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Clinical research studies in functional gastrointestinal disorders

Functional Gastrointestinal Disorders (FGID) affects almost 40% of the population. They are when an individual has gut symptoms but no active organic disease (e.g. no cancer, inflammation, infection etc). The most commonly recognised FGID is irritable bowel syndrome, which affects 10% of people. 

We are a world-renowned clinical academic group in FGIDs and the supervisor (Dr Imran Aziz, Consultant Gastroenterologist) has over 100 publications. 

Since 2020, Dr Aziz has supervised seven BMedSci students, all of whom have been involved in 

• been involved in patient-facing clinical studies
• achieved a first for their BSc degree
• presented at national conferences
• published a first author scientific paper within a year 

Learn more about this project

Supervisors

Dr Imran Aziz (imran.aziz1@nhs.net)

Professor David Sanders (david.sanders1@nhs.net)

Abstract and methodology

This clinical project in gastroenterology will focus on functional gastrointestinal disorders (FGIDs), which are the most commonly encountered within hospital gastroenterology practise and also in GP, yet largely undertaught within medical schools. The student will become familiar with understanding these conditions and also involved in clinical studies being undertaken in this patient group.

During the intercalation process, you will have the chance to meet with the consultant supervisors within our department who are offering upcoming projects. You may be working with a database or clinical letters, you may have the opportunity to get involved with departmental recruiting (if you wish) for other studies, you will work alongside our nursing and medical team and will gain clinical skills whilst supporting an endoscopy list.

The student will gather data, learn how to analyse this and write up as presentations and papers. They will be regularly supervised and mentored by Dr Imran Aziz, a senior lecturer and consultant gastroenterologist within an international profile.

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

The student will learn how to analyse datasets using SPSS, present work orally and as poster presentations at conferences, write original articles, submit papers as first author, and address reviewers comments. The student will also have the opportunity to attend clinical gastroenterology sessions and weekly departmental lectures. 

The student will be expected to submit their work to conferences and attend these. 

Finally, the student will have the opportunity to collect data for other ongoing clinically-based projects culminating in co-authorship in future papers.

Ethics requirements

Original research involving human tissues/human participants and/or patient details and information: UREC or NHS REC ethics approval needed

Rare disease phenotyping and genotype-phenotype correlation for HNRNP-related disorders

In-depth phenotyping of individuals with HNRNP-related disorders.

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Supervisors

Professor Meena Balasubramanian (m.balasubramanian@sheffield.ac.uk)

Stuart Wilson (stuart.wilson@sheffield.ac.uk)

Abstract and methodology

Heterogeneous nuclear ribonucleoproteins (HNRNPs) are a large family of RNA-binding proteins that play a part in mRNA biogenesis with roles in pre-mRNA splicing, polyadenylation, capping, modification, export, localisation, translation, and turnover (Wu et al., 2018). Their ability to contribute to multiple steps in the biogenesis and use of mRNAs demonstrates their versatility as a protein family. The functional flexibility the HNRNP gene family possesses can be explained in part by their ability to produce multiple alternatively spliced isoforms and their ability to form complexes with other HNRNP members (Geuens et al., 2016).

HNRNPs have been linked to various diseases, including cancer; neurodevelopmental disorders such as spinal muscular atrophy, amyotrophic lateral sclerosis, congenital myasthenic syndrome, multiple sclerosis, Alzheimer’s disease, and fronto-temporal lobe dementia (Low et al., 2021). Their key roles in regulating transcriptional and post-transcriptional gene expression and their links to numerous diseases mean that it is important to research these conditions with potential wider utility.

In this project, the student will recruit patients with HNRNP-related disorders to an ongoing natural history study for which the primary supervisor is the PI. The project will focus on collating clinical information, undertaking literature review, generating methylation episignature and publishing deep dive datasets in this group of disorders.

The methods include 

• Clinical phenotyping;
• Data collation from clinical records
• Developmental assessment and co-ordination
• DNA samples for methylation episignature
• Patient consent
• Writing up case series of patients with rare genetic disorders

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

Variant interpretation; clinical phenotyping; lab work if interested.

Ethics requirements

NHS Service Evaluation number required.

University ethics checks will additionally be required.

Role of NBAS in human disease using zebrafish models

Neuroblastoma amplified sequence gene (NBAS) affects skeletal development in zebrafish and drug screening assays can be used to identify targets that can rescue NBAS activity in a zebrafish model.

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Supervisors

Professor Meena Balasubramanian (m.balasubramanian@sheffield.ac.uk)

Professor Steve Renshaw (s.a.renshaw@sheffield.ac.uk) 

Abstract and methodology

Whole genome sequencing studies have led to a vast amount of new candidate genes for human diseases. One such gene is NBAS (neuroblastoma amplified sequence gene) which when mutated results in acute liver failure and skeletal abnormalities such as SOPH syndrome, short stature, optic atrophy or Pelger-Huet anomaly [Maksimova et al., 2010]. Patients with NBAS mutations are subjected to a lifetime of recurrent fractures, repeated episodes of acute liver failure needing recurrent hospital admissions and immune deficiency [Balasubramanian et al., 2017]. Recently we have developed a zebrafish model which carries mutations in NBAS and displays skeletal malformations that are reminiscent of the human condition. Analysis suggests that NBAS may play a role in the secretion of collagen.

The overarching hypothesis would be 'NBAS causes a multi-system disorder affecting skeletal development, liver and immune abnormalities in zebrafish: unravelling disease mechanism'.

Methods include:

• Analysing skeletal and liver abnormalities in NBAS mutant zebrafish
• Comparing with manifestations in Crispr fish
• Drug screening to identify potential therapeutic hits for further work-up

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training or teaching

• Genotype-phenotype correlation
• Zebrafish genotyping
• Skeletal analysis in zebrafish
• Immune response in zebrafish model
• Literature review of nbas phenotypes 

This BSc project builds upon our work focusing on the zebrafish model to unravel the molecular causes of this disease and to develop a platform for high-throughput drug screens to identify drugs that may one day be used in the clinic. During your training year, you will use cutting-edge techniques such as lightsheet and AIRY scan microscopy, CRISPR/Cas9 gene editing and robot based drug library screening.

Ethics requirements

Non-human tissue: no ethics approval required

A prospective feasibility study of a salivary collection method for the measurement of salivary glucocorticoids in neonates

Can we use salivary glucocorticoids to better understand adrenal function in neonates?

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Supervisors

Dr Charlotte Elder (c.j.elder@sheffield.ac.uk)

Dr Joseph Tonge (joseph.tonge@sheffield.ac.uk)

Abstract and methodology

The adrenal glands produce a number of different steroid hormones; those involved in metabolism (glucocorticoids, principally cortisol and its more inactive form, cortisone), salt and water balance (aldosterone) and sex steroids (oestrogen and testosterone). Inadequate cortisol production, adrenal insufficiency, is challenging to diagnose and is associated with considerable morbidity and mortality. 

The use of salivary samples to screen and diagnose disease is growing in popularity. The non-invasive nature of salivary collection, negating the need for blood tests and needles, makes it a particularly attractive medium for use in children. Dr Elder’s research group has been developing non-invasive screening and diagnostic tests for adrenal insufficiency using salivary samples. To tackle the significant obstacles to salivary collection in young children we have previously developed and validated salivary collection techniques for use in pre-school age children and infants. We would like to extend this work to the neonatal population, especially premature infants. Validating a salivary collection technique in neonates would then facilitate salivary glucocorticoid sampling to study adrenal function in neonates, to better define abnormal.

Aims

• To evaluate whether the SalivaBio is a suitable salivary collection device for the use in neonates of different gestational ages (SCiN-1a study)
• To evaluate parents’ and healthcare professionals’ opinions on the utility, tolerability and acceptability of salivary collection in the in-patient neonatal population (SCiN-1b study)
• To describe the relationship between serum cortisol and salivary cortisol / cortisone in the premature and term neonatal population (SCiN-2 study)

Methods

A multi-centre clinical study on neonatal ICUs (NICU) investigating a new way to measure adrenal function in this age group. The collection of salivary samples from neonates will follow a standardised protocol. It is anticipated the studies will be run across three NICU sites: Sheffield, Nottingham and GOSH, London. The student will be primarily based in Sheffield but would have the opportunity to attend other sites to assist with study recruitment, and to train staff to use the collection technique. They will also be required to collect survey data from healthcare providers on their thoughts on the salivary collection technique. 

• SCiN-1a study: To determine whether the SalivaBio can be used to collect 0.5mL saliva (required volume for analysis of salivary steroids) in 80% of participants we will be evaluating salivary collection in a variety of patients – across different gestational ages and including those receiving ventilatory support. The amount of saliva collected, time taken and contamination rates will all be studied.
• SCiN-1b study: Two questionnaire studies evaluating the ease, tolerability and acceptability of salivary collection, one in parents and one in NICU healthcare professionals.
• SCiN-2 study: Analysis of paired samples to describe the relationship of serum cortisol and the salivary glucocorticoids (cortisol & cortisone) by gestational age and weight.

Outcomes

By the end of the intercalation project, the expectation is the student will have worked with their supervisors and sites to complete the studies and analyse the results. Being the first studies of their kind, we anticipate the work may lead to presentations, at both national and international conferences, and a publication (no guarantees as this is dependent on successful completion of the studies and the results).

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

Dr Elder is an experienced supervisor, and the student will benefit from support and training from the wider research group. Dr Tonge will co-supervise the project and has worked on validation of salivary collection techniques in young children and the pilot study for SCiN. The student will get experience in literature reviewing with critical appraisal, clinical studies, following protocols, questionnaire surveys, collecting data, analysing data and presenting results. 

Working patterns may be reasonably flexible but occasionally meetings with project supervisor/day-to-day supervisor may be outside of normal office hours due to nature of clinical work. Should attendance be required at neonatal units outside of Sheffield, travel expenses will be reimbursed.

The student, if they wish and time permits, may attend some paediatric endocrinology clinics at Sheffield Children’s Hospital to develop a greater understanding of how adrenal insufficiency is managed. 

Ethics requirements

Original research involving human tissues/human participants and/or patient details and information: UREC or NHS REC ethics approval needed.

Binding the battle: targeting RNA-binding proteins to control infection and inflammation

Infectious diseases continue to pose a significant threat to global health, accounting for a substantial proportion of morbidity and mortality worldwide. The hypothesis this work addresses is that the primary white blood cell, the neutrophil, is tightly regulated during infection via RNA binding proteins, with novel therapeutic insights into controlling inflammation and improving outcomes in infectious diseases on a global scale.

Learn more about this project

Supervisors

Catherine Loynes (c.loynes@sheffield.ac.uk)

Steve Renshaw (s.a.renshaw@sheffield.ac.uk)

Abstract and methodology

Despite advances in diagnostics, therapeutics, and vaccines, the emergence of antibiotic-resistant pathogens and novel infectious agents underscores the urgent need for deeper insights into host immune responses. Manipulation of human neutrophils is difficult when investigating host-pathogen interactions, therefore we use a well-established in vivo zebrafish model of infection, where genes can easily be mutated or pharmacologically inhibited.

Recently published data using infection zebrafish models, suggest that the RNA-binding protein (RBP) ELAVL1 is involved in antimicrobial defence and represents a novel RBP that acts as both pattern recognition receptors and direct antimicrobial effectors in vertebrate innate immunity. 

Using zebrafish, you will investigate the role of Elavl1 during infection. You will analyse infection outcomes and neutrophil biology regulated by 2 paralogues, Elavl1a and Elavl1b. Following infection of Elavl1a/b mutant larvae with fluorescent staphylococcus aureus, you will analyse neutrophil recruitment and engulfment (phagocytosis) of bacteria in the presence and absence of Elavl1 function. Zebrafish will be treated with chemical inhibitors (TIIA) to block Elavl1 function, complementing your genetic manipulation experiments, and you will assess larval survival and bacterial burden using widefield and spinning disk confocal microscopy. You will identify novel molecular mechanisms controlling host responses that work via Elavl1, with potential for therapeutic intervention.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training or teaching

Full training will be given in the following areas, including translatable skills: 

• Learning how to culture bacteria safely in a Category 2 laboratory.
• Handling adult and larval zebrafish.
• Becoming competent at infecting zebrafish larvae with bacteria.
• Generating data from key neutrophil function assays.
• Competence in data analysis, interpretation and presentation using Graphpad prism, Snapgene, NIS Elements, Fiji.
• Learning scientific writing styles at journal clubs and through thesis write-up.

All wet lab training will be supervised by Cathering Loynes. You will have specific aquarium and light microscope facility inductions by lead technicians.

Ethics requirements

Non-human tissue: no ethics approval required

Developing new molecules to treat leishmaniasis and malaria

We have developed a computer-based model that has identified compounds that inhibit a key enzyme required in leishmania parasites, the causative agent of leishmaniasis . A small number of such compounds were tested in the relevant organism and were also shown to parasites. We now wish to expand the study to see whether we can

• develop more potent and specific compounds
• characterise the enzyme and the inhibitor complexes
• assess selectivity of the compounds using in vitro and cell culture models
• use the data generated to improve the predictive capability of our computer models

Learn more about this project

Supervisors

Jon Sayers (j.r.sayers@sheffield.ac.uk)    

Fadi Soukarieh (f.soukarieh@sheffield.ac.uk)

Abstract and methodology

Leishmania species (and closely related genus Trypanosoma) cause a variety of neglected tropical diseases, including visceral and cutaneous leishmaniasis, sleeping sickness and Chagas disease. These infections cause significant morbidity and mortality. Using computer-based analysis of the 3D structures Leishmania flap endonuclease protein, we have identified a small set of compounds that selectively inhibit the parasite enzyme but not the human equivalent. Furthermore, the compounds killed parasites grown in the lab. 

This project is laboratory based. Prior experience is unnecessary. All training will be provided by the research group. You will learn how to grow the organism safely and carry out susceptibility tests using a small number of our novel anti-FEN compounds. This is likely to take a few weeks. After this you will produce genetically engineered E. coli to manufacture Leishmania FEN proteins and use it to characterise the interaction between inhibitor and enzyme. You will also produce crystals of FEN protein with inhibitor and carry out X-ray crystallography to determine protein-inhibitor complex structure. You will be trained in the use of molecular structure viewing, fluorescence-based enzyme inhibitor assays and structure determination. Your results will support our efforts in rational drug design for the chemotherapies targeting these important pathogens.

Type of project

Lab/Bench Project: primarily working in a lab environment

Additional training or teaching

Training in molecular docking, in silico screening and protein structure analysis will be provided in-house.

Ethics requirements

Non-human tissue: no ethics approval required

Searching for new antibiotics

How do inhibitors of bacterial nucleases kill their target organisms? What is the target spectrum of our anti-nuclease compounds?

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Supervisors

Jon Sayers (j.r.sayers@sheffield.ac.uk)    

Fadi Soukarieh (f.soukarieh@sheffield.ac.uk)

Abstract and methodology

The threat of antimicrobial resistance has led to a search for new targets. We will approach a previously unexplored target, an enzyme that destroys DNA called a flap endonuclease. Flap endonucleases (FENs) process branched DNA fragments. If this process is blocked the bacteria die rapidly. We have examined E. coli, Neisseria and Pseudomonas bacteria but want to explore other targets.

In this project you will examine a range of both Gram positive and Gram negative bacteria to determine the spectrum of these anti-FEN compounds.

You will also explore the mechanism by which the compounds act using range of lab-based and computer aided genomics analysis. For example you will use genetic engineering to produce the target protein for laboratory-based characterisation and confirmation of direct binding to the FEN enzyme.

Type of project

Lab/Bench Project: primarily working in a lab environment

Additional training or teaching

No prior experience is necessary as all training will be provided by the research group and our collaborators. You will learn how to handle common bacteria safely and carry out antibiotic susceptibility tests using a small number of our novel anti-FEN compounds. This is likely to take a few weeks. After this you will produce genetically engineered e. coli to manufacture specific FEN proteins from one or two susceptible bacteria and use it to characterise the interaction between inhibitor and enzyme. 

You will also attempt to produce crystals of FEN protein with inhibitor (either from newly identified organisms or ones we know already are susceptible). This protein will be used in X-ray crystallography for determination of the 3D structure of the protein-inhibitor complex. 

You will also be trained in the use of molecular structure viewing, fluorescence-based enzyme inhibitor assays and structure determination. 

The outcome of this work will support our efforts in rational drug design for the antimicrobial chemotherapies of the future.

Ethics requirements

Non-human tissue: no ethics approval required

Involvement of the brain in painful diabetic peripheral neuropathy

What is the progression of structure and functional changes within the brain in painful diabetic peripheral neuropathy (DPN)?

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Supervisors

Dr Gordon Sloan (gordon.sloan@sheffield.ac.uk)

Dr Dinesh Selvarajah (d.selvarajah@sheffield.ac.uk)

Abstract and methodology

Overall aim: Determine the changes in brain structure in key regions associated with somatosensory function (S1 cortex and thalamus) and nociception (insular cortex and anterior cingulate cortex) from baseline in patients with painful DPN compared to patients with painless DPN or no DPN.

The student will both be involved in the assessment of participants within the study, which involve detailed clinical and neurophysiological tests. The students will be trained to perform some of these study visits independently. Moreover, the study will involve analysis of the data, including brain imaging data.

In addition to the report, it is expected that this study will lead to publications in peer reviewed journals, for which the student will be included within the authorship. Moreover, the student may be able to present the work at national and international professional conferences.

Type of project

Clinical or Surgical project - based in the clinical environment with patients/including service evaluation

Additional training or teaching

The student will be given teaching on how to analyze brain imaging data using specific analysis software packages. 

Ethics requirements

Original research involving human tissues/human participants and/or patient details and information: UREC or NHS REC ethics approval obtained already

AI methods for analysis of magnetic resonance imaging in people with diabetes

Can AI-driven analysis of abdominal MRI detect early effects of diabetes on multiple organs?

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Supervisors

Professor Steven Sourbron (s.sourbron@sheffield.ac.uk)

Ebony Gunwhy (e.gunwhy@sheffield.ac.uk)

Abstract and methodology

In the past few years off-the-shelf artificial intelligence (AI) methods have become widely available that can analyse complex MRI images of the abdomen in minutes: a task which only five years ago would have cost a single person weeks of intensive manual labour. This vast amount of new information promises the discovery of biomarkers that can detect subtle effects of subclinical disease. 

We are currently evaluating these ideas in an ongoing study which has collected with MRI scans of 525 people with diabetes, in an EU project on diabetic kidney disease (). The aim of the study was to see if novel, advanced MRI methods are able to detect the effects of diabetes in the kidney long before these become apparent in current clinical indices such as blood and urine measurements. While the study focused on the kidney, diabetes is a multi-organ disease and many of the organs affect by it can be studied using the same scans (pancreas and liver, but also spleen, blood vessels, gut, fat).

Training, verifying and retraining AI systems requires a good understanding of anatomy, medical terminology as well as the effect disease may have on the images. The students who take this project will play a central role in this process, and use the results to test whether AI-generated results allow early detection of the effects of diabetes.

Type of project

Lab/Bench Project - primarily working in a lab environment

Additional training or teaching

• Visualisation, interpretation and analysis of MRI
• Basic understanding of AI methods for medical image analysis
• Clinical interpretation of novel MRI biomarkers in diabetes.
• Communication and working within an international consortium of scientists and clinicians from different backgrounds

Ethics requirements

Non-human tissue: no ethics approval required.

Secondary data or tissue sample: UREC or NHS REC ethics approval already received for the intended research project.

First-phase ejection fraction in pulmonary hypertension

Can first-phase ejection fraction (EF1) predict clinical outcomes and treatment response in pulmonary hypertension, particularly in patients with co-morbid left heart disease?

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Supervisors

Dr Roger Thompson (R.Thompson@sheffield.ac.uk)     

Dr Hameed Abdul (ahameed@nhs.net)

Aims

This project aims to evaluate EF1 as a biomarker for prognosis and therapeutic efficacy in PH, focusing on subgroups with left heart comorbidities.

Objectives

• Assess correlations between EF1 and clinical outcomes such as survival and disease progression.
• Investigate EF1 changes in response to PH-specific treatments.
• Identify differences in EF1 utility between PH patients with and without left heart disease.

Methodology

The study will use data from the ASPIRE registry, a comprehensive database containing imaging, clinical, and outcome data from over 1,500 patients. Retrospective analysis will focus on PH patients diagnosed via right heart catheterisation, with subgroup stratification for those with co-morbid left heart disease. EF1 will be calculated from stored cardiac magnetic resonance images using specialised software for image analysis, measuring the fraction of stroke volume ejected in the first phase of systole. Data extraction will include demographics, haemodynamics, functional class, and follow-up events. 

Statistical analysis will employ R software for multivariable Cox regression to predict outcomes, logistic regression for treatment response, and Kaplan-Meier survival curves. Machine learning techniques, such as random forests, may be applied to identify EF1-based predictive models. Training in R programming, image processing, and statistical methods will be provided. Ethical approval is in place for registry use.

The project will generate data demonstrating EF1's prognostic value, potentially identifying thresholds for risk stratification in PH with left heart comorbidities. Specific findings may include hazard ratios for mortality based on EF1 quartiles and correlations with treatment-induced improvements (e.g. in walk test distance and quality of life). Results could contribute to a peer-reviewed publication, with the student as co-author, and be presented at conferences like the European Respiratory Society meeting.

Type of project

Clinical or surgical project: based in the clinical environment with patients/including service evaluation

Additional training or teaching

Students will receive hands-on training in cardiac image analysis, data management from clinical registries, and statistics via R (including regression modelling and survival analysis). Students will attend weekly PH multidisciplinary team meetings, clinics, and research seminars. Good clinical practice training will also be completed.

While most of the research is retrospective, there will be opportunities to contribute to prospective clinically-facing research studies throughout the project. Experience of cardiac image analysis and cardiopulmonary physiology would prove particularly useful for future careers in radiology, respiratory medicine or cardiology. 

Ethics requirements

Secondary data or tissue samples: UREC or NHS REC ethics approval already received for the intended research project.