MRC IMPACT PhD projects

impact-logo-jpeg-300pxApplication deadlines: Applications for the 2018 academic year are now open. The deadline is 11pm Wednesday 28 February 2018
Number of Studentships available: 4 at the University of Birmingham and 4 at the University of Leicester and 4 at the University of Nottingham
Please email us with enquiries:


University of Birmingham

Project title: New paradigm of GPCR signalling at intracellular sites in metabolic diseases
Supervisors:  Professor Davide Calebiro (University of Birmingham),  Dr Stephen J. Hill (University of Nottingham) and  Professor Gareth Lavery  (University of Birmingham)

G protein-coupled receptors (GPCRs) mediate the effects of several hormones and neurotransmitters and are major pharmacological targets. Whereas GPCRs were long believed to signal exclusively at the plasma membrane, our recent findings indicate that these receptors signal also at intracellular sites, such as early endosomes or the Golgi. In this project, advanced live-cell imaging methods, such as FRET/BRET, FCS and single-molecule microscopy, will be combined with state-of-the-art metabolomics to investigate the role of GPCR signalling at intracellular sites in adipocyte metabolism. We expect these experiments to lead to a deeper understanding of the mechanisms involved in the regulation of adipocyte metabolism and to the identification of new molecular targets for the therapy of metabolic diseases. The successful applicant will join a vibrant, dynamic and internationally-recognised team at the Institute of Metabolism and Systems Research and at the Centre of Membrane Proteins and Receptors of the Universities of Birmingham and Nottingham.

Project title: Identifying platelet derived proteins that regulate the thrombo-inflammatory recruitment of monocytes in atherosclerosis.
Supervisors:  Professor Ed Rainger (University of Birmingham), Professor Alison Goodall (University of Leicester) and Dr Myriam Chimen (University of Birmingham)

It has long been appreciated that platelets play an important role in the symptomatic stages of cardiovascular disease by contributing to the formation of the thrombus which precipitates heart attack and stroke. However, we now realise that platelets also interact with the inflammatory response to support initiation and development of atherosclerotic plaque long before symptomatic disease is apparent. Why is this important? Because platelets did not evolve as key cellular components of the immune and inflammatory responses, meaning that their contributions (thrombo-inflammation) are not appropriately regulated and can result in pathology. We now believe that platelet activation and shedding of platelet derived extracellular vesicles (PEV) is a major communication route between leukocytes and monocytes in the circulation. In this study we will identify the ‘cargo’ transferred from platelets to monocytes via PEV and using in vitro and in vivo assays, determine how this regulates monocyte recruitment and migration.

Project title: Exploration of the global manipulation of transcriptional networks by oncogenic human papillomavirus
Supervisors:  Dr Joanna Parish (University of Birmingham) and Dr Sally Roberts (University of Birmingham)

Human papillomaviruses (HPV) cause cancers of the anogenital and oropharyngeal tracts. The HPV life cycle is dependent on the differentiation of infected keratinocytes. Infection is established in the undifferentiated basal keratinocytes where the chromatinised viral DNA is maintained and viral transcripts encoding viral oncoproteins are expressed. Differentiation of cells within the epithelium coincides with activation of the late virus promoter and capsid protein synthesis. As well as controlling expression of their own genes, viruses create a host environment that supports replication. The mechanisms of virus-mediated transcriptional reprogramming during the HPV life cycle are not understood but we hypothesize that HPV epigenetically reprograms the host to create a cellular milieu supportive of viral persistence and these changes contribute to HPV-driven carcinogenesis. The student will use state-of-the-art models of HPV-infected tissue, and advanced technological methods to dissect genome wide host manipulation during infection and determine those changes that contribute to HPV-driven cancer. 

Project title: Understanding how tetraspanins and the ‘molecular scissor’ ADAM10 promote blood cancer
upervisors:  Dr Mike Tomlinson (University of Birmingham), Dr Steve Briddon (University of Nottingham), Dr Farhat Khanim (University of Birmingham) and Professor Nick Holliday (University of Nottingham)

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive blood cancer that is in urgent need of more effective therapies.  Over 65% of T-ALL is driven by activating mutations in the cell fate regulator Notch1, which allow its activation by the ‘molecular scissor’ ADAM10.  We have discovered that ADAM10 substrate specificity is dictated by its association with one of six regulatory tetraspanins - Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33.  We propose that ADAM10 is not one scissor, but six different scissors depending on the associated tetraspanin.  The aims of this project are to determine (1) which tetraspanin(s) promotes cleavage of mutant Notch1 in T-ALL, (2) whether cleavage occurs at the cell surface or on vesicles following endocytosis, and (3) whether targeting TspanC8s with antibodies can inhibit proliferation of T-ALL cell lines and primary cells from patients.  Experimental techniques will include CRISPR/Cas9 genome editing and advanced fluorescent microscopy.

Project title: The human gut microbiome as a reservoir of antibiotic resistance
Supervisors: Professor Willem van Schaik (University of Birmingham) and Dr Sarah Kuehne (University of Birmingham)

The human gut harbours a complex microbial community (‘the gut microbiome’), which contributes to human health. Previous work by Professor Van Schaik has revealed that the gut microbiome comprises a large number of antibiotic resistance genes. Current methodologies to study the gut microbiome do not allow for the identification of the bacteria that carry these resistance genes. The extent by which resistance genes can spread in gut microbiome also remains unclear.

In this project, you will use innovative experimental approaches to determine the bacterial reservoirs of antibiotic resistance genes in the gut microbiome. Strains harbouring resistance genes will be cultured and characterized by genome sequencing. Finally, conjugation assays will be performed to assess the ability of these bacteria to serve as donors of resistance genes to opportunistic pathogens.

This project will importantly deepen our understanding of the mechanisms that contribute to the rapid spread of antibiotic resistance in bacterial ecosystems.

Project title: Does obesity-associated synovitis promote joint pain in osteoarthritis?
Supervisors: Dr Simon Wyn Jones (University of Birmingham) and Professor Victoria Chapman (University of Nottingham)

Generic analgesics for OA patients provide minimal relief and are associated with severe side effects, emphasising the need for a disease-specific targeted approach.  In knee OA, distinct patterns of inflamed synovial tissue (synovitis) are associated with pain and synovitis promotes OA pain severity due to the sensitizing action of inflammatory cytokines on joint nociceptors.

We recently reported that the synovial fluid of obese OA patients is more inflammatory compared to normal-weight patients, with the cells of the joint lining (synovial fibroblasts) secreting more pro-inflammatory cytokines.  This suggests that the intrinsic phenotype of the obese OA synovial fibroblast is a major contributor to the inflammatory OA joint environment.  This project will therefore determine whether obesity-associated synovitis promotes joint pain in OA and determine the functional role of inflammation-associated RNA transcripts in mediating OA pain.

Project title: Understanding of metabolism and functions for non-coding RNA in Prader-Willi syndrome
Supervisors: Dr Pawel Grzechnik (University of Birmingham) and Professor Chris Bunce (University of Birmingham)

The goal of the project is to understand transcriptional processes leading to neuro-developmental disorder known as Prader-Willi syndrome (PWS). PWS it is the most common syndromal cause of life-threatening obesity in humans. PWS patients display broad pathological spectrum including dysmorphic changes, behavioural problems and mild intellectual disabilities. The syndrome results from the loss of expression of various chromatin associated, non-coding RNAs synthesized from the PWS region. Thus, the aim of this project is to investigate how non-coding RNAs transcribed from the PWS locus affect global transcription and chromatin organization. Elucidating of molecular mechanisms of Prader-Willi syndrome will help to better understand roles for non-coding RNA in the development of the human body. The project will employ a wide variety of molecular and cell biology techniques including genome editing, RNA sequencing, chromosome conformation capture techniques and RNA and protein visualization in situ

Project title: Identifying Novel Therapies to Prevent Atherosclerosis
Supervisors: Professor Roy Bicknell (University of Birmingham) and Professor Ed Rainger (University of Birmingham) and Dr Asif Iqbal (University of Birmingham)

There is intense interest in identifying the genes that predispose to the development of atherosclerosis. We recently carried out an expression analysis of human tissue using microarrays that identified several candidate genes. Generating knockout mice and crossing them to apoE knockout mice followed by placing the double knockout mice on a high fat diet confirmed that at least two of the genes strongly promote atherosclerosis. The aim of this project is to examine whether blocking of these genes using several molecular approaches can prevent development of the atherosclerotic plaques in mice.

That our novel genes are major promoters of atherosclerosis and that blocking their activity can prevent the development of plaques in ApoE knockout mice.

Experimental Methods and Research Plan
Experimental Methods to be learned in the project: Basic molecular biology, DNA cloning, protein expression, gene expression analysis using microarrays, mouse models of disease, genetic alteration of mice using CRISPR, mouse pathology, histochemical tissue analysis

Project Title: Understanding how extracellular environmental factors promote altered intracellular signalling and gene expression networks using transcriptomics in tumour models: development of Cholangitis and Cholangiocarcinoma
Supervisors: Dr Padma-Sheela Jayaraman (University of Birmingham) and Professor Anna Grabowska (University of Nottingham)

Invasive Cholangiocarcinoma (CCA) is an aggressive cancer of the bile duct with very poor prognosis and few treatments. Primary Sclerosing Cholangitis (PSC) is a chronic inflammatory disease of the bile duct where there is no effective treatment other than liver transplantation. New treatments for both are urgently required.

The Proline Rich Homeodomain (PRH/HHEX) protein is a transcription factor with a role in tumour formation in a variety of cancers. PRH is essential for liver and bile duct development. PRH regulates gene expression using multiple mechanisms including recruitment of epigenetic regulators. PRH protein levels are altered in CCA and we wish to investigate the hypothesis that alterations in PRH proteins are regulated by the extracellular environment through activation of, inflammatory or bile acid signalling pathways or through stromal cell interactions. To understand the role of the extracellular environment we will use a combination of cell lines, primary bile duct tissues, in vivo mouse models and primary xenograft derived tissues coupled with transcriptomics approaches.

University of Leicester

Project title: Unravelling the interplay between tau and the kynurenine pathway in neurodegenerative disease
Supervisors: Professor Flaviano Giorgini and Professor Charalambos Kyriacou
Supervisor Department: Genetics

Tryptophan metabolism via the kynurenine pathway produces neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. The enzyme kynurenine 3-monooxygenase (KMO) plays a central role regulating metabolic flux through this pathway. We have shown that inhibition of KMO activity in several models of neurodegeneration normalizes metabolic perturbations in this pathway and ameliorates disease phenotypes. However, the therapeutic potential of modulating KMO activity to target the toxicity of tau – an aggregation-prone protein closely linked to the pathology of Alzheimer’s and Parkinson’s diseases – has never been explored. This PhD studentship will employ a fruit fly model of tauopathy to explore the effects of kynurenine pathway manipulation on neurodegeneration-related phenotypes using genetic and pharmacological approaches. Several technologies will be employed, including behavioural and neurodegeneration assays in Drosophila and biochemical/cell-based assays exploring the tau aggregation/phosphorylation, as well as analysis of pathway metabolites and neurotransmitters.

Project title: Identification of cochlear stress granules in hidden hearing loss
Supervisors: Dr Martine Hamann and Professor Flaviano Giorgini
Supervisor Department: Neuroscience, Psychology and Behaviour

Studies on noise-induced hearing loss classically focus on the drastic damage inflicted upon cochlear hair cells. Noise-induced hearing loss is often visible after a few months, as the cochlear damage becomes irreversible. Stress granules are cytoplasmic aggregates of proteins and RNAs that appear under stress conditions. Our recent studies have identified stress granules in cochlear hair cells minutes following acoustic over-exposure. The project will explore whether cochlear stress granules are biomarkers of the early stages of hidden hearing loss. The presence of stress granules will be evaluated by immunofluorescence for specific stress granule markers.  Proteomic and transcriptomic analysis will provide mechanistic insights into their function and their specific link to signalling pathways. The project will also test the ability of antioxidants to reduce the presence of stress granules and stop or delay the damage of cochlear structures that is indicative of permanent hearing loss.

Project title: How the interaction of air pollution, respiratory pathogens and the microbiota exacerbates respiratory disease
Dr Julie MorrisseyProfessor Julian KetleyProfessor Peter Andrew and Dr Neil Greening
Supervisor Department: Genetics

Air pollution particularly that due to particulate matter (PM), is the largest single global health risk, with increasing PM matching rises in respiratory diseases, notably chronic obstructive pulmonary disease (COPD). COPD, the third largest cause of death, is a respiratory disease that involves progressive loss of lung function and is characterised by periodic exacerbations that worsen the disease. PM is a cause of exacerbation and following our novel work on the effect of PM on respiratory pathogens, we propose that PM changes the respiratory microbiome, potentiating respiratory infection that in turn exacerbates COPD. In this project you will determine how PM affects the nasopharyngeal microbiome of COPD patients, and the pathogens associated with COPD exacerbation. You will establish the correlations between the effect of PM on bacteria, COPD exacerbation, and clinical outcome. 

The project involves clinical research with patient contact, in vivo infection models, cutting edge molecular microbiology and bioinformatics. 

Project title: Use of the tumour explant platform combined with digital pathology evaluation to characterise the response of the tumour microenvironment to anticancer therapy.
Professor Catrin Pritchard and Professor Marion MacFarlane
Supervisor Department: Cancer Studies

Attrition is a major problem in anticancer drug development with ~95% of drugs tested in Phase I trials not reaching the market. The demand for better pre-clinical models that more accurately predict success in clinical trials has motivated us to invest in a patient-relevant tumour “explant” platform ( In this approach, tumour samples are obtained fresh from surgery and cultured ex vivo as small fragments that retain the tumour microenvironment intact. Drug responses are assessed in situ, mimicking patient responses. The aim of this studentship is to further develop the platform by incorporating digital pathology to evaluate tumour/stroma responses to anticancer agents. Digital pathology is an image-based platform enabled by computer technology that has recently been adapted for multi-colour fluorescence imaging. The student will be trained in this technology, so gaining expertise in cutting-edge digital methods and their application to cancer diagnosis, development of new therapies and biomarkers.

Project title: Contribution of the gut microbiome and potential therapeutic targets in cardiovascular disease risk
Professor Toru SuzukiProfessor Marco Oggioni and Dr Liam Heaney
Supervisor Department: Cardiovascular Sciences

This multidisciplinary project combines the use of microbiology, in vivo research models and analytical science to identify bacterial contributions for the production of trimethylamine (TMA). TMAO, a downstream metabolite of TMA, is a circulating metabolic biomarker of the gut microbiome that has been shown to associate with increased severity and adverse events (e.g. mortality/hospitalisation) in cardiovascular diseases including heart failure and myocardial infarction. A series of projects will be performed to identify the bacteria responsible for the production of TMA in the gut, as well as those capable of metabolising TMA as a potential therapeutic intervention to reduce the bioavailability of TMA and therefore reduce circulating levels of TMAO. The projects will include the use of next generation sequencing for microbiome analysis and gene expression profiling, animal models of bacterial infection, and bio fluid analyses using common laboratory techniques and advanced techniques including liquid chromatography-mass spectrometry for metabolome analysis.

Project title: Sex-specific genetic architecture of Idiopathic Pulmonary Fibrosis 
Professor Louise Wain and Professor Gisli Jenkins
Supervisor Department: Health Sciences

Idiopathic Pulmonary Fibrosis (IPF) is a rare, chronic and progressive lung disease with poor prognosis and limited treatment options. More men than women are diagnosed with IPF and the primary aim of this project will be to understand the genetic factors that drive this difference in order to further our understanding of the disease process to aid development of new therapeutic strategies.  The student will be based within an internationally-recognised respiratory genetic epidemiology group and benefit from close collaborations with leading IPF clinicians and researchers from the UK and USA.  A broad training in genetic epidemiology will equip the student for a career in the fast-moving and opportunity-rich field of human disease genetics. Applicants should have a background in bioinformatics, epidemiology, statistics or genetics (or similar), with an aptitude for computing (prior programming experience advantageous but not essential) and a keen interest in how genetics affects human health and disease.

University of Nottingham

Project Title: Integrins in liver fibrosis
Supervisors: Professor Guruprasad Aithal, Dr Andrew Bennett, Professor Simon Macdonald and Dr Jane Grove

In the liver, several av-containing integrin heterodimers have been described: aVb1, aVb3, aVb5, aVb6 and aVb8. Integrins are involved in the activation of TGFb and mechanosensing of tissue stiffness. We will 1) determine the pattern and level of expression of av and b1,3,5,6 and 8 integrins at the protein level in human liver samples from patients with varying degrees of fibrosis and use co-localization with activated hepatic stellate cell markers to indicate potential involvement with disease, 2) establish a primary human stellate culture system on hydrogels of varying stiffness to model fibrosis in vitro and determine expression of av-containing integrin heterodimers at varying stages of stellate cell activation, 3) assess efficacy of a panel of soluble integrin inhibitors upon stellate cell activation examining TGFb activation and stiffness induced signal transduction and 4) determine whether soluble integrin inhibitors can reverse stellate cell activation to a quiescent state once fibrogenic processes are established.

Project Title:The role of the Glycocalyx Structure in Vascular Permeability
Supervisor: Dr Kenton Arkill, Professor Dave Bates and Dr Cathy Merry

When fluid and proteins leak out of the blood into the tissues, severe disease can occur, and this happens acutely in sepsis and cancer, but chronically in diabetes. Capillary walls, including the endothelial glycocalyx, control molecular movement out of the vasculature. This glycocalyx is a size and charge filter that is disrupted in pathological states, and a key consideration in drug delivery methods and fluid therapies. The filter structure remains poorly defined due to incomplete in-vitro models.

This project will use new cryo-electron microscopy and ion beam mass spectroscopy techniques to define the physiological structure, and the mechanisms behind glycocalyx control. The outcomes will form the bedrock to elucidate how pathologies such as diabetes, can be therapeutically rectified.

The student will join Dr Arkill’s multidisciplinary team based in the Tumour and Vascular Research Laboratories but includes training and use of Glycobiology and the Nanoscale and Microscale Research Centre.

Project title: High-resolution iron mapping to study the role of brain iron complexes in the basal forebrain in neuropsychiatric disorders
Supervisor: Professor Richard Bowtell Professor Dorothee Auer, Professor Penny Gowland and Dr Galina Pavlovskaya

The mechanisms of brain iron changes underlying neurodegenerative diseases are largely unknown. One hypothesis suggests that erythrocytes leak through an impaired blood-brain barrier leading to activation of microglia. This results in intracellular deposition of haemosiderin, a disorganised iron storage complex which contains unbound iron ions. In this state, iron is neurotoxic producing free radicals and causing oxidative stress. The nucleus basalis of Meynert is a cholinergic basal forebrain nucleus which is affected early in the course of many neuropsychiatric disorders. Brain iron can be detected using gradient-echo MRI with areas of high iron appearing hypo-intense in magnitude images. Advanced susceptibility mapping at high field is needed for reliable quantification. Disentangling the mechanisms that lead to iron-mediated neurotoxicity is at the frontier of multidisciplinary research and clinical imaging. Moreover, non-invasive iron mapping using MRI provides a mechanistic biomarker for disease prediction that can be exploited in future clinical trials.

Project title: Structural refinement of teixobactin for treating complex Propionibacterium acnes infection
Supervisor: Dr Weng Chan, Professor Paul Williams, and Dr Sarah Kuehne (University of Birmingham)


Propionibacterium acnes, an aerotolerant anaerobic Gram-positive organism, is commonly known as a skin commensal due to its colonisation of the sebaceous glands and hair follicles. However, P. acnes can act as an opportunistic pathogen to cause invasive infections, particularly those associated with medical implants. P. acnes is the most frequently isolated pathogen in prosthetic shoulder joint infections, and is increasingly found in medical device-related cerebro- and cardiovascular infections. Until recently, P. acnes has been susceptible to a wide range of antibiotics. However, over the past 2 decades, resistance to metronidazole, macrolides, tetracycline and trimethoprim-sulfamethoxazole has been observed with increasing frequency. Hence, new classes of antibiotics are necessary to specifically combat medical device-associated infections caused by P. acnes.

Teixobactin is a recently discovered peptide antibiotic with potent antimicrobial activity against P. acnes. This project will entail the synthesis and microbiological evaluation of dual-action teixobactin analogues as potential antimicrobials for the treatment of P. acnes infections.

The student will receive advanced training in chemical microbiology, including core skills in medicinal chemistry, synthetic organic and peptide chemistry, and antimicrobial and biofilm dispersion assays. The student will have the opportunity to spend time (30%) at UoB.

Project title: Towards Clinical Imaging of Inhibition of Mucus Degradation in Respiratory Diseases
Supervisor: Professor Galina Pavlovskaya, Professor Alan Knox, Dr Dominick Shaw and Dr Richard Graham

Airwwy mucus plugs cause airway obstruction in patients with airways disease, such as cystic fibrosis and bronchiectasis. Little is known about the effects of therapy on plug composition, airway ventilation or clinical outcome. Mucin (a major component of the plug) degradation is critical for plug clearance but in vivo methods monitoring this are lacking. We hypothesise that these changes in plug physical properties can be captured by 23Na MRI methods and propose to apply multi-scale 23Na MRI for this purpose. We will use the 9.4T scanner to tune up the relevant 23Na contrast at the molecular level ex-vivo using sputa samples of healthy volunteers and patients with bronchiectasis and cystic fribrosis pre- and post-intervention (carbocysteine/nebulised DNAse/ivacaftor) for novel 23Na whole body lung imaging at 3T and 7T in health and disease at SPMIC Nottingham. We complement results of these finding with mathematical modelling.

Project title: Defining the effects of IL33 axis genetic variants on viral induced inflammation in asthma
Supervisor: Professor Ian Sayers and Professor David Cousins (University of Leicester 

Asthma is a complex respiratory disease, with both genetic and environmental factors contributing to susceptibility and exacerbation. Rhinovirus is a major cause of exacerbations; however the contribution of host genetics and molecular mechanisms underlying these processes and are not well defined. Rhinovirus induces interleukin 33 (IL33) release from bronchial epithelial cells which activates a range of inflammatory cells that drive the exacerbation. As genetic variation in the IL33 and IL33 receptor (IL1RL1) loci have been associated with exacerbation risk we hypothesise that these variants can modulate bronchial epithelial cell responses to virus and how inflammatory cells respond to IL33 ultimately determining the magnitude of inflammation observed. This project will use a combination of cell and molecular biology, immunology and genetics to investigate epithelial cell – inflammatory cell cross talk and has scope to advance our understanding of virus induced exacerbation in asthma where there is an unmet clinical need.

Project title: NEK Kinases as novel therapeutic targets in malaria
Supervisor: Professor Rita Tewari and Professor Andrew Fry (University of Leicester)

Applications are invited from highly motivated and enthusiastic candidates for an MRC-funded PhD studentship aimed at understanding atypical cell division processes and identifying new therapeutic approaches to malaria. Plasmodium, the causative agent of malaria, leads to 200 million cases and kills more than half a million people annually with resistance to current drugs is emerging rapidly. This project will explore the roles of four NEK kinases particularly in the transmission stages and test their potential as novel therapeutic targets for malaria.

The objectives are to: (i) define the localisation of NEKs during the proliferative stages using cutting edge imaging techniques; (ii) use transgenic NEK parasite lines to identify interacting partners; and (iii) study the function of NEKs using conditional gene targeting. This multidisciplinary project will be supervised by international leaders in the fields of malaria cell biology1and NEK kinases,2,, with research visits to Crick Institute and MRC Harwell Research Centre.

Project title: Single molecule approaches to study G protein activation and arrestin recruitment by B1 adrenergic receptor
Supervisor: Professor Dmitry Veprintsev, Dr Stephen Briddon and Professor Mark Wheatley (University of Birmingham)

G protein coupled receptors convert extracellular signals mediated by hormones and neurotransmitters into intracellular responses. Interactions between receptors could lead to dramatic changes in their signalling properties and significantly expand the “pharmacological universe” of GPCRs. The aim of the project is to understand the molecular basis for functional modulation of receptors in hetero-dimers. We will combine alanine scanning mutagenesis with the state of the art FRET and BRET-based techniques to study the impact of mutations on dimerisation and signalling properties of CB2 and CCR5. While the large datasets generated will be too complex for manual analysis, the quantity of data does however allow modern machine learning techniques to be utilised. We will develop novel machine-learning approaches that can  model the complex relationships between the many interdependent variables, and to incorporate existing knowledge of the structure and function of GPCRs to augment and condition the learning.