Identifying Molecular Targets for the Treatment of Rheumatoid Arthritis

Supervisors: Dr Megan MacLeod and Prof Paul Garside


The immune system is vital to protect us against infectious agents such as viruses and bacteria. However, it can also be the root cause of a variety of damaging inflammatory diseases. These autoimmune diseases occur when the immune system attacks the body’s own tissues, mistaking them for a dangerous pathogen. While current treatments can temper the consequences of autoimmune diseases, no absolute cures are available. We want to stop the immune cells that recognise host tissues and thereby reduce or maybe even cure autoimmune disease.

Rheumatoid arthritis (RA) is an autoimmune disease that affects joint tissues causing chronic pain and reduced mobility in over 400 000 people in the UK alone. Immune cells called CD4 T cells are implicated in the early stages of RA and play a continued role in the chronic inflammation that underlies the disease.

The aim of this PhD project is to investigate whether it is possible to turn off CD4 T cells such as those involved in autoimmune disease by driving them into a state of ‘tolerance’. We have established a mouse model that enables us to tolerise previously activated CD4 T cells by inducing antigen specific cell death. This project will take advantage of a novel T cell reporter mouse to determine the molecular pathways responsible for the cell death and investigate whether these pathways are altered in CD4 T cells from patients with RA and might therefore provide therapeutic targets. The project will generate important data that could lead to new treatments to permanently turn off self-reactive CD4 T cells and thereby cure RA.

Analysing the roles for macrophages and chemokines in the regulation of mammary gland development

Supervisors: Prof Gerard Graham and Prof Robert Nibbs


Macrophages are important regulators of branching morphogenesis in a range of developmental contexts. However, our understanding of the regulation of their recruitment and dynamics at morphogenic sites is currently poorly developed. Recently we have shown that the atypical chemokine receptor ACKR2 is an essential regulator of macrophage dynamics during branching morphogenesis. We have studied this in detail with regards the development of the lymphatic vasculature and our preliminary data demonstrate that ACKR2 is also important in regulating the branching of the ductal epithelial network during postnatal mammary gland development. ACKR2 may therefore be a general regulator of macrophage dynamics during branching morphogenesis. The purpose of the study described within this studentship application is to use advanced molecular, in vivo and imaging technologies to detail the involvement of ACKR2 in macrophage dynamics specifically in the context of mammary gland development. This will represent an important component of our MRC Programme Grant funded activities and will benefit from a collaboration with an international expert in this area, Prof Jeff Pollard (University of Edinburgh). We believe therefore that this studentship will provide outstanding training opportunities.

Genome-wide associations of antibiotic-resistance and infectivity determinants in Escherichia coli

Supervisors: Prof David Smith and Prof Tom Evans


Ameliorating the increasing threat of resistance of bacteria to frontline antibiotics is of increasing concern and adjuncts, alternatives and/or additional options for controlling resistance have become an international imperative.  Improved understanding of antibiotic-resistant (AbxR) bacteria is required in order to identify characteristics of resistant bacteria associated with both resistance and virulence.  
Among the bacteria identified as major concerns are Escherichia coli and Klebsiella pneumoniae carrying ESBL (extended spectrum β-lactamase) or carbapenemase (collectively ESBL/C) determinants and which have emerged as major challenges in both healthcare-associated and community-acquired settings.  Also of note, these features are often associated with resistance to multiple antibiotics thus limiting options for severe infections including UTIs, sepsis, meningitis and pneumonia.

In this project, genotypic and phenotypic approaches will be combined to address the following key questions:
1. Are ESBL/C strains typified by AbxR elements solely or are other genomic features shared?
2. Is “pathogenicity” an artefact of resistance or are there specific pathogenicity factors common to ESBL/C?
3. Does carriage of AbxR have wider implications for physiology/fitness ESBL/C?

By addressing these questions, this project is expected to define potential candidates to offer options for detection, monitoring and targeting AbxR bacteria, in particular ESBL/C E. coli and Klebsiella.

The role of Enhancers of Polycomb EPC1 and EPC2 in the acute myeloid leukaemia

Supervisors: Dr Xu Huang and Dr Alison Michie


Given the importance of epigenetic regulators in leukaemia, using a customised lentivirus knockdown screen, we previously identified the EP400 chromatin complex components EPC1 and EPC2 as critical oncogenic co-factors in acute myeloid leukaemia (AML). Our data establish a novel regulatory axis containing EPC, and its associated complex components, as mediators of MYC turnover in myeloid leukaemia cells which concomitantly prevent sensitisation of AML cells to MYC-induced apoptosis thus negating endogenous tumour suppressor mechanisms. This study, utilizing combined systems biology approaches with established cancer stem cell in vitro and in vivo function assays, would focus on further characterising the role of EPC in leukaemogenesis with potential discovery of novel pathological features and biomarkers of AML. This project is expected to provide a fundamental scientific understanding of mechanisms on the role of EPC in AML. This valuable information will be used to initiate next stage of the drug discovery project, i.e. establish EPC and its related complex as promising therapeutic targets in AML, further develop novel EP400 components specific inhibitors as a selective drug for AML and propose the effective combination treatment with other available drugs in AML.

Regulation of cellular mechanical properties by the actin-myosin cytoskeleton

Supervisors: Prof Michael Olson and Dr Huabing Yin


Cells move through three-dimensional tissues during physiological processes such as embryonic development and angiogenesis. In addition, the movement of cancer cells away from primary tumours and through tissues is the first stage in cancer metastasis. For the most part, research on cell movement has focussed on how cells adapt their adhesions to other cells or to the extracellular protein matrix, as well as looking at how internal changes to cytoskeletal structures influence the motility of individual cells. However, a factor that is often overlooked is the influence that altered cell elasticity has on cell movement through three dimensional tissues. One reason being that measuring cellular biomechanical properties requires specialised approaches that are not typically available in biological research laboratories. In this innovative PhD project, cell biology methods including molecular biology, state-of-the-art imaging and mass-spectrometry based proteomics, will be combined with bio-engineering approaches such as atomic force microscopy and nanofabrication to determine how regulators of the actin-myosin cytoskeleton influence cell elasticity and consequently affect how cells move through constrained 3-D environments. Screening genes that are involved in cytoskeleton structure and regulation for their roles in modulating cell elasticity will identify critical regulators of cell movement, helping us to understand the fundamental biology involved with the regulation of physical properties of cells. This project will be an outstanding opportunity to gain experience at the interface between biology and physics, an emerging field with relevance to basic and clinical research that will continue to develop in the future.

The role of lncRNA in the response to vascular injury

Supervisors: Prof Andrew Baker and Dr Angela Bradshaw


Vascular injury, induced by divergent stimuli, leads to neointima formation, a process involving complex interplay between multiple cell types that naturally reside in the vessel wall and those that infiltrate vascular tissue post-injury. The resulting endothelial dysfunction, vascular smooth muscle cell phenotype switching and inflammation lead to neointima formation, a scenario that remains a major clinical burden. Our recent work has highlighted the importance of non-coding RNA, particularly miRNA and lncRNA, in post-injury neointima formation. In this studentship, we will define at the molecular, cellular and whole animal levels the connectivity between non-coding RNA and vascular cell regulation and function. Specifically, we have identified more than 5 lncRNA that are substantially modulated by inflammatory and growth factor signals in the vessel wall. We will use a range of techniques to manipulate signalling pathways that regulate these lncRNA, determine RNA and protein binding partners to assess function and understand the pathological effect of lncRNA modulation in relevant model systems. Collectively, this will provide a detailed fundamental understanding of the regulation and role of non-coding RNA in vascular neointima formation as well as provide innovative approaches for future translation to the clinic. Further, this work will provide a breadth of expertise in basic and translational research within a well-funded research group.

Runx1 and Heart Disease Post-Myocardial Infarction

Supervisors: Dr Christopher Loughrey; Dr Stuart Nicklin; and Prof Ewan Cameron


Coronary heart disease (CHD) leading to myocardial ischaemia is the predominant cause of heart failure (HF) and premature mortality in the UK. CHD occurs when the blood vessels of the heart (coronary arteries) become
narrowed by fatty material (atheroma) and reduce blood flow to heart muscle (myocardial ischaemia). If the coronary artery is occluded then an area of lethal tissue injury in heart muscle called a myocardial infarction (MI) can be produced. The subsequent structural and functional changes in the surviving heart muscle can lead to poor cardiac pump function and HF. Novel therapeutic strategies to preserve cardiac pump function are urgently needed to treat patients with myocardial infarction and thereby improve patient survival rates and quality of life.

The Runx family of genes (Runx1,2&3) encode for DNA binding transcription factors (Runx1,2&3) which regulate protein expression. Recently, increased Runx1 expression has been demonstrated in the hearts of patients with MI. In line with these data, our recent work demonstrates increased Runx1 expression in a mouse model of MI. However, despite these observations, the role Runx1 plays in heart function remains unknown. We have made a novel and exciting discovery that higher Runx1 expression levels correlate with poor cardiac pump function. In order to corroborate this finding, we have produced a heart-specific knockout of Runx1. When MI is induced in this transgenic model, cardiac pump function is markedly improved suggesting that reducing Runx1 expression in the heart is a potentially novel therapeutic approach to limit the progression of cardiac dysfunction in patients with MI. This studentship will investigate whether reduction of Runx1 levels in the heart via somatic gene transfer using viral gene transfer vectors can improve cardiac pump function in a mouse model of MI. The project will enable the student to be trained in in vivo rodent models of MI, integrative physiology, molecular biology and gene transfer approaches.

Pulmonary hypertension: Sex, drugs and ROCK and Rho

Supervisors: Prof Mandy MacLean and Dr David Welsh


This will bring together the Scottish Pulmonary Vascular Unit ( who are the only Scottish Clinical Centre for patients with Pulmonary Hypertension and the research group of Prof Mandy MacLean. Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature resulting in right heart failure and death. PAH occurs more frequently in females compared to males but the reasons for this are unclear. PASMCs normally exhibit low rates of proliferation, migration, and apoptosis to maintain a low resistance pulmonary circulation. However alterations in signalling pathways can lead to abnormal proliferation, apoptosis and migration. In human pulmonary arterial smooth muscle cells (hPASMCs) the most important signalling pathway is the bone morphogenetic protein receptor type 2 (BMPR2) pathway. A mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene underpins heritable PAH (hPAH). MAP kinases also underpin proliferative responses in human pulmonary cells. We have recently identified basal differences in proliferative signalling between male and female hPASMCs. Compared with male hPASMCs, female cells have decreased BMPR2 signalling, increased pERK2, increased estrogen synthesis, increased estrogen metabolism, increased estrogen receptor alpha  and increased proliferation to key mitogens including PDGF and serotonin. This PhD will focus on unravelling the reasons behind these phenotypic differences in both hPASMCs and pulmonary fibroblasts and further investigation into the pERK/ROCK and Rho system which underpins serotonin-induced and oestrogen-induced proliferation in hPASMCs. We have characterised serotonin-dependent models of PH where only females develop PH and these will be studied to examine the effect of gender on these systems in vivo. For example the therapeutic effects of the ROCK inhibitor Fusadil will be studied in these models and in the sugen/hypoxic model (males and females). Pulmonary vs systemic differences will also be identified by comparing arterial SMCs derived from gluteal biopsies. The student will learn in vivo skills such as in vivo (haemodynamic measurements, drug dosing and ovariectomy) in vitro and in situ expression studies, molecular biology and imaging. They will also be exposed to a clinical environment.

Role of Nox5 NADPH oxidase in the pathogenesis of abdominal aortic aneurysm


Abstract:  Prof Tomasz Guzik and Prof Rhian Touyz

Abdominal aortic aneurysms (AAAs) are a significant clinical problem with high morbidity and mortality. No treatments are available to effectively slow down or prevent the development of the disease. Mechanisms implicated in AAA include increased metalloproteinase activation, vascular inflammation and mechanical stress, processes that are linked to oxidative stress (increased bioavailability of reactive oxygen species (ROS). In this proposal, we focus on ROS-generating systems, particularly Nox5, a recently identified; Ca++ regulated isoform of NADPH oxidase. We have shown that Nox5 is important in human atherosclerosis, and that it is expressed in human AAA. Based on these observations we propose that hyperactivation of Nox5 in vascular smooth muscle cells (VSMC) by factors known to induce AAA, leads to AAA formation through modification of VSMC function, the induction metalloproteinase activation and vascular inflammation. This could identify a novel key mechanism of AAA, which may be targeted therapeutically. Our studies will address the novel role of Nox5 in the pathobiology of AAA, using human samples, molecular studies and animal models.

The Molecular Control of Mesenchymal Stem Cell Differentiation to Fat and Bone by Anti-Diabetic Drugs

Supervisors: Dr Ian Salt; Dr Stephen Yarwood; and Prof Faisal Ahmed


Bone health is impaired in both type 1 and type 2 diabetes mellitus (T1DM and T2DM) due to a shift in the balance of differentiation of mesenchymal stem cells (MSCs) from bone formation towards fat. We aim here to determine the molecular and cellular control of MSC differentiation to either fat (adipogenesis) or bone (osteogenesis) in the context of anti-diabetic drug treatment. This is important because the widely-used drug, metformin, has been reported to have anabolic effects on bone whereas other insulin-sensitising drugs, such as the thiazolidinediones (TZDs), reduce bone mineral density with a corresponding increase in marrow fat and fracture incidence. As many anti-diabetic drugs have been reported to influence AMP-activated protein kinase (AMPK) activity, which has been reported to alter bone formation, our working hypothesis is that AMPK signalling pathway plays a cardinal role in regulating these processes through the regulation of expression of Runx2 and PPARī§ transcription factors. We will therefore determine the role of AMPK in the control of murine (pluripotent CH310T1/2 cells) and human models (human bone marrow-derived MSCs) of MSC differentiation in response to osteogenic (metformin) and adipogenic (TZD) anti-diabetic drug treatment. The student will determine:

1) The Role of AMPK in the control of MSC Differentiation towards Fat and Bone
2) The Mechanisms by which AMPK activation Influences MSC Differentiation

Exploring the genetic basis of craniofacial syndromes using an evolutionary mutant model

Supervisors: Dr Kevin Parsons and Dr Quentin Fogg


Studying only a few organisms limits science to the answers that those organisms can provide and can have serious consequences (e.g. the ‘translational disconnect). Craniofacial syndromes, which are among the most common heritable human disorders, represent an area of research that has been limited by available experimental models. However, the increasing number of sequenced genomes for non-traditional models is beginning to curb this issue. For this project we aim to leverage the wide range of craniofacial phenotypes available in African cichlids as well as their recently derived genomic resources. The wide range of phenotypes in closely related species are effectively ‘mutants’ and provide an ideal system to examine the underlying mechanisms of craniofacial variation within a clinical framework. Specifically, we aim to determine 1) the genetic basis of craniofacial shape and bone structure, 2) verify candidate genes, and 3) identify the mechanisms underlying joint formation and its biomechanical properties. This project will take advantage of an interdisciplinary supervisory team which spans basic evolutionary biology, development, genetics, anatomy, and engineering. Therefore, this project will involve a broad range of training and we seek an enthusiastic student with knowledge in some of these areas, and a willingness to learn from different fields.

For further information, please contact: Dr Kevin Parsons:

Actions of a GnRH agonist that blocks puberty on neural physiology and cognitive function during development and ageing

Supervisors: Dr Jane Robinson and Prof Neil Evans


Puberty is a time of huge change in development and cognitive function which in turn impacts on many aspects of adult life. The mechanisms underlying this suite of changes are poorly understood. Employing an in vivo ovine model this project will use GnRH agonist treatment to delay puberty and thereby separate normal hormonal events from developmental age. Behaviour and physiological endpoints have been validated recently and several peer reviewed papers document the results. This project is an extension of our earlier work.  Groups of animals have been established and behavioural and physiological data collected. Neural tissue is available from 1) agonist treated, 2) agonist treated animals supplemented with testosterone and 3) control animals at one year of age. Three groups of animals are being monitored for a further period and cognitive behavioural testing will be performed during this studentship before further tissue is collected from these animals. The project will also investigate changes in brain function in specific brain areas including the hippocampus and amygdala. The results will be of clinical relevance as, in addition to the cognitive changes that occur at puberty, age related cognitive decline may be affected by changes in the reproductive axis. Thus, GnRH has been implicated in disease states like Alzheimer’s disease. A greater understanding of how hormones affect cognitive function could be of benefit in the treatment of age/development related cognitive change.

The link between ageing and cancer: Insights from long-lived mice

Supervisors: Prof Colin Selman and Prof Peter Adams


We are currently living much longer than previous generations. However, healthspan is not keeping pace with lifespan, meaning that our risk of experiencing pathologies which impact on health and vitality is also increasing. For example, age is the biggest single risk factor for most cancers although we do not understand the reasons for this. Given the current disconnect between life-expectancy and healthy life-expectancy, it is critical to understand the processes underlying ageing and driving age-related disease. In mice, several dietary, genetic and small molecule interventions extend lifespan and some also delay and/or decrease cancer incidence. Cellular senescence, a stable proliferation arrest, is associated with an altered pro-inflammatory secretory pathway, and is a critical tumour suppressor mechanism. The altered secretory pathway of senescent cells (Senescence Associated Secretory Phenotype; SASP), also promotes clearance of senescent cells by the immune system. Consequently, senescence-associated proliferation arrest and SASP-mediated immune clearance collaborate in tumour suppression. We hypothesize that cancer suppression in long-lived mice is, at least in part, mediated through enhanced senescence-mediated tumour suppression. You will investigate senescence-mediated tumour progression and its functional significance in long-lived genetically mutant mice using histology, molecular biology and cell culture. Ultimately this project will help develop a critical new understanding of the relationship between ageing and cancer in mammals.

Routinely collected sexual health data from young people in Glasgow: integrity, data linkage and use in intervention development

Supervisors: Dr Linsay Gray; Dr Lisa McDaid; and Prof Alastair Leyland


Early sexual debut has been associated with negative sexual health outcomes and research suggests the need to intervene early to help young people delay sexual debut, manage their sexual relationships and avoid negative consequences. We propose a primarily methodological study, using data from electronic sexual health records of young people attending specialist sexual health services in NHS Greater Glasgow and Clyde, to examine the potential for data linkage to other sources such as Scottish Birth Records, records of prescriptions, hospital admissions, mental health service use, social work, criminal justice and education records, as well as measures of area-based deprivation.  The studentship will: 1) explore the integrity of the data for completeness, inconsistencies and potential linkage; 2) explore possibilities and gain appropriate consent (with support) for data linkage to a range of other data sources via a range of means; and 3) measure sexual health outcomes from longitudinal analysis (e.g. repeat attendance, disclosure of risks, diversity of sexual repertoire etc) from within the National Sexual Health IT System data set. 

Glucose Homeostasis and the Unfolded Protein Response

Supervisors: Prof Neil Bulleid; Prof Gwyn Gould; and Dr Ian Salt


It is now well established that there is a causal link between obesity and the onset of insulin resistance and type II diabetes.  In addition, it has been shown that one consequence of obesity is cellular stress, particularly emanating from the endoplasmic reticulum (ER).  ER stress is most usually driven by the misfolding of proteins entering the secretory pathway and is, therefore, referred to as an unfolded protein response (UPR).  Despite our knowledge of a correlative link between ER stress and insulin resistance we do not know how alterations to metabolic status can lead to an UPR.  This project aims to delineate the mechanism(s) underlying the induction of a stress response during hyper- or hypoglycaemia.  We will use well established cell culture models of pancreatic β-cells and adipocytes to study the consequence of altered insulin or adiponectin secretion on ER stress and cell viability.  The project will involve live cell microscopy to monitor changes in redox homeostasis as well as following protein folding, secretion, the UPR and apoptosis.  The results will provide valuable insight into the link between obesity, ER stress and insulin resistance leading to type II diabetes. 

Development of a novel MRI based metabolic imaging method

Supervisors: Dr William Holmes; Prof Joachim Gross; and Prof Mhairi Macrae


Metabolism is vital to life, abnormalities in metabolism are important indicators in several medical conditions, for example cancers are characterized by hyper-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-ioning 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 project aims to build on our pilot research and further develop and validate an 17O MRI approach to imaging metabolism in-vivo. This work will take place at on the 7Tesla MRI systems at the Glasgow Experimental MRI Centre. In-vivo application will be undertaken using rodent models of both stroke and glioblastoma and validated using [14C] 2-deoxyglucose autoradiography.

Neural stem cell therapy for stroke: A rodent-based project to identify potential MRI indices of functional recovery

Supervisors: Prof Keith Muir; Dr Jozien Goense; and Dr Christopher McCabe


The neural stem cell product CTX0E03 is a conditionally immortalised cell line developed for treatment of ischaemic stroke.  A preliminary clinical safety trial (PISCES) has been completed in Glasgow and a second clinical trial is planned. Evidence from rodent stroke models support enhanced functional recovery when CTX0E03 cells are implanted directly into the brain adjacent to the stroke site, 4 weeks after the stroke has been induced.Further clinical development of stem cell therapies will rely on the development of biomarkers of cell action. At present it is thought that few cells survive, yet they are able to exert beneficial functional effects.  Direct imaging of grafted cells is unlikely to prove valuable, and potential markers of cell effects on neuronal organisation are required.Project:  Training will be provided in rodent stroke surgery, assessment of sensorimotor deficits, stereotaxic injection into CNS and MRI image analysis. In the rodent stroke model, potential MRI markers will be sought in a study that will follow the late direct injection of CTX0E03 cells 4 weeks after stroke by serial brain imaging and neurobehavioural studies. Imaging (e.g. diffusion tensor imaging, high resolution structural MRI, 1H MRS, fMRI with forepaw stimulation, functional connectivity and T2* maps to identify cerebral angiogenesis) will be undertaken at the Glasgow Experimental MRI Facility (GEMRIC).