Projects for September 2024
Advancing diabetes screening through data driven approaches
Professor Laura Gray (UoL) lg48@leicester.ac.uk, Dr Joie Ensor (UoB) and Prof Kamlesh Khunti (UoL)
This exciting project aims to update the Diabetes UK “Know your Risk” tool (https://riskscore.diabetes.org.uk/start) which is based on the Leicester Diabetes Risk Score. This tool asks for information about seven risk factors and assigns points to each answer, the total score reflects the individual’s risk of having undiagnosed type 2 diabetes or prediabetes. It is recommended that those with a high score visit their doctor for a diabetes test. Early identification of diabetes promotes early treatment, improving health outcomes.
This project looks to update the Leicester Diabetes Risk Score by:
Reviewing published validations and updates of the score and assessing their performance.
Assessing potential updates to the score algorithm and the risk factors included.
Validating the score using primary care data.
This project is part of an exciting collaboration with the University of Birmingham, with supervisors based at both institutions. The student undertaking this project will have the opportunity to use their statistical skills to make improvements to this tool, impacting care and improving outcomes for people at risk of diabetes. This project would suit someone with a mathematical background. This opportunity will give skills in systematic reviewing, risk prediction modelling, and using real-world data.
Metabolite profiling and bacterial community structures in polymicrobial infections
Dr Christian Jenul (UoL) cwj2@leicester.ac.uk , Dr Katrin Schilcher (UoL) and Dr Freya Harrison (UoW)
This project seeks to understand how bacterial pathogens from polymicrobial infections interact with each other and how these interactions shape infection progress and outcome. We will use bacterial pathogens that frequently co-infect the lungs of people with a genetic condition called cystic fibrosis (CF). These bacterial pathogens secrete metabolites into the infection environment, which allow them to compete or cooperate with other microbial organisms. We will use a unique porcine ex vivo lung model to re-create the CF lung environment and subsequently apply microscopy, mass spectrometry guided metabolite analysis and bacterial genetics to i) unravel how co-infecting bacterial pathogens influence each other’s behaviour, ii) how this influences the dynamics of the infection and iii) how these processes are stirred by secreted metabolites. The successful student will receive hands-on training in bacterial genetics, mass spectrometry and metabolite analysis and get the chance to work with an established ex vivo lung model. Understanding the dynamic processes that shape the interaction between bacterial pathogens will ultimately help the development of new treatment strategies for polymicrobial infections.
Model-driven and data-driven solutions for regulatory and HTA decision-making to address emerging challenges in drug development in cancer
Prof Sylwia Bujkiewicz (UoL) sylwia.bujkiewicz@le.ac.uk , Prof Richard Riley and Dr Sam Khan with Dr Daniel Jackson AstraZeneca
When new cancer therapies are developed, they are evaluated in clinical trials assessing treatment’s impact on patients’ outcomes. Long-term survival is an outcome typically of interest to decision-makers, who recommend which new treatments should be available on NHS. However, modern cancer therapies are often targeted to small subsets of patients who harbour a particular biomarker. Therefore, data from clinical trials evaluating the effectiveness of therapies in a cancer subtype may be limited. Other sources of data; based on alternative outcomes, study types or other cancers, may need to be synthesised efficiently for reliable policy decisions. You will apply a range of modern tools from biostatistics (including Bayesian statistics, meta-analysis and survival analysis), epidemiology and data science and develop novel approaches for evaluation of cancer therapies.
This project is part of an exciting collaboration with University of Birmingham and AstraZeneca. You will benefit from an experienced supervisory team with expertise in statistics and oncology and an industry partner. This PhD in Biostatistics will provide you with an opportunity to develop advanced analytical skills, gain insight into drug development and decision-making processes and influence important decisions in healthcare. A suitable candidate will have MSc in Statistics, Medical Statistics or a related discipline.
Understanding centrosome abnormalities in oesophageal adenocarcinoma
Dr Robert Mahen (UoL) rm722@leicester.ac.uk , Dr Gianmarco Contino (UoB) and Prof Andrew Fry (UoL)
Centrosomes are microtubule-based organelles with important functions in diverse cellular processes. They are critical for cell division, cell migration and cell shape changes – all of which are important to the development of cancer. Centrosomal abnormalities have long been recognised in cancerous tissue, and evidence is growing that they directly drive carcinogenesis. However, how centrosomes become defective in tumor tissue, and how this might contribute to the development of specific types of cancer is still mysterious.
In this project we will tackle this mystery by using cutting edge forms of microscopy and genomics to understand how centrosomes assemble and function, both in healthy and cancerous cells. We will investigate how abnormal centrosomes contribute to the development of a lethal form of cancer – oesophageal adenocarcinoma. Overall, this project is an exciting opportunity to receive interdisciplinary training in different types of advanced imaging, genomics and cellular models of cancer, and you will have the opportunity to work in different labs at both the University of Leicester and the University of Birmingham.
Assessing the Contributions of the Phase-Variable Sialic Acid and Phosphorylcholine Epitopes of Non-Typeable Haemophilus influenzae to Immunoevasion during Chronic Infections
Prof Chris Bayliss (UoL) cdb12@leicester.ac.uk , Dr Chris Holmes (UoL), Prof Luisa Martinez-Pomares (UoN) and Prof Chris Brightling (UoL)
Non-typeable Haemophilus influenzae (NTHi) significantly contribute to human disease including chronic obstructive pulmonary disorder (COPD). This complex disease involves numerous host immune modulators. Replication of NTHi bacteria in the diseased lung is associated with chronic disease but it is not clear how these bacteria survive host immune responses. Multiple NTHi genes undergo rapid ON and OFF switching, called phase variation (PV), due to hypermutable repetitive DNA tracts. Two phase-variable genes drive addition of negatively (sialic acid) and positively (phosphorylcholine) charged epitopes onto the lipooligosaccharide. These molecules influence bacterial interactions with host immune cells. This project focuses on investigating how PV affects immune evasion in model systems and clinical samples from chronic disease patients. Led by Prof. Chris Bayliss and Dr. Chris Holmes, molecular approaches will be utilized to monitor whether NTHi PV facilitates immune evasion. Immunological assays, such as resistance to neutrophils, will be developed during sessions at the University of Nottingham with Prof. Luisa Martinez-Pomares. Analysis of clinical COPD samples will be overseen by Prof. Chris Brightling. These studies will help explain the extent to which PV of surface molecules underlies elicitation of host immune responses and ability of NTHi to survive and cause inflammation in complex chronic diseases.
Modelling cardiac function in healthy hearts and diabetes
Dr Anvesha Singh (UoL) as707@leicester.ac.uk , Prof Csaba Sinka (UoL), Prof Susan Francis (UoN) and Prof Gerry McCann (UoL)
There is a global pandemic of type-2 diabetes. Diabetic cardiomyopathy is a well-recognised complication, which manifests with early alterations in left ventricular (LV) structure and function. Its pathophysiology and management remains poorly understood. This inter-disciplinary (Engineering, Cardiology, Physics) and cross-institution (Universities of Leicester and Nottingham) project aims to develop a state-of-the-art computational model of the heart in a healthy individual and those with diabetic cardiomyopathy. The starting point is a multi-physics based computational framework coupling the differential equations describing the constitutive behaviour of heart muscle, transmembrane potential, conductance and active stress leading to the contraction of the myocardium. Calibration of the constitutive model parameters will be carried out using cardiac magnetic resonance (CMR) imaging and electrocardiographic (ECG) data. The project will focus on the study of the nature of the active stress and its mechanical description as the current formulations are relatively simplistic. We will develop a direct coupling parameter which includes cardiac microstructure information for both healthy and diabetic patients. Development of an ex-vivo model of diabetic cardiomyopathy will increase our understanding of the pathophysiology of remodelling and allow testing of potential therapies.
What is the role of Reactive Sulfur Species in myocardial infarction-induced inflammation?
Dr Christopher Switzer (UoL) cs876@leicester.ac.uk and Prof Melanie Madhani (UoB)
Embark on an exhilarating journey at the forefront of cardiovascular research by joining this cutting-edge PhD program in collaboration with the University of Birmingham, specifically focused on the dynamic interplay of Reactive Sulfur Species (RSS) in the aftermath of acute myocardial infarction (AMI). AMI, a global health concern, triggers a cascade of events, including inflammatory responses that impact cardiac function. Led by world-renowned experts Prof Madhani and Dr Switzer, our research explores the enigmatic role of RSS in this critical scenario. Prof Madhani’s discovery of RSS in oxygen-deprived cardiac cells sets the stage, while Dr Switzer’s revelations of the dual nature of RSS, possessing both cyto-protective and pro-inflammatory attributes, add an intriguing dimension to whether RSS can influence the inflammatory response after AMI. Cutting-edge techniques, such as live cell imaging and mass spectrometry, will unveil the impact of RSS on inflammatory signalling and gene expression in cardiac cells. The anticipated outcomes of this ground-breaking research will not only enrich our understanding of RSS but also pave the way for transformative strategies to mitigate tissue damage in myocardial infarction patients. You will contribute to unravelling the secrets of an unexplored realm in redox biology, making a lasting impact on cardiovascular science.
Defining the impact of T cell activation on the protective and migratory capacity of mucosal CD4+ T cells in tuberculosis
Prof Andrea Cooper (UoL) amc72@leicester.ac.uk , Dr Helen McGettrick (UoB) and Dr John Pearl (UoL)
In this exciting joint PhD project between the University of Leicester (UoL) and the University of Birmingham (UoB), the student will join a collegiate international consortium investigating lung immunity to tuberculosis (TB) and driving innovation in the TB vaccine pipeline. Development of an effective vaccine is the single most effective tool to reduce the worldwide TB. The multi-million Euro consortium brings together fundamental immunologists, clinical specialists, experts in non-human primate models and vaccine developers and manufacturers. The student will investigate the fundamental aspects of immune protection using immunology, immunohistology, flow cytometry, bioinformatics analysis and will learn in vivo imaging and spatial transcriptomics. The project will focus on the the ability of T cells to undertake adhesion and migration into the lung of TB-infected mice (UoL). At UoB, multi-cellular in vitro models of leucocyte adhesion and migration will used to dissect the role of specific molecules in T cell migration. A unique aspect of this studentship is the ability to undertake in vitro and in vivo models in the context of complementary human and non-human primate data. This is a super opportunity because of the range of techniques and approaches, the networking and the potential for internationalization of the student’s experience.
iCASE Projects
Harnessing data from wearable devices for the prognosis of long-term conditions and mortality: application to clinical risk scores
Prof Thomas Yates (UoL) ty20@le.ac.uk , Dr Francesco Zaccardi (UoL) and Dr Alex Rowlands (UoL) with Dr Richard Russell and Dr Kishan Bakrania Reinsurance Group of America
How we lead our lives effects our health, yet this information is typically not considered when predicting future risk of chronic disease or mortality. For example, an individual with a high genetic risk of a disease or a high risk based on routine clinical data is placed in the same high risk pool regardless of how physically active they are, despite the fact that physical activity can modify much of this risk for some long-term conditions and mortality outcomes. The studentship will include training in cutting edge analytical approaches for using data gathered from wrist worn accelerometers (similar to those found in smart watches and physical activity trackers) in generating patterns of physical behaviours, ranging from sleep to physical activity. The relevance of these novel metrics to predicting the onset of common chronic disease or early mortality will then be explored using flexible parametric models, which will include developing new risk prediction tools.
Using CryoEM to trap and visualise PROTAC drugs in action against cancer targets
Dr James Hodgkinson (UoL) JTHodgkinson@le.ac.uk , Prof John Schwabe (M), and Dr Emma Hesketh (UoL) with Alex Brown, Duncan Smith and Valerie Pye for industrial partner Sygnature Discovery (Peak Proteins)
This PhD project is an exciting opportunity to explore the innovative drug strategy involving proteolysis targeting chimeras (PROTACs) using Cryo-Electron microscopy, a cutting-edge structural biology technique, at the University of Leicester. The project is in collaboration with a world-leading drug discovery CRO. PROTACs are novel bi-functional drugs that promise to ‘drug the undruggable’ by marking target proteins for degradation rather than inhibition. The proteins SOS1, a guanine nucleotide exchange factor, and LSD1, a lysine histone demethylase, are important cancer therapeutic targets with substantial prospects for future drug development.
SOS1 plays an essential role in the KRAS signalling pathway. Inhibitors of SOS1 have shown considerable potential for targeting RAS-driven tumours. LSD1 plays a critical role in the endothelial to mesenchymal transition that is a key step in allowing tumours to metastasize. Inhibition of LSD1 has been shown to be a promising treatment for melanoma. To determine the structure-activity relationship of these PROTACS, you will use state of the art cryo-electron microscopy at the regional facility based at Leicester, and chemically synthesise novel PROTACs for evaluation using cryo-electron microscopy. In partnership with the drug discovery CRO you will learn interdisciplinary techniques in medicinal chemistry, protein expression/purification and structural biology amongst industry experts.
Tumour-Specific Delivery of MCL1 Inhibitors Using Novel Peroxynitrite Cleavable Antibody-Drug Conjugates
Prof Steve Bull (UoL) sdb45@leicester.ac.uk , Dr James Hodgkinson (UoL) and Prof Martin Dyer (UoL) with Dr Lurdes Duarte from industrial partner Isogenica
The startling statistic that 1 in 2 people are predicted to develop some form of cancer during their lifetime means there is an urgent need to develop new cancer therapeutics. However many cancer drugs adversely affect healthy cells which can cause serious side effects in patients that prevent these drugs from progressing into the clinic. To overcome this, this studentship will target the preparation and evaluation of novel antibody-drug conjugates (ADCs) for the targeted delivery of inhibitors of key MCL1 proteins that are critical for malignant B-cell proliferation in leukaemia. MCL1 is an important cancer drug target, however clinical trials with current MCL1 inhibitors have been halted due to safety issues. Antibody mediated delivery of these MCL1 inhibitors to malignant B-cells using ADCs could harness the high therapeutic potential of these MCL1 inhibitors, whilst removing potential safety concerns. In this studentship you will be involved in a highly interdisciplinary chemical biology project, involving the chemical synthesis of novel MCL1 antibody-drug conjugates to treat B-cell malignancies that cause leukaemia. This studentship will provide you with many of the chemical biology skills required to pursue a career in the life sciences in academia/biotech or carry out drug discovery in the pharmaceutical industry.
