sciences
Dr Ross Forgan, School of Chemistry

PhD project summary:
The Shiels and Forgan labs have been using a chemical biology approach to direct the ease of functionalisation of metal-organic frameworks (MOFs) to build delivery vehicles for therapeutic agents. MOFs are porous coordination network materials of metal ions linked by organic ligands that have prodigious molecular storage capacities, but often accelerate ageing or are cytotoxic to primary cells. We seek a PhD student to develop MOFs to selectively deliver therapeutics into senescent cells. This exciting collaboration has already been successful in developing bio-compatible MOFs, and we now wish to further study the effect of MOF size and surface chemistry on efficacy. This will encompass the study of lead MOFs and release of therapeutic compounds in primary senescent cells and diseased cell lines. The student will employ real time cell analysis and gene expression analysis for a range of biomarkers of ageing, apoptosis and related ncRNA regulators. Additionally we will test a lead MOF/senotherapeutic combination in an in vivo model of accelerated ageing.


Regulation of ubiquitin signalling in Parkinson’s Disease

Supervisors:
Prof Helen Walden, Institute of Molecular Cell and Systems Biology
Dr Thimo Kurz, Institute of Molecular Cell and Systems Biology

PhD project summary:
Parkinson’s Disease (PD) is the second most common neurodegenerative disorder, with symptoms including loss of motor control, and the progressive loss of dopaminergic neurons. Although PD is primarily a sporadic disorder, there are ~20 genes associated with heritable forms of Parkinsonism.. Several of these genes encode components of the ubiquitin system, required for cell signaling, and proteasomal degradation. One of these is Parkin, an E3 ubiquitin ligase, with hundreds of protein targets. Parkin is a highly regulated enzyme. It exists in an autoinhibited conformation (Chaugule et al., 2011; Kumar et al., 2015), until it is activated at the mitochondria by the kinase PINK1, which modifies both Parkin, and ubiquitin, to activate Parkin (Kumar et al., 2017). However, fewer than 15% of Parkin targets are mitochondrial, and it is not yet understood how other pools of Parkin are activated. This project will be to understand how Parkin is regulated outside of the mitochondria, and how post-translational modifications of Parkin activity, substrate repertoire, and Parkin function. 


Stable perception of external stimuli over time: oculo-motor and visual processing mechanisms

Supervisors:
Dr Alessio Fracasso, Institute of Neuroscience and Psychology
Prof Lars Muckli, Institute of Neuroscience and Psychology 

PhD project summary:
While sitting in a café, we frequently move our eyes from our cup of coffee to look at the book in our hands or to glance at any arriving customers. And despite these continuous disruptions to our visual processing caused by the eye movements, we perceive the visual scene as stable. Moreover, we are still aware of the exact position of the coffee cup with respect to the location of our body. To maintain a stable visual representation of the world in both eye-centered and body-centered coordinates, our brain needs to continuously keep track of the eye position to adjust its activity according to the introduced sensory change. While the problem of visual stability and coordinated transform has been explored extensively in monkey electrophysiology, its understanding in human vision remains limited. The present project will examine the relationship between the oculo-motor and visual system in the human brain with the use of ultra-high field functional neuroimaging (7T), computational modelling and psychophysics. We believe the findings will shed light on the problem of visual stability and thus bridge the fields of monkey electrophysiology and human cognitive science.


The role of endothelial nitric oxide signaling in age-related vascular dysfunction

Supervisors:
Prof James Leiper, Institute of Cardiovascular and Medical Sciences
Professor Colin Selman, Institute of Biodiversity Animal Health and Comparative Medicine

PhD project summary:
This project aims to test the novel hypothesis: ‘Vascular endothelial cell nitric oxide (NO) signalling is a significant determinant of age-related vascular dysfunction’. We will focus on the impact of ageing on endothelial NO synthesis, metabolism and vascular function. Reduced NO production and vascular dysfunction are characteristics of human cardiovascular disorders. However, the contribution of NO to age-related vascular dysfunction remains unclear. Using novel genetically modified strains of mice we will monitor endothelial NO synthesis, gene expression and metabolism during ageing. We will identify downstream mediators of NO signalling in ageing and test the therapeutic potential of nitric oxide supplementation.


The role of neurogenesis and epigenetic modifications for the maintenance of long-term health across the lifespan

Supervisors:
Dr Tyler Stevenson, Institute of Biodiversity, Animal Health and Comparative Medicine
Prof Neil Evans, Institute of Biodiversity, Animal Health and Comparative Medicine

PhD project summary:
This studentship will focus on the role of neurogenesis and epigenetic modifications for animal health in a seasonal environment. Epigenomic flexibility is an evolutionarily conserved molecular process required for normal healthy body rhythms. The objectives of the studentship are to identify novel, evolutionarily conserved mechanisms that regulate seasonal changes in epigenome function across a range of species, and to place variation in genomic flexibility into a functional context. This multi-disciplinary, integrative project will take advantage of the several research-intensive groups in the Institute of Biodiversity, Animal Health & Comparative Medicine. The student will learn molecular biology techniques such as qPCR, and in situ hybridization, alongside immunohistochemistry and hormonal measurements. A key focus is to implement cutting edge genome editing techniques to establish the necessity and sufficiency of target genes of interest. Therefore, the student will learn how to manipulate gene expression in vivo and link gene expression with animal health. The student will be exposed to broad fields of research including: neuroanatomy, neuroscience, chronobiology, physiology and animal behaviour. Students will be encouraged to collaborate and present their findings at conferences.


Understanding Genome Encoded Barriers to Virus Transmission

Supervisors:
Dr Sam Wilson, Institute of Infection, Immunity and Inflammation
Prof Massimo Palmarini, Institute of Infection, Immunity and Inflammation

PhD project summary:
Seasonal Influenza A viruses (IAVs) cause a massive disease burden worldwide every year. Periodically, IAVs ‘spillover’ from animal reservoirs and can cause devastating pandemics resulting in millions of deaths worldwide. To cross the species barrier and seed a new pandemic, the virus must adapt and overcome the innate immune defences of the human host. This project seeks to identify the antiviral factors that form a barrier to the cross-species transmission of IAVs (and other viruses). The student will use libraries of interferon stimulated genes (ISGs), from a variety of species, to screen fluorescently-labeled viruses and identify host genome-encoded
defences that block IAV replication. Once identified, the student will use a variety of molecular virology techniques to unravel how these defences work and illuminate the role these defences might play in constraining cross-species transmission.

 

 


Unravelling the dietary triggers of Crohn’s Disease

Supervisors:
Dr Konstantinos Gerasimidis, School of Medicine, Denistry and Nursing
Prof Simon Milling, Institute of Infection, Immmunity and Inflmmation
Dr Umer Zeeshan Ijaz, School of Engineering

PhD project summary:
A medical liquid-only diet (also known as Exclusive Enteral Nutrition-EEN) is one of the most potent treatments for active Crohn’s Disease (CD). Because adherence to EEN is very difficult, EEN is not a viable option to use for long-term maintenance of disease remission. Our recent research also shows that the benefit of EEN is lost in most patients, and gut inflammation increases to pre-treatment levels, within the first 2 weeks of a patient’s return to their habitual food. Therefore, there is a need to identify disease-causing dietary components and develop personalized therapies to prolong disease remission. We have recently developed CD-TREAT, a novel diet, which is based on every-day ordinary food. In animal experiments and in a pilot clinical trial, CD-TREAT improved disease activity markers. We next want to investigate whether CD-TREAT can be used for long-term disease management, following EEN treatment. This PhD will:

a) Test, in a clinical trial, whether CD-TREAT diet is superior, compared to habitual food, for mitigating rise in gut inflammation that occurs following cessation of EEN treatment.
b) In CD patients returning to habitual food after cessation of EEN, to identify the dietary components which trigger the rise in gut inflammation.
c) To characterise the sequence of immune events during reversion to inflammation, and to perform in vitro experiments to explore the mechanisms mediating these events.
During this PhD the student will gain expertise in nutrition, clinical gastroenterology and immunology, and will experience true translational research in the interface between clinical medicine and basic science.


Using EEG Brain-Computer Interaction to Improve Performance

Supervisors:
Dr Martin Lages, Neuroscience and Psychology, University of Glasgow
Dr Marios Philiastides, Neuroscience and Psychology, University of Glasgow

PhD Project Summary:
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.


Using transgenic mouse models to define the function of receptors for short chain fatty acids

Supervisors:
Prof Graeme Milligan, Institue of Molecular Cells and Systems Biology
Prof Andrew Tobin, Institue of Molecular Cells and Systems Biology
Dr Brian Hudson, Institue of Molecular Cells and Systems Biology

PhD project summary:
wide range of physiological functions at the interface of metabolism and immunity. Until recently a lack of useful selective and high affinity ligands has limited opportunity to thoroughly analyse specific roles of these in health and disease. To overcome this we have generated and begun to study a set of transgenic mouse lines in which we have replaced the mouse form of the receptor FFA2 with humanised forms of this receptor that can be activated by novel small molecule agonists and blocked by ‘human specific’ antagonists. After initial training in modern quantitative approaches in pharmacology, studies will focus on tissues from these transgenic lines and in the development of disease models which may be treated with ligands that activate or block these receptors. The studies will hence combine use of transfected cells, and both ex vivo and in vivo analysis, to gain understanding of how ligands at the receptors for short chain fatty acids might be best considered as future therapeutic medicines.


Applicant Instructions

PLEASE NOTE THAT APPLICANTS ARE APPLYING TO THE PROGRAMME AND NOT FOR SPECIFIC PROJECTS AT THIS STAGE – THE PROJECT ABSTRACTS LISTED ARE EXAMPLE PROJECTS ONLY.

ELIGIBILITY

Qualifications criteria
Applicants applying for a MVLS DTP 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 MVLS grant provides funding for tuition fees and stipend for UK and EU nationals that meet all the required eligibility criteria.

APPLY 

You can apply HERE. Within the application, at the programme of study search field option, please select 'MVLS – DTP Studentship’[PLEASE ENSURE THAT THIS PROGRAMME STUDY OPTION IS SELECTED, IF NOT YOUR APPLICATION WILL NOT BE DIRECTED TO THE CORRECT PROGRAMME AREA]

Please note that, in step 11 within the online application process, you are asked to detail supervisor/project title information. You cannot detail this information because you are applying to the programme and not for a specific project at this stage. However, within the research title text box area, please highlight which theme (see themes below) you are interested in and project/supervisor information (if known). Alternatively, add the following text: 'MVLS DTP' to all these sections. There is no requirement to upload a research proposal.  

  • Basic Bioscience Underpinning Health 
  • Food Security
  • World Class Underpinning Bioscience 

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

  • CV/Resume
  • Degree certificate (if you have graduated prior to 1 July 2020)
  • 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].