Applications are now open for a range of exciting projects to study Complex Disease for a September 2019 start, with many opportunities that involve working with the NIHR Leicester BRC.
The deadline for submissions is Sunday 20 January 2019. Interviews will take place the week commencing 11 February 2019. Full details of the application process are available here: https://more.bham.ac.uk/mrc-impact/phd-opportunities/
- Detection of pathogen-specific bacteriophages in face-mask samples to distinguish colonisation from infection in exacerbations of chronic lung disease
Supervisors: Mike Barer (UoL) and Martha Clokie (UoL)
Bacteriophages are surrogate indicators of the bacterial populations they infect; they are also readily aerosolised. In this project we combine two leading edge research programmes at Leicester to investigate how phages may be used to better understand and manage the lung diseases chronic obstructive pulmonary disease (COPD) and asthma in which the airways contain high microbial populations. When people suffer deteriorations (exacerbations) culture often detects pathogens and, despite weak evidence that these organisms are responsible, patients are treated with antibiotics. The student will use our Mask Aerosol Sampling System (MASS) to take exhaled breath samples from patients when stable and when unwell and will focus on analysis of the exhaled phage population in these samples. A central hypothesis is that bacteria involved in disease pathogenesis will be stressed and more likely to induce phage activation; we already know that phages are abundant in respiratory samples. The work will be supported by the respiratory section of our NIHR Biomedical Research Centre and ongoing studies on COPD and asthma. The student will learn novel techniques in aerobiology, metagenomics and phage biology as well as key aspects of working with patients (ethics, consent and study power assessment).
2. New ways to deal with selection bias in genetic studies of disease progression
Supervisors: Frank Dudbridge (UoL), Louise Wain (UoL) and Gisli Jenkins (UoN)
In this project you will develop and apply new statistical methods to identify which genes affect survival time with idiopathic pulmonary fibrosis, and which genes affect growth rates of abdominal aortic aneurysms. The findings will indicate new approaches to treatment and management of these diseases. Such studies of disease progression can be biased by unknown factors that affect both the risk of developing disease and the course of disease once established. Our group has recently developed new statistical approaches to correct this bias, using the results of genome-wide association studies. A substantial part of this project will be evaluating and developing improved methods building on our initial approaches. This will require programming of statistical analyses and computer simulations, and you should therefore have a demonstrated aptitude for statistical programming. You will also analyse large datasets in Leicester and Nottingham on disease progression in idiopathic pulmonary fibrosis and abdominal aortic aneurysm. You should therefore have an aptitude for working with big data and for presenting results to cross-institutional collaborators clearly and succinctly. You will join one of the largest genetic epidemiology groups in the UK, with excellent opportunities for networking and career development in a fast moving and high profile area.
3. Converting insult into injury: Cellular and structural biology studies of a macromolecular complex that links inflammation with scarring in fibrotic disease
Supervisors: Bibek Gooptu (UoL) and and Andrew Quigley (Diamond)
45% of deaths in the developed world arise as a result of fibrosis – replacement of normal tissue with scar. Fibrosis is a basic response to severe or sustained insult. If confined, fibrosis can limit further tissue damage, but when widespread it leads to organ failure, cancer risk, and death. We study how different insults cause fibrosis, focusing on lung and liver disease. We have recently identified a molecular complex that represents a junction between acute inflammation and chronic scarring pathways, and may be an important target for future drug therapies. This project will use state-of-the-art cellular and structural biology approaches to understand the molecular details of how the complex assembles, works, and may be targeted by drugs. It will be studied in the context of intracellular (glycoprotein misfolding) and extracellular (bacterial molecule) insults. The work is excitingly cross-disciplinary (membrane protein crystallography, cryo-EM, cell biology, and integration within clinical/translational studies). It is also cross-institutional (Leicester Institute of Structural and Chemical Biology, NIHR Leicester BRC, Research Complex at Harwell, Diamond Light Source). The supervisors span these institutions and areas of expertise, from clinical to atomic resolution studies, and can offer outstanding training and support.
4. Targeting the gut microbiome to prevent human diseases associated with obesity and poor metabolic health
Supervisors: Karen Brown (UoL), Tom Yates and Julian Ketley (UoL)
Excess body weight, insulin resistance and inflammation are underlying causes of the metabolic syndrome and greatly increase the risk of type 2 diabetes and cardiovascular disease, which in turn are risk factors for metabolically-driven cancers. The gut microbiome is increasingly recognised as playing a role in human health, including conditions associated with poor metabolic status. The natural compound resveratrol is being widely investigated for its ability to prevent/treat numerous diseases. In rodents, resveratrol protects against the adverse effects of a high-fat diet, improving glucose and lipid homeostasis and reducing body fat and blood pressure. It also inhibits the pro-tumourigenic effects of a high-fat diet in a mouse colorectal cancer model. Interestingly, clinical trial results suggest resveratrol is most effective in people with metabolic disturbances. This interdisciplinary project between the Cancer and Diabetes Research Centres and Department of Genetics and Genome Biology, will investigate whether consumption of resveratrol by humans alters the gut microbiome. It will also explore how resveratrol metabolites generated by gut bacterial may contribute to the efficacy of this compound. The results will provide novel insight on how resveratrol may exert protective effects in people with metabolic disturbances, and increase understanding of how preventive therapies may be personalised.
5. Identifying novel therapies to prevent myocardial injury in type-2-diabetes
Supervisors: Andre NG (UoL), Melanie Madhani (UoB) and Warwick Dunn (UoB)
Type-2-diabetes (T2D) is a global epidemic associated with a major risk factor for coronary artery disease. Patients with T2D undergoing coronary artery bypass grafting (CABG) surgery have increased morbidity and mortality following cardiac surgery when compared to non-diabetic CABG patients. There are numerous risk factors that may influence myocardial injury following cardiac surgery. These include inability to precondition, increased redox oxygen species (ROS), altered glucose transport and/or metabolism. In addition, autonomic function is abnormal in T2D with additional interaction in the genesis of potentially lethal arrhythmia. As such, this may contribute to higher incidence of peri-operative myocardial infarction and arrhythmias. Thus, there is a clear need to improve myocardial protection in T2D-patients. This project will investigate novel therapies against diabetic myocardial injury and will utilise a number of sophisticated new techniques developed by the supervisors. The successful candidate will gain a good training platform in cardiac biochemistry, pharmacology and physiology. In particular, the Langendorff model, whole heart electrophysiology, cardiac metabolomics, and redox metabolome. The candidate will be based at Professor Ng (Leicester BHF Cardiovascular Research Centre), Dr Madhani (Institute of Cardiovascular Sciences, Birmingham) and Professor Dunn (Phenome Centre Birmingham) labs. They will also link with the Midlands Cardiovascular Research Network activities.
6. Investigation of metabolomic biomarkers of heart failure
Supervisors: Toru Suzuki (UoL), Leong NG (UoL) and Chris Titman
Heart failure is a leading cause of death and hospitalisations in the elderly. Early diagnosis and accurate differentiation of pathologies in addition to risk stratification are needed for personalised treatment. Much research has been done to try to understand the mechanisms of the condition at the molecular and genetic levels, but metabolite profiles and their contribution has not been fully understood. Therefore, we hypothesise that unique metabolite patterns will provide additional diagnostic and prognostic information of heart failure. We also hypothesise that short chain fatty acids will play a role in regulating energy metabolism in the heart. This study will utilise blood-based metabolomics approaches to analyse metabolite profiles from samples collected from heart failure patients. The first phase of the study is a discovery phase, using the high definition mass spectrometers to analyse and characterise the metabolite profiles of patients, and further differentiate these profiles according to clinical information. The metabolites of interest will be further identified and validated quantitatively using stable-isotope dilution technique using a high sensitivity triple quadrupole mass spectrometer (UHPLC-TQ MS). The relevant metabolic pathways will also be investigated further to understand the pathogenesis of heart failure at the metabolite level.
7. Artificial Intelligence and Machine Learning for Enhanced Phenotyping of Breath Metabolomics Data
Supervisors: Salman Siddiqui (UoL), Yudong Zhang (UoL) and Paul Monks
Exhaled breath contains a rich matrix of volatile chemicals (metabolites) that may be useful as disease biomarkers. However manual visual evaluation of metabolites from exhaled breath samples is subject to significant inter-expert and intra-expert variations. Furthermore conventional statistical techniques need to make prior assumptions on data models. The PhD program will develop computer vision and deep learning (particularly convolutional neural network) techniques for the analysis and discovery of biomarkers from exhaled samples. Breath metabolomics data has already been acquired in approximately 600 patients with acute exacerbations of cardio respiratory disease in a large exhaled breath metabolomics program funded by the EPSRC/MRC. Breath samples have been acquired using GCxGC-MS and PTR-MS technologies in the acute state and during recovery from an exacerbation. The PhD will focus on biomarker discovery and replication within these existing rich datasets. The project will be hosted jointly in the Department of Computer Science, NIHR Biomedical Research Centre at Leicester University and East Midlands Breathomics Molecular Pathology Node. A range of training opportunities in artificial intelligence and data science will be made available to the successful candidate.