Master of Research in Biomedical Sciences (Integrative Mammalian Biology/Systems Biology)
Applications are now CLOSED
About the Programme
There will be up to four fully funded scholarships available in 2015 to allow suitably qualified candidates to integrate systems biology approaches with whole animal physiology, pharmacology or veterinary science within our popular MRes Biomedical Sciences program. These are funded by the Medical Research Council (MRC). The MRC supports systems biology approaches to science as well as promoting training in animal sciences. Glasgow University is one of four centres of excellence in the training of integrative mammalian biology and was awarded funding by the BBSRC, British Pharmacological Society, KTN, Medical Research Council and Scottish Higher Education Funding Council (now SFC). Glasgow University also offers a wide range of expertise in Systems Biology.
As part of the MRC support for these activities, these scholarships are available for our one year MRes in Integrative Mammalian Biology/Systems Biology. The scholarships pay a stipend for living expenses and cover all tuition fees. The MRes will follow our highly successful model of taught modules (taking up about a third of the course) and two projects. One project will involve a systems approach (e.g. mathematical modelling, computing, ‘omics’, bio-engineering) which will be related to or integrated with a whole animal physiology/veterinary project in an iterative fashion. The course will be a specialisation within the existing MRes in Biomedical Sciences
Who can Apply?
Candidates for these scholarships must have at least an upper second class Honours degree or equivalent in a relevant subject (for instance physiology, pharmacology, neuroscience or veterinary medicine but we also welcome students with backgrounds in systems approaches such as mathematical modeling, computing, ‘omics’, bio-engineering) and be eligible by residence for a UK research council scholarship (see further details on tab 'How to Apply').
All candidates intending to specialise in Integrative Mammalian Biology must already have, or be in a position to obtain before the start of the course, a Home Office licence before the start of the course.
The Studentship will be supervised by staff drawn from the College of Medical, Veterinary and Life Sciences and the College of Science and Engineering.
MRes Biomedical Sciences (IMB/systems specialisation)
Single stand alone in vivo projects
Effects of exercise training studies in animal models of heart disease
Dr. Ole J Kemi
Exercise training results in many different adaptations that are considered beneficial to both healthy individuals and patients suffering from various diseases such as cardiac, vascular, muscle, and metabolic diseases. These benefits stem from adaptations both to organs and cell systems that make up organs, but because of this cannot be studied in detail in human subjects and patients. Thus, animal models are required. In our laboratory, we use animal models to study the effects of exercise training in heart disease, by combining state-of-the-art procedures for surgically inducing and establishing heart disease such as myocardial infarction and heart failure by permanent coronary artery ligation, as well as intensity-controlled aerobic endurance-type exercise running by custom-made rodent treadmill systems. Because these procedures are experimental and in vivo in nature, they require validation to reduce experimental variability and to mimic the human condition. This project will assess the immediate effect on left ventricular systolic pump function and dilatation 1 week before, and 1 and 4 weeks after inducing myocardial infarction by coronary artery ligation in adult Wistar rats. These assessments will be performed by in vivo ultrasound echocardiography. Hearts will also be excised to morphologically study the size of the infarct scar tissue relative to the left ventricle. Adjacent to the cardiac studies, whole body aerobic exercise capacity will also be studied 1 week prior to myocardial infarction and 1 and 4 weeks post-myocardial infarction by a standardized treadmill ramp test protocol. Thus, this project will provide training in several quantitative in vivo techniques as well as animal handling procedures.
Using in vivo techniques in a mouse model of myocardial infarction to assess the effect of cathepsins on cardiac function.
Dr. Christopher Loughrey
The work in the laboratory focuses on using an integrative approach to investigate the mechanisms underlying heart disease. Coronary Heart disease leading to myocardial infarction (heart attack) is the leading cause of premature death in the UK. There is limited access to human tissue and what tissue is available is often in a variable state due to the fact that many patients are at different stages of the disease and are on different treatment regimes. This means that animal models of cardiac disease play a vital role in enabling an investigator to characterise the pathogenesis of cardiac disease and identify potential therapeutic targets for treatment strategies. We have a developed a mouse model of myocardial infarction using microsurgical techniques within the laboratory. We use state of the art technology to characterise this model including techniques ranging from pressure-volume catheters which are inserted into the mouse hearts and echocardiography to measure the mechanical function of the heart and electrocardiography to measure the heart’s electrical activity. This study will provide crucial theoretical and practical in vivo training under close supervision which will provide the student with the skills to characterise cardiac function in the mouse model of myocardial infarction. We are currently investigating the role of specific proteases called cathepsins which are elevated in heart and serum samples from human patients with cardiac disease. The students will have the opportunity to investigate whether these proteases are either detrimental or improve heart function within this model and therefore have the opportunity to potentially discover new findings which will advance our knowledge of cardiac disease.
Assessment of central neuropathic pain in laboratory rodents by telemetric recording of heart rate, heart rate variability and blood pressure.
Dr. John Riddell & Delwyth Graham
Pain is a major symptom of human disease and injury and a significant welfare issue in animals. There is therefore a requirement for a better understanding of the mechanisms of different persistent pain conditions and for the development of more effective analgesics, particularly for neuropathic pain, which is generally poorly controlled. We have developed a rodent model of the central neuropathic pain that frequently develops in spinal cord injury patients. In this rat contusion injury model, behavioural signs of tactile allodynia, thermal hyperalgesia, cold allodynia and spontaneous pain can be detected. We will use this model to investigate the correspondence between behavioural signs of pain and alterations in heart rate, heart rate variability and blood pressure. These cardiovascular parameters will be monitored in awake behaving animals by surgical implantation of telemetric devices prior to spinal cord injury or sham surgery. Animals will be monitored during normal cage behaviour and in response to various forms of tactile and thermal stimuli. Spinal cord injured animals will be compared to sham operated animals in order to differentiate any cardiovascular responses accompanying acute nociception from those specific to a neuropathic pain state. The effect of analgesics on cardiovascular and behavioural responses may also be explored. The aim is to identify cardiovascular parameters which are suitable as surrogate measures of pain and could be used in studies of pain mechanisms and for testing the effectiveness of analgesics. Information obtained will also help inform as to the necessity for and effectiveness of pain relief in rodent models of spinal cord injury, where investigation of pain is not the prime purpose of the study.
Do spinal cord projection neurones degenerate when axotomised by spinal cord injury or are they available for rescue?
Dr. John Riddell
Spinal cord injury leads to axotomy of neurons that carry sensory signals to the brain and from the brain to the spinal cord. The interrupted communication is one reason for the loss of function accompanying injury. One strategy for restoring function after spinal cord injury is to find ways of promoting regeneration of these axons across the injury site in order to restore connections. However, this strategy will only be possible if the neurons from which the axotomised axons arise survive the axotomy. If some or all of the axotomised neurons die then they will no longer be available as a target for a regeneration promoting strategy and it will be essential to find a means of promoting the survival of axotomised neurons. Although this issue has been investigated for descending neurons, the results are conflicting. One possible reason for this is that the ability of axons to transport tracers (by which projection neurons ascending and descending the spinal cord are identified) may change after axotomy. In this project we will reinvestigate this question and extend observations to ascending spinal pathways which have not so far been studied. To overcome any problem with changes in tracer transport, ascending or descending tracts in the spinal cord will be pre-labelled. That is, tract tracing will be performed before the injury, using a tracer that remains in the neurons for a long period of time. The numbers of retrogradely labelled neurons in the brain (for descending systems) or in the spinal cord (for ascending systems) will be quantified in spinal cord injured animals and compared to those in the same regions of naive animals. The project will involve the use of tract tracing, spinal cord injury models, perfusion fixation, immunocytochemistry, histological processing, confocal microscopy and image analysis.
Assessment of the role of exosomal miRNAs in cell:cell communication in the kidney
Dr. Laura Denby
Chronic kidney disease (CKD) is defined as the progressive loss of renal function over time. Patients with CKD can progress to end-stage renal disease (ESRD), where patients require renal replacement therapy in the form of dialysis or transplantation. Treating these patients is very costly accounting for ~2% of the NHS budget. Therefore, a better understanding of CKD pathogenesis is required to improve treatment options. MicroRNAs (miRNA) have been found to be a novel class of endogenous negative regulators of gene expression and have been shown to dysregulated in renal disease. Screening miRNA modulation in several models of renal disease, I found that miR-21 and miR-214 were consistently and significantly upregulated. A novel area of miRNA research is that miRNA appear to be involved in cell:cell communication mediated via exosomes. The role of such exosome-mediated miRNA communications in the kidney has not been investigated, but it has been hypothesised that urinary exosomes could mediate downstream communication to tubular cells. This proposal aims to test the hypothesis that miRNAs contained within exosomes are involved in kidney cell:cell communication. This project will utilise the anti-Thy1.1 model of immune mediated glomerulonephritis. Initially, kidney cells (podocytes, tubular and mesangial cells) will be stimulated with TGF-β to mimic injury, and exosomes extracted from the culture media. Animals will have glomerulonephritis induced and renal damage in animals will be assessed by in vivo glomerular filtration rate (GFR), histological scoring of glomerular damage and immunohistochemistry and qRT-PCR for markers of damage. Animals will have blood pressure measured (tail-cuff), urinary assessment of kidney function (metabolic cage), and exosome extraction from serum and urine. Exosomal size will be examined by Nanosight technology. RNA will be extracted from exosomes and miRNA expression will be determined by qRT-PCR.
Assessment of intranasal delivery as a novel administration route in the treatment of ischaemic stroke
Dr. Lorraine Work (lab supervisor – Dr. Emily Ord)
Stroke is the 3rd leading cause of death in the UK and the leading cause of acquired adult disability, costing the NHS in excess of £2.5 billion annually (www.theheart.org). Only 2-5% of all stroke patients receive any clinical intervention and as such significant research has been devoted to finding new interventions for stroke patients. Although pre-clinical studies have reported numerous successes, route and speed of administration remains a substantial limiting factor for clinical translation. The brain parenchyma is tightly regulated from the systemic circulation by the blood-brain barrier and direct stereotactic administration of agents is highly invasive and cannot be performed on patients within the limited therapeutic time window. Intranasal delivery of therapeutic agents has been reported as a novel route of administration to target the brain parenchyma. This novel route of administration has significant clinical relevance, with potential for high risk patients to carry nasal sprays to administer at the onset of ischaemia. This project aims to assess the efficacy of CNS transduction following intranasal delivery of either a novel viral vector expressing a reporter gene or labelled microRNAs. Expression will be assessed qualitatively using immunohistochemistry and confocal microscopy and quantitatively using quantitative real time PCR. Both dose range and longevity of expression will be investigated to determine the optimal agent for future studies. The current project will utilise the stroke-prone spontaneously hypertensive rat. This strain offers a more relevant pre-clinical model for stroke as it exhibits a number of the co-morbidities of cardiovascular disease including: hypertension, nephropathy, insulin resistance, hyperinsulinemia, hypertriglyceridemia and hypercholesterolemia.
Immunology of infection with murine norovirus
Dr. Simon Milling
Noroviruses cause epidemic gastrointestinal disease throughout the world, which can be life-threatening in neonates or the elderly. Infection with norovirus also predisposes to the development of inflammatory bowel disease. However, no good animal models exist to study the immune responses generated against intestinal viral infections, severely hampering the rational design of prophylactic and therapeutic strategies for combating these diseases. With this project, we will investigate the immunology of infection with murine norovirus (MNV). MNV is a recently-discovered natural pathogen of mice that provides an ideal system for mechanistic investigations into how the immune system responds to intestinal viral infections. MNV infects macrophages and dendritic cells in the small intestine. Because these are the cell populations that control intestinal immune responses, this is the best strategy to gain an understanding of viral pathogenesis. The aim of this project is to use MNV infection as a model to elucidate the role of dendritic cells and macrophages in intestinal anti-viral immune responses. These cells will be collected from infected animals using a range of in vivo techniques, including mesenteric lymphadenectomy and thoracic duct cannulation. By identifying the functions of the cells responding to MNV in vivo, we aim to help the development of therapeutic strategies to combat intestinal viral pathogens and prevent the development of viral-associated inflammatory disease.
Postnatal maturation of the neural control of breathing
Dr Leanne McKay
Breathing is a unique, essential and continuous behaviour in mammals, constantly adapting to environmental stimuli from birth until death. At birth the mammalian respiratory system is immature resulting in an irregular and often disordered breathing pattern. As the respiratory system matures, breathing pattern becomes more stable and regular. This project will investigate postnatal maturation of the respiratory system and determine the mechanisms underlying and leading to respiratory failure e.g. apnoeas, in behaving, intact animals. There is emerging evidence that two distinct brainstem neural oscillators play a critical role in respiratory rhythm generation: the preBotzinger Complex (preBotC) and the Retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG); however, it is unknown how the RTN/pFRG interacts with the preBötC to produce rhythmic breathing in vivo. The unique neuronal properties of each respiratory oscillator will be pharmacologically manipulated during specific developmental time windows, prenatally and postnatally, to tease apart the role of these oscillators in respiratory control in vivo. Respiratory pattern will be recorded in vivo from birth to mature ages, during sleep and wakefulness, to determine under which conditions there is susceptibility to respiratory failure. Studying how the two respiratory oscillators are coupled during development and maturity is essential for understanding respiratory control and the mechanisms that lead to failure of the respiratory system, e.g. sleep disordered breathing characterised by apnoea.
Role of the reticulospinal pathways in the control of movement
Dr. John Riddell
The control of voluntary movement tends to be attributed largely to the corticospinal tract and the ability to grasp, for example, is generally considered to be a function of this pathway. However, there is increasing evidence that reticulospinal pathways may also be important in motor control of the hand and gathering interest in the possibility that these pathways may be able to compensate for damage to the corticospinal tract after stroke or spinal cord injury. In preliminary electrophysiological experiments in rats we have observed evidence for a strong projection from the reticular formation to areas of the spinal cord appropriate for the control of movement. In this project we will follow up these observations to determine the area of origin of this reticulospinal projection and examine the connections it forms with neurons in the spinal cord. Initially we will use tract tracing techniques to visualise the reticulospinal pathway and combine this with immunocytochemistry to identify connections with specific types of spinal cord neurons. For example, our preliminary electrophysiological evidence suggests that there may be direct connections onto motor neurons so that this is one possibility we will investigate. The project will provide valuable information on the pathways and circuits controlling movement and will provide a basis for examining whether these pathways show compensatory adaptations following damage to other descending systems, such as following spinal cord injury.
Single stand alone systems projects
Computer modelling of heart cells
Professor GL Smith
This project concerns the use of simple computational models to predict the time course and magnitude of arrhythmic currents in isolated heart cells. The work will use previous research from our lab to develop a simple (Excel-based) model that calculates the time course of
depolarising currents in heart cells due to subcellular Ca changes of different geometries. Higher programming languages can be used if the student has some previous computing experience.
Modelling chronic inflammation and cancer
Dr. Joanna B. Wilson & Dr. Karl Burgess
Chronic inflammation results as a response by the immune system that is either misdirected or directed to an insult that cannot be irradiated. Chronic inflammation is evident in most autoimmune disorders (such as rheumatoid arthritis) as well as being a feature of several types of cancer. The main focus in the laboratory is the development and study of transgenic models of cancer, including virus-associated cancer. In addition, we study factors associated with chronic inflammation and their role in cancer predisposition. A project is available to investigate the role and mechanism of a family of sugar binding proteins in inflammation. These proteins, termed the “chi-lectins” are involved in inflammation and are found to be upregulated in a large array of diseases, from autoimmune disorders to cancer. The project will involve an analysis of their action and inhibition in our transgenic model of chronic inflammation associated cancer. A systems approach using glycoarrays (through the Consortium of Functional Glycomics) will be used to investigate the sugar ligands of these proteins.
Metabolomic changes in response to environmental stress
Prof Mike Barrett & Dr Karl Burgess
Metabolomics offers the capability to study cellular dynamism in novel ways. It is possible, for example, to determine physiological responses to a multitude of environmental perturbations. In this project we will focus on simple bacteria and follow their metabolic response to perturbations including the addition of drugs to the cells, the addition of oxidative stress and to changes in “diet” by adding high levels of fat to their culture medium. Phenotypic responses (e.g. growth rates and microscopic morphological changes) will be determined along with comprehensive measurements of the cellular metabolome. The metabolomics work will involve production of bacterial cell extracts, followed by metabolite production and a liquid chromatography mass spectrometry platform to measure the actual metabolites. Standard software will then be used to identify and quantify metabolites and describe how their abundance changes through the environmental perturbations induced. Datasets will be interpreted within the context of these environmental perturbations and will provide training on acquisition and interpretation of large datasets.
Polyomic Analysis in the stroke-prone spontaneously hypertensive rat
Dr Martin W. McBride & Professor Rainer Breitling
To characterise and gain insights into the molecular processes and interactions that result in left ventricular hypertrophy we will undertake high-through put molecular analysis of cardiac tissue from our SHRSP, WKY and chromosome 14 congenic strains. We have previously generated large-scale multilevel transcriptomic (miRNA and mRNA) and 2D-DIGE proteomic datasets. In this project we will generate metabolomic profiles from the cardiac tissues and a key component of these comprehensive studies will be to integrate distinct data modalities using in-house software solutions and publically and commercially available software; Perseus and Ingenuity Pathway. We will conduct metabolomic analysis to characterise and assess differences in metabolic stress from cardiac tissue isolated from out SHRSP, WKY and chromosome 14 congenic strains. We will assess differences in metabolic signatures connected to many biochemical pathways, in order to identify changes in the metabolic fingerprint (i.e. metabolites/ targets from tissues). Metabolites will be separated and distinguished by polarity and mass using hydrophilic interaction liquid chromatography coupled to an Orbitrap high-resolution mass spectrometer (HILIC-MS). Quantitative changes in metabolites and identification of targets for further analysis will use MZmine, mzMatch and IDEOM, an in-house package incorporating a number of software solutions including multiple filtering packages for typical artefacts of mass spectrometry. In addition, any metabolites identified as potentially useful biomarkers will be verified using tandem mass spectrometry and comparison against authentic standards. Biological insights will be gained and data integrated using Ingenuity Pathway Analysis.
An Investigation of Gene Expression Clustering Methods from Microarray Experiments
Dr John D. McClure & Dr. Martin W. McBride (systems)
Microarray experiments and other “Omics” methods have, over the past decade and a half, greatly extended our ability to interrogate organisms’ transcriptomes across tissue types and conditions. Whilst this has led to many new discoveries, the very large datasets created have not been fully utilised as yet. Given that the transcriptomic signals from genes are highly interconnected, there has been a desire find clusters of co-regulated genes across different conditions. However, traditional clustering methods have generally performed poorly. This is partly as they attempt to cluster all the genes, even though most genes are unlikely to be expressed or changing across the groups in a single experiment. New methods, specifically designed for the very large Omic datasets, have been used successfully, but are normally highly computationally, labour intensive and specialised. This reduces their general applicability. The aim of this project is to investigate whether less computationally intensive and more user-friendly methods can be found to effectively discover gene clusters in microarray data. The biology underpinning the clusters found will then be assessed using IPA (www.ingenuity.com). The project will involve using R (www.r-project.org). The project will also involve using IPA to further investigate the results found. Training will be given in these methods.
Modeling trypanosome metabolism with uncertainty.
Prof Mike Barrett
Kinetic models of metabolism are powerful tools of systems biology. They typically use a single set of enzymatic parameters, chosen by the modeler; this approach has difficulties accounting for the unavoidable uncertainty associated with biological experiments and incomplete knowledge. In this project, we want to address this issue by developing a new type of kinetic model, which explicitly incorporates uncertainty in a statistically principled manner, using trypanosome metabolism as our test case. This project will be centred in making computer-based predictions on parameter ranges of individual enzymes that can explain whole model outputs. A detailed classical model is available as a starting point. Selected parameters that turn out to be particularly influential for predicted parasite biology will be quantified and updated based on targeted experimentation.
A role for ribokinase in maintaining metabolic phosphate balance.
Prof Mike Barrett
Trypanosomes cause the disease sleeping sickness. These parasites have an intriguing metabolism whereby they compartmentalize many of the early steps of glycolysis within an organelle, the glycosome. It appears that compartmentalization allows them to regulate glucose metabolism by carefully balancing phosphate and redox balance within the organelle. This project proposes to determine the rate at which ribose 5-phosphate and ribose accumulate within trypanosomes in wild type cells and also cells in which the ribokinase enzyme is down regulated. State of the art laboratory-based metabolomic analysis taking measurements in time series will describe the rates at which these metabolites interconvert. The data will be added to dynamic models of trypanosome metabolism as iterative rounds of model building aim to reproduce laboratory observations.
Double in vivo and systems projects
Note: where indicated, these projects may also be available as separate stand alone in vivo or systems projects.
Modelling chronic inflammation and cancer
Dr. Joanna B. Wilson (in vivo modelling) and Dr. Karl Burgess (metabolomics)
Chronic inflammation results as a response by the immune system that is either misdirected or directed to an insult that cannot be irradiated. Chronic inflammation is evident in most autoimmune disorders (such as rheumatoid arthritis) as well as being a feature of several types of cancer. The main focus in the laboratory is the development and study of transgenic models of cancer, including virus-associated cancer. In addition, we study factors associated with chronic inflammation and their role in cancer predisposition. Project 1. In this project various factors that promote inflammation and/or oxidative stress, such as CD30 and s100A9 (respectively), will be inhibited in vivo to examine their potential as therapeutic targets. In vivo imaging will be used to quantify the inflammation through the study. Project 2, the metabolomic impact of the treatment regimes used in project 1 will be explored, comparing the finger prints of treated tissues against controls and using this to explore the underlying mechanisms at work.
NOTE: these projects may also be available as stand alone projects
A metabolomic approach to identify novel target microRNA(s) for therapeutic intervention in experimental stroke
Dr. Martin W. McBride (systems) & Dr. Lorraine M. Work (in vivo)
Currently, stroke patients occupy 1/5 acute and 1/4 longterm hospital beds. In real terms there has been a 30% increase in the total cost of stroke to the UK economy from 1991-2007 and, with an ageing population, this is only going to increase further. Improving care for those with stroke is a global health priority and novel treatments are sorely needed. Reperfusion therapy is the cornerstone of treatment for acute ischaemic stroke, yet therapy can only be delivered to a fraction of patients. MicroRNAs (miRNAs) are small RNAs which regulate post-transcriptional gene expression and their expression has been shown to be altered in many neurological disorders. A single miRNA can alter the expression of many genes and as such, their manipulation could have significant therapeutic potential in multi-factorial disorders such as stroke. To characterise and gain insights into the molecular processes and interactions that result from altered signature patterns of miRNA expression, we will undertake further high-through put molecular analysis of tissue taken from the peri-infarct region following experimental stroke in hypertensive rats. In project 1 we will generate metabolomic profiles from this tissue taken at both 24 and 72 hours after stroke to allow longitudinal changes in tissue surrounding both the evolving and final lesion to be studied. A key component of these comprehensive studies will be to integrate previously generated miRNA signature patterns with metabolic profiles using in-house software solutions and publically and commercially available software; Perseus and Ingenuity Pathway Analysis miRNAs will be prioritised based on their potential functional effect within the metabolomic profile. Based on the results of the integration of these 2 analysis platforms, candidate miRNA(s) will be taken forward into project 2 to determine their therapeutic efficacy when administered after experimental stroke. Candidate miRNA(s) will be administered in a robust pre-clinical stroke model using spontaneously hypertensive stroke prone rats (SHRSP) which exhibit a number of the co-morbidities associated with stroke (e.g. hypertension, altered glucose handling & basal inflammatory status). The effect of miRNA modulation on neurological deficit will be determined longitudinally to day 14 post-stroke along with final infarct measure. A number of ex vivo analyses will include immunohistochemistry, in situ hybridisation and quantitative real-time PCR. This comprehensive research proposal will demonstrate the potential for integration of a systems-based approach to a complex disease in a clinically relevant animal model.
MicroRNAs involved in the response to spinal cord injury and mechanisms of repair
Dr John Riddell & Dr Lorraine Work
MicroRNAs are small non-coding RNAs, which bind to target mRNAs thereby regulating (mainly inhibiting) their expression. They are emerging as key modulators of post-transcriptional gene regulation and in the nervous system have widespread roles in development and in regulating the connectivity of the adult brain. There is also evidence that they play a role following ischaemic and traumatic damage to the nervous system. However, the role of miRNAs in spinal cord injury is poorly understood and it is likely that they can have either a detrimental or neuroprotective/reparative effect. We are currently conducting an open array study in which miRNAs in cerebrospinal fluid from spinal cord injured animals and sham controls will be compared. The aim of these projects is to validate the expression changes found using the microarray approach (Project 1: systems based) and then to investigate the functional role of one or more selected miRNAs in a spinal cord injury model (Project 2: in vivo based). The projects may also be available as stand alone projects.
In the first project the most interesting miRNAs identified in the open array study will be selected for validation. Expression of the chosen miRNA targets will be investigated using western blotting at different time points after injury and in situ hybridisation will be used to determine the distribution of the miRNAs within the spinal cord and their likely source. This will provide further information on the role of miRNAs in the pathology of spinal cord injury and in the reparative response. This will be essential in order to identify those miRNAs that might profitably be manipulated to minimise the mechanisms of secondary damage following spinal cord injury and harnessing mechanisms of repair.
In the second Project, the most promising of the miRNAs validated in the first project will be selected for further investigation. The aim of this project will be to determine the role of the selected miRNA in the response to spinal cord injury using a rodent spinal cord contusion injury model. Vector-based modulators (inhibiting or over expressing) of the miRNA will be used to block the actions of the chosen miRNA either by direct injection into the spinal cord close to the injury site or by intrathecal injection. The effect of this on the response to spinal cord injury will be investigated and compared to animals with injuries but without the miRNA blocker. The nature of the investigation will depend on the targets of the chosen miRNA and the processes they regulate but may include axonal regeneration, plasticity, remyelination, glial scarring, immune response, or neural cell death. Investigation of pathological mechanism may be complemented by assessment of functional outcome measures.
Cytokines produced by mesenchymal stem cells in culture and following transplantation for spinal cord repair: potential for modulation of the immune response.
Dr. Jo Mountford & Dr. John Riddell
Transplants of stem cells, including mesenchymal stem cells (MSCs), is one promising therapy under investigation for spinal cord injury. Transplants of MSCs obtained from bone marrow improve functional outcome in rodent models of spinal cord injury and one potential mechanism of action is modulation of the immune response at the injury site by the secretion of cytokines. A more practical way of producing quality controlled batches of cells on a large scale (as required for a translatable therapy), is to derive them from human embryonic stem cells (hESCs) and we are currently testing hESC-derived MSCs in animal models of spinal cord injury. The aim of this project is to investigate the cytokines produced by hESC-derived MSCs in culture (Project 1: systems based) and then to determine whether, following transplantation into a spinal cord injury, release of the same cytokines modifies the immune response (Project 2: in vivo based project). These projects may also be available as stand alone projects.
Bone marrow derived MSCs have been shown to secrete cytokines in culture but we do not know whether hESC derived MSCs also secrete cytokines. In the first project, we will culture hESC-derived MSCs and collect conditioned medium from the cultures for cytokine analysis. Cytokines will be detected using the luminex cytokine array system. The analysis will be carried out at an early time point following differentiation and after the number of passages normally used to expand cell numbers for transplantation. This will enable us to determine whether the secretion pattern is affected by the age of the cells and whether secretion levels are appropriate at the time the cells are prepared for transplantation.
It is generally assumed that MSCs continue to secrete cytokines when transplanted. In the second project, hESC-derived MSCs will be transplanted into the injury site of rodents with contusion injuries of the spinal cord. Two weeks after transplantation cerebrospinal fluid (csf) samples will be taken from the animals and this will be subjected to the same cytokine analysis as the conditioned medium in project 1. Western blot and ELISA will be performed if cytokines are not detectable in csf. To determine whether the cells skew the activation of macrophages at the injury site towards those with beneficial (M2) rather than detrimental (M1) actions. The numbers of macrophages with M1 and M2 phenotypes at the injury site will be quantified by immunocytochemical labelling of perfusion fixed spinal cord material taken from the transplanted injury site (or non-transplanted injury site in sham animals) and/or by flow cytometry of dissociated spinal cord tissue freshly removed from injured or sham animals.
Abnormal development of uterine/placental vasculature during pregnancy in the SHRSP; in vivo characterisation and metabolomic assessment
Dr Delyth Graham (in vivo) & Dr Martin McBride (systems)
Preeclampsia is a disease of first pregnancies, where abnormal trophoblast invasion in the uterine arteries leads to inadequate placental perfusion and foetal growth restriction. Disturbed intrauterine growth in humans has previously been shown to negatively influence the development of the cardiovascular system leading to cardiovascular disease in adult life (Barker hypothesis). In the spontaneously hypertensive stroke prone rat (SHRSP), offspring from first litters have been shown to develop severe hypertension and exaggerated sensitivity to salt challenge during maturity compared to offspring from subsequent litters from the same parents. We hypothesise that abnormal development of the uterine/placental vasculature during first pregnancy leads to foetal growth restriction and cardiovascular disease in adulthood.
In the first project (in vivo based) we will examine the first-time pregnant SHRSP as a model of spontaneous preeclampsia. This will involve the comparison of haemodynamic profiles (radiotelemetry), urinary protein excretion and uterine artery function and structure in aged matched female SHRSP during first and subsequent pregnancies and in non-pregnant rats. Uterine arteries will be harvested from pregnant rats at 18 days gestation and used for histology and myography (to assess uterine artery function and structure), and also to generate tissues for the transcriptomic/ metabolomic assessment (systems base project). Urine will be collected using metabolic cages. Litter size and neonate weight will also be compared in subsets of females allowed to progress to parturition.
In the second project (systems based) we will use the previously harvested uterine/placental artery tissue, urine and plasma to generate metabolomic profiles by mass spectrometry (HILIC-MS). This will allow us to characterise and compare multiple metabolic signatures in non-pregnant, normal pregnant and pregnant rats with inadequate placental perfusion. The data generated in this project will allow us to explore the underlying molecular mechanisms contributing to abnormal development of uterine/placental vasculature during pregnancy in the SHRSP rat.
Modelling Myocardial infarction using MRI data
Professor GL Smith and Dr Colin Berry
Our research focus is acute myocardial infarction which is a leading global cause of premature illness and death.1 We use magnetic resonance imaging (MRI) in our research since it is highly informative for heart function and injury. Pre-clinical studies using cardiac MRI in animal models provide useful information which may not be possible to obtain clinically. The BHF Glasgow Cardiovascular Research Centre has recently established a state-of-the art 3.0 Tesla MRI facility.2We are undertaking translational research with MRI and mathematical models to better understand the pathophysiology of adverse remodelling after acute myocardial infarction (MI).This translational approach means that we study the research problem using standardised methods which can be used in a similar way from experimental studies through to downstream clinical studies. Ultimately, the use of the same MRI methods in animal models and patients will help provide clinically-relevant results. In this MRes project, we will focus on imaging the rabbit heart. This model is well established in our Centre (Professor Godfrey Smith’s group3). Our MRI team have recent experience of rabbit heart imaging at 3.0 Tesla (in vivo and ex vivo). Furthermore, both teams currently collaborate with Professor Luo4 and Hill in the Mathematical Biology Group. This study will bring together these groups in order to image and model the healthy rabbit heart in vivo. MRI methods will involve trueFISP cine for mass and function. Computer methods will potentially involve non-linear techniques and finite element modelling. The student will be supervised and supported throughout the project in order to achieve learning and development objectives. The first objective is to develop and optimise survival imaging in the rabbit, using a team-based approach to identify problems and solutions. The second objective is to provide cardiac MRI data which will be useful for mathematical modelling. These are key methodological steps which would set the scene for the next stage, which would be survival imaging before and after experimental MI. Paired MRI data would then be used to study mathematically the affects of acute injury on heart structure and function.
How to Apply
Deadline for applications: 2015 NOW CLOSED
To apply for the MRC Scholarship funded Master of Research in Biomedical Sciences (Integrative Mammalian Biology) postgraduate degree, you will need to apply online. You will not be allowed to apply by any other means. Our system allows you to fill out the standard application form online and submit this to the University within 42 days of starting your application. Please read this page in full before you apply. Part of the selection process will involve an interview.
Candidates for this scholarship must have at least an upper second class Honours degree or equivalent in a relevant subject (for instance physiology, pharmacology, neuroscience or veterinary medicine but we also welcome students with backgrounds in systems approaches such as mathematical modelling, computing, ‘omics’, bio-engineering).
Candidates must also be eligible by residence for a Medical Research Council Award. (Applicants must ordinarily have been resident in the UK, or from the EU and studying in the UK, for at least the three years prior to applying).
Applicants to this programme, whose first language is not English, are required to meet the same English language requirements as listed under Entry Requirements for the MRes in Biomedical Sciences. Only a small number of scholarships are offered for this programme, which is not available to any additional fee paying students.
Completing your Application
To ensure you apply for the correct course please note that you should enter the following using the drop-down menus/search button:
- Academic Career: Postgraduate Taught
- Mode of Study: Full Time
- Programme of Study: MRes in Biomedical Sciences (Integrative Mammalian Biology)
This is the MRC funded scholarship and includes Systems Biology and should not be confused with any of the other MRes programmes*
*Other MRes programmes in Biomedical Sciences programmes include:
MRes in Biomedical Sciences (Integrative Mammalian Biology) SFC fee waiver
MRes in Biomedical Sciences
Supporting documents must include:
- Evidence of Academic Qualification, eg degree transcripts
- Language test (if relevant)
- Personal statement: 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 could 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 but should include other relevant experience that makes you particularly suitable for this scholarship.
- Reference 1 This should be from an academic who has knowledge of your academic ability from your most recent study/programme and should be on headed paper.
- Reference 2 This should be from an academic who has knowledge of your academic ability and should be on headed paper.
If you are unable to submit any of the supporting documents online, they should be sent to:
Institute of Cardiovascular and Medical Sciences, BHF GCRC, RC209
126 University Place
University of Glasgow
Glasgow, G12 8TA
Dates: Classes start September 2015 (provisional date) for most courses and you may be expected to attend induction sessions the week before
Informal enquiries can be directed to Dr Lorraine Work