Medical Research Council (MRC) Studentships
Doctoral Training in Medical Research
THIS PROGRAMME IS NOW CLOSED
Deadline: This Programme is now closed. First round application closing date: May 6.
Stipend: £13,726 per annum
Start date: October 2013
Details of the PhD projects available are listed over the next tabs.
This MRC funded programme provides students with cutting-edge research opportunities in Medical Research. Projects will align with MRC strategic priorities, www.mrc.ac.uk
We strongly recommend that students examine the PhD opportunities and contact potential supervisors to discuss the projects before applying. If students are interested in more than one project they may indicate the order of preference.
Applicant Instructions
These are 3.5-year PhD studentships and students should apply online here.
Applicants will normally be expected to reside (or have residency) within the UK. EU nationals will have to demonstrate that they have spent the three years prior to application resident in the UK (this can include residence whilst undertaking undergraduate study). Applicants should have obtained, or expect to obtain a 2:1 or 1st class Honours degree in a relevant subject. The financial package will include a 3.5 year stipend, approved University fees, Research Training Support Grant and a conference allowance.
On the Programme of Study section of the application please select “MVLS PhD” from the drop down menu. On this same page please place the project title(s) within the free text area and note the project supervisor(s).
Please ensure that all supporting documents are uploaded at point of application, for example:
- Copy of Academic and Professional qualifications
- CV (including letter of application/personal statement)
- 2 x references
Further supporting documents are requested on the online applications system, and should be uploaded where relevant. General enquiries regarding the programme and application procedure should be directed to Alexis Merry: Alexis.Merry@glasgow.ac.uk
Title: Investigating genetic modifiers to modulate the development of stroke caused by mutations in collagen
Supervisor: Dr Tom Van Agtmael / William Mullen
COL4A1 and COL4A2 (collagen IV alpha chain 1 and 2) are major components of the basement membrane, a specialised extracellular matrix structure that separates the endothelium from smooth muscle cells in the vasculature. COL4A1 and COL4A2 mutations lead to clinical defects including haemorrhagic stroke, muscular dystrophy as well as eye and kidney disease. The mutations have been associated with basement membrane defects but they can also cause endoplasmic reticulum stress. Therefore, the disease causing mechanism remains unknown. This poor understanding of the molecular and cellular consequences of collagen IV mutations has hampered the development of potential treatments for these currently incurable diseases. Thus, this project will determine the mechanisms by which collagen IV mutations cause disease to modulate these disease pathways. To investigate novel pathways that influence clinical outcome in patients, experiments will be performed to characterise genetic modifiers that underlie the absence of disease development in unaffected carriers of a COL4A2 mutation. By determining the molecular mechanism of collagen IV mutations and modulating pathways that can influence disease development, this project may identify future treatment avenues for collagen IV patients. These data may also be applicable to other diseases in which ER-stress and/or basement membrane defects have been implicated.
Title: The role of VEGF, PDGF and serotonin in pulmonary arterial hypertension (PAH)
Supervisor: Professor Mandy Maclean
In rodents, SUGEN (SU5416, a synthetic VEGFR-2 inhibitor), in combination with hypoxia (SU/Hx model), induces PAH and pulmonary artery endothelial cell (EC) death and obliteration of the artery by proliferating ECs. This would suggest that VEGF normally affords protection against PAH. This is consistent with studies demonstrating elevated lung VEGF ameliorates PAH. However, VEGF administration can concomitantly aggravate the fibrogenic process and is over-expressed in plexiform lesions. Imatinib, an inhibitor of the PDGF receptor) is effective against the development of PAH clinically and in the SU/Hx mouse model. It’s activity is serotonin-dependent and subsequently it was shown that development of PAH was serotonin dependent. The clinical effects of imatinib are associated with decreased plasma serotonin, so this work is very translatable. This suggests a complex relationship between VEGF, PDGF and serotonin. Here we will investigate this relationship as we believe this will lead to a greater understanding of the disease pathobiology and offer new therapeutic strategies. Our hypothesis is that serotonin overcomes the protective effects of VEGF and facilitates the pathological effects of VEGF. The student will investigate this using in vivo models and skills, human PAH pulmonary cells from controls and patients with PAH, molecular and cellular biology techniques.
Title: Regulation of aldosterone production and blood pressure by microRNAs
Supervisor: Professor Eleanor Davies / Scott McKenzie
The steroid hormone aldosterone is produced by the adrenal gland and plays an important role in sodium homeostasis and blood pressure control and its circulating level is an important determinant of cardiovascular risk and outcome. Approximately 10-15 % of patients with hypertension have excess aldosterone production (Primary hyperaldosteronism). Understanding its production and regulation is central to understanding its role in these common conditions and to the development of new cardiovascular treatments.
Recent studies have shown that microRNA molecules have a significant impact on mammalian regulatory mechanisms, and our preliminary studies show this is also true of aldosterone production. This project will combine our extensive experience of aldosterone research with cutting edge molecular biology and bioinformatic methods to examine microRNA profiles in the circulation and in the adrenal glands in patients with hypertension due to excess aldosterone production. By investigating and analysing these microRNAs patterns, this project has the potential to discover novel biomarkers for the diagnosis of primary aldosteronism, while also shedding light on the molecular events that initiate tumour formation and excess aldosterone overproduction.
Title: Pregnancy adaptation as a model to study microRNA regulation of vascular function
Supervisors: Dr Dilys Freeman / Dr Christian Delles / Martin McBride / John McClure
There is increasing evidence that microRNAs are involved in the regulation of vascular function and that microRNA profiles are disturbed in hypertension and type 2 diabetes. Vascular function is improved over time as part of the healthy adaptation to pregnancy but this process is impaired in obese women. Maternal obesity is a risk factor for preeclampsia which is characterised by widespread endothelial dysfunction and hypertension. Current evidence suggests that an, as yet unidentified, trigger from the placenta may provoke this condition. In a longitudinal study of pregnancy in lean and obese women this project aims to establish the role of microRNA in the regulation of vascular function. Initially a microRNA array analysis will be carried out to discover the changes in serum microRNA profile over gestation and to compare lean and obese women. Results will be validated in a separate pregnancy cohort that includes women with preeclampsia (the PIP study). Trophoblasts will be isolated from the placenta of lean and obese pregnant women undergoing Caesarean-section and candidate microRNA and downstream regulatory target mRNA and protein expression measured. Pathway analysis will be used to identify key molecular pathways that are regulated by microRNA and are related to changes in vascular function. Vascular function will also be assessed by wire myography in blood vessels dissected from adipose tissue. An understanding of the regulation of vascular function is important in understanding the pathophysiology of obesity-linked pregnancy complication such as preeclampsia as well as having wider-based implications for diseases of endothelial function in the non-pregnant.
Title: Constructing the systems biology of CML with a view to improving treatment
Supervisors: Professor Tessa Holyoake /Dr Heather Jorgensen /Dr Simon Rogers
Chronic myeloid leukaemia (CML) is a blood cancer driven by the constitutively active oncoprotein BCR-ABL. Although current therapies (tyrosine kinase inhibitors, TKIs) very successfully inhibit the activity of BCR-ABL and induce apoptosis in the majority of CML cells, a small population of primitive CML stem cells evades therapy and persists to re-seed the disease upon cessation of treatment. This small TKI-resistant population must be targeted to improve therapy and ultimately eradicate the disease. We have multiple datasets that describe CML biology in terms of transcriptomic (including microRNA), proteomic and epigenetic differences. By augmenting these data with transcriptomic profiles of CML stem cells resistant to TKI therapy, there is great potential to identify proteins and/or pathways critical to CML in the TKI persistent/resistant population.
In this multi-disciplinary project, we propose first to develop a database that describes CML biology from a transcriptomic, proteomic and epigenetic perspective. Then we aim to identify novel targets for CML therapy by interrogating this database for appropriate expression profiles. Finally, we intend to explore and extend existing statistical and machine learning methodologies to identify large-scale, inter-level regulatory mechanisms specific to the disease phenotype. By constructing the systems biology of CML, we hope to form a more holistic understanding of this disease and of stem cell cancers more widely.
Title: Oncogenic pathway analysis in Acute Myeloid Leukaemia
Supervisor: Dr Karen Keeshan / Professor Tessa Holyoake
The TRIB family of pseudokinase genes have recently emerged as having important roles in proliferation, survival, motility, and metabolism. There is a strong correlation between dysregulated Trib expression, acute myeloid (AML) and lymphoid Leukaemia (ALL) and cell proliferation. Our previous work has shown that elevated TRIB2 oncogene expression correlates with a specific subset of AML and ALL with NOTCH1 mutatons and dysregulated C/EBPalpa. However, how and where TRIB expression is regulated in normal and malignant haematopoiesis is poorly understood, nor is it known what signals control the expression of Trib proteins in a cell-type, cell-context, and cell-cycle dependent manner. Our work indicates that the cell cycle regulator E2F1 plays a key role in the control of Trib2 expression. Our hypothesis is that dysregulated E2F1 and cell cycle pathways contribute to increased Trib2 expression, leading to the degradation of key proteins that are important for normal haematopoietic differentiation, resulting in the differenentiation block and increased proliferation seen in acute leukaemic disease. Understanding the E2F1-Trib2 axis and the regulation of this pathway and the downstream effects of such regulation has important biological significance to the development of new targeted therapies in leukaemia. This proposal aims to investigate the regulation of the E2F1-Trib2 relationship during normal haematopoiesis and specifically in AML.
Title: Brain damage after stroke: role of Angiotensin-1-7
Supervisor: Dr Chris McCabe / Dr Stuart Nicklin /Dr Lorraine Work
The renin angiotensin system (RAS), is crucial in the control of blood pressure regulation and volume homeostasis. Angiotensin (1-7), a biologically active peptide of the RAS, is thought to counteract the deleterious effects of AngiotensinII, through actions at a distinct G Protein coupled receptor, Mas. The role of this counter-regulatory arm of the RAS in acute stroke has yet to be extensively investigated. The studentship will use in vitro cell culture models to investigate the mechanistic effects of Ang (1-7). These studies will be complemented by in vivo and MRI studies in clinically relevant rodent models of stroke (permanent, transient, embolic with rt-PA) where effects of Ang (1-7) will be investigated during the first critical hours following stroke. This project will be one of the first to investigate the role of Ang (1-7) during acute stroke and will provide exciting and valuable insights into a novel therapeutic pathway for the treatment of acute stroke.
Title: The molecular action of novel drugs designed to treat cardiovascular disease
Supervisor: Dr Stephen John Yarwood
IL-6 is an atherogenic cytokine that induces pro-inflammatory gene expression by activating the JAK/STAT signalling pathway. One crucial mechanism for down-regulating JAK/STAT signalling is via the SOCS (suppressor of cytokine signalling) family of proteins, which have an important protective role in acute and chronic inflammatory disease. Novel treatments based on the regulation of SOCS3 levels in vascular endothelial cells could therefore have extremely important value in the treatment of diseases like atherosclerosis. We have identified a heterocyclic small molecule (MW <300) from a screen of compounds that can positively regulate the transcription of the SOCS3 gene. Our aims are to identify more potent compounds and to determine how they control SOCS3 expression. Using this approach, we will identify their protein target and validate whether it is therapeutically relevant as a new way to treat atherosclerosis.
Title: Peripubertal hormones and male cognitive development
Supervisor: Dr Jane Robinson /Professor Neil Evans
Puberty is a time of great developmental and cognitive change which impacts on many aspects of our adult life. The mechanisms that underlie this suite of changes are not fully understood. Using an in vivo ovine model this project will separate the hormonal events that occur at puberty from developmental age and examine the effects on cognitive function, specifically aspects of learning behaviour. Using behavioural and neurobiological techniques the project will investigate the functional/anatomical changes that underlie such peri-pubertal cognitive changes. In addition, the project will investigate whether these peripubertal changes in brain function/anatomy/behaviour are driven by brain or gonadal hormones and whether there is a critical window of time during pubertal development that permanently fixes gender specific patterns of behaviour. The results are of clinical interest as, in addition to the cognitive change that occurs at puberty, age related cognitive decline including conditions such as Alzheimer’s disease may be affected by changes in circulating concentrations of reproductive hormones. A greater understanding of how hormones affect cognitive function could, thus, be of clinical benefit for the understanding and possible treatment of age related cognitive change, be they at puberty (e.g ADHD) or in old age (dementias).
Title: Functional analysis of mice with targeted deletion of a gene newly-implicated in schizophrenia
Supervisor: Professor Brian Morris
Schizophrenia is a common and severely debilitating disease with a strong genetic influence. We have recently found that a gene involved in glutamatergic signalling - MAP2K7 –shows a strong genetic association with schizophrenia. This projectaims to test the hypothesis that the MAP2K7 gene plays a causal role in neurochemical and cognitive processes that are compromised in schizophrenia. The project will focus on testing for schizophrenia-related phenotypes in mice with a genetic deletion of the Map2k7 gene, as compared to control mice. A variety of technical approaches will be used. Neurochemical and molecular techniques will include RT-PCR, in situ hybridisation and immunohistochemistry. Behavioural techniques will include working memory and attentional tasks. The project aims to answer three related questions:
1) Does Map2k7 deficiency produce the neurochemical changes characteristic of schizophrenia (glutamatergic and GABAergic deficits in the prefrontal cortex and hippocampus) ?
2) Does Map2k7 interact functionally with other schizophrenia risk genes (neuregulin, dysbindin), and does Map2k7 deficiency impair glutamatergic signalling ?
3) Does Map2k7 deficiency produce behavioural changes characteristic of schizophrenia (deficits in working memory and attentional processing) ?
It is anticipated that the results will provide new insight into the aetiology of key functional deficits in schizophrenia. The project may also identify a new translational model for schizophrenia. In addition, the project will provide training in a wide range of techniques that are currently a major focus of research activity.
Title: Caenorhabditis elegans autophagy and development
Supervisor: Dr Iain Johnstone / Dr Nia Bryant
Autophagy (macroautophagy) is known as a bulk cellular degradation process. Its best-understood functions are as a response to nutrient starvation where it can provide cells with an internal source of nutrients, and to diverse forms of stress whereby damaged and defective proteins, membranes and intact organelles can be turned over and metabolites recovered (Rabinowitz and White, 2010). In recent years autophagy has been linked to an almost bewildering list of human diseases. A growing body of evidence points to functions for autophagy during normal multi-cellular animal development, including functions that are not be easily observed in cell culture. Using the model animal C. elegans, we have found evidence linking autophagy to collagen secretion, formation of extra-cellular matrix and the control of organ and animal size. Further elucidation of these roles in basic development is important for the correct interpretation of the roles of autophagy in disease processes.
Title: Control of ESCRT function by mitotic kinases and phosphatases
Supervisor: Professor Gwyn Gould / Dr Chris McInerny
ESCRT proteins play an integral role in processes such as cell cycle control, apoptosis, autophagy, cell fate determination, migration, invasion and cytokinesis. Understanding how ESCRT proteins are regulated therefore has the potential to impact both a wide array of biological processes and also shed light on many complex disease processes.
Using fission yeast as a model system, we have identified novel genetic and biochemical interactions between polo kinase (Plk) and a sub-subset of ESCRT proteins, suggesting that Plk may regulate distinct aspects of ESCRT biology. Similarly, we have observed interactions between the phosphatase Cdc14p and ESCRT proteins.
This studentship will define the functional consequences of these interactions using an array of well established methods, providing a wide training in cell and molecular biology in an exciting and fast moving area of biology.
Title: Life and death decisions of memory CD4 T cells
Supervisor: Dr Megan MacLeod / Professor Paul Garside
Autoimmune diseases, such as rheumatoid arthritis (RA), occur when an individual’s immune system responds to molecules within their own organs. This self-reactivity causes tissue damage that in RA leads to painful joint swelling and destruction. Current treatments can abrogate some factors responsible for this pathology but rarely achieve remission.
CD4 T cells are implicated in the initial stages of RA and play a continued role in chronic inflammation. A greater understanding of how to switch off these CD4 T cells will provide the means to design novel, rationally targeted therapeutics. However, autoimmune patients are diagnosed following disease onset, after self-reactive CD4 T cells have been activated. These activated or memory CD4 T cells are harder to control than naïve cells and we know little about the molecular signals required to switch them off.
The aim of this studentship is to investigate the molecular pathways that enable memory CD4 T cells to translate external signals into cellular decisions, in particular the decision to live or die. Using a range of in vivo mouse models and ex vivo cell assays with CD4 T cell from RA patients, this studentship offers training across a wide range of techniques. The project will generate important data that could lead to new targets to permanently turn off self-reactive CD4 T cells and thereby control RA.