Department of Infection, Immunity and Cardiovascular Disease projects

Intercalated BSc Medical Sciences Research available projects

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Projects:

Investigating novel tissue resident macrophage populations in vivo

Main Supervisor

Dr Iwan Evans (i.r.evans@sheffield.ac.uk)

Second Supervisor

Dr Martin Zeidler (m.zeidler@sheffield.ac.uk)

Aim and Objectives

The white blood cells known as macrophages play an essential role in development, homeostasis, immunity and repair. The macrophage lineage is highly heterogeneous owing to the existence of tissue-resident populations alongside the ability to become activated to a range of states (termed macrophage polarisation).

Our lab used the genetically-tractable model organism Drosophila melanogaster (fruit flies) to understand regulation of macrophage function in vivo. We have recently discovered, for the first time, the existence of developmentally-regulated macrophage subpopulations in this organism. Fruit flies have been extensively utilised to understand immunity, not least in its role in the discovery of the immunoregulatory role of Toll receptors, for which Hoffmann received the Nobel Prize for Medicine.

This project aims to understand the function of these subpopulation macrophages and their relationship to vertebrate macrophages in more detail.

In order to understand the importance of these subpopulations the student will use genetic strategies to ablate subpopulation macrophages at various stages of the fly life cycle and examine the consequences for development, survival and immunity. In particular the student will examine the ability of the organism to fight off infections and repair damage when the macrophage subpopulations are removed. We will also address the effects of expanding these subpopulations.

Genes that are differentially expressed between subpopulations will also be investigated to understand the contributions that they make to immune responses in vivo.

Research Methodology

This project involves genetics, molecular biology, in vivo imaging, microscopy, image processing and analysis and statistical analysis. The student will take charge of their own Drosophila stocks and conduct genetic crosses to generate progeny in which subpopulation macrophages have been manipulated or candidate genes removed/overexpressed. The resulting fly embryos, larvae and adults will be analysed in a range of assays to understand the role of these subpopulation macrophages. Live imaging will then be analysed using software including Fiji and quantitative data obtained from these images. Other non-microscopic data will also be collected (e.g. survival of flies following infection/injury).

Expected Outcome

This project will enable us to understand the role of Drosophila macrophage subpopulations in response to infection, during development and during aging.

We will assess the role of candidate genes differentially expressed between subpopulations in these responses.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Full training in all techniques will be provided by my lab. This will include fly genetics, fly husbandry, dissection techniques, in vivo imaging, microscopy, image processing and analysis, statistical analysis in Prism.

We have weekly lab meetings and also take part in bimonthly fly meetings with groups in BMS. We have an annual lab retreat with other immunity-focused groups in IICD/BMS and are part of the Bateson Centre.

Better TB contact tracing. A mixed methods analysis in South Yorkshire

Main Supervisor

Dr Paul Collini (p.collini@sheffield.ac.uk)

Second Supervisor

Dr Daniel Cohen (Danielle.Cohen1@nhs.net)

Aim and Objectives

AIM: To evaluate the process and immediate outcomes of TB contact tracing in South Yorkshire
Objective 1. Measure and compare the numbers and promptness when identifying, investigating and treating contacts recorded in South Yorkshire cohort between 2019 and 2022 according to index case characteristics
Objective 2. Survey providers of TB contact tracing to describe factors affecting the contact tracing process
Objective 3. Survey recipients of TB contact tracing to describe lay knowledge, beliefs and behaviour affecting uptake of contact tracing

Research Methodology

Mixed methods study. Part 1. Retrospective case control study. The student will use existing data from the National TB Surveillance database for South Yorkshire and case records, to compare the contact tracing outcomes between index cases with smear positive pulmonary TB and control cases with other types of TB. Outcomes/dependent variables: number of contacts identified, evaluated, tested, diagnosed, treated for latent TB infection, timing of identification of cases, the promptness of investigation, accuracy and completeness of information. Predictor/exposure variables; social risk factors, country of origin/birth, spoken language. This will commence in November 2023. Part 2. Qualitative study. The student will conduct structured interviews with TB community nurses from each of the 4 South Yorkshire services and a sample of index patients and identified contacts from the Sheffield service. These will be evaluated using thematic analysis.

Expected Outcome

This study will provide a detailed description of the contact tracing process and outcomes in South Yorkshire. It will enable a more complete analysis of the efficacy of contact screening for smear positive pulmonary TB index cases against national standards and any benefit from contact screening of other TB index cases. By also providing analysis of intermediate indicators of effectiveness, such as promptness or these processes and engagement with treatment and aligning these with information from providers and recipients of contact tracing the study can provide valuable data and hypotheses regarding factors determining the effectiveness of investigations which can be tested in a future interventional study.

Type of Project

Qualitative Project/non-lab based - primarily using qualitative methods

Additional Training

You will receive training in Tuberculosis management and control, training to use the NTBS database and training in the use of qualitative methods in research.

AI system to detect cardiac pathology diseases

Main Supervisor

Dr Andy Swift (a.j.swift@sheffield.ac.uk)

Second Supervisor

Mr Michael Sharkey (m.j.sharey@sheffield.ac.uk)

Aim and Objectives

1) Collect different modalities cardiac imaging data (MRI, X-ray, CT, echo)
2) Create a data structure linking different diseases and scanning modalities
3) Apply different AI classifier techniques to detect different cardiac pathologist
4) Combine the different AI classifiers and extract a main framework for cardiac disease detection.

The hypothesis question is:
Can an automatic classification network detect and distinguish effectively between pulmonary hypertension and non pulmonary hypertension cases using multi scanning modalities?

Research Methodology

For this project the student need some coding skills (python or matlab). He need to know data structure handle and scanning images protocols like NIFTI and DICOM. Moreover he need to know some basic understanding of how neural networks works and basic knowledge of AI systems. By the end of this project the student could be capable to build a basic pipeline to evaluate AI system in a clinical diseases.

Expected Outcome

An basic AI system to detect the cardiac pathology of a patient based on different scanning image modalities (MRI,CT, and X-ray ).

Type of Project

Qualitative Project/non-lab based - primarily using qualitative methods

Additional Training

Training in python and AI coding. Moreover training in R statistics analysis and courses.

Remote haemodynamic monitoring for personalised and experimental medicine in patients with pulmonary arterial hypertension

Main Supervisor

Dr Alex Rothman (a.rothman@sheffield.ac.uk)

Second Supervisor

Dr Jennifer Middleton (j.middleton@sheffield.ac.uk)

Aim and Objectives

In research, and in medicine, we make critical judgements based on snapshot data collected at semi-structured time intervals, the duration of which is often informed only by ritual or historic investigation. If we could remotely capture critical measures of health and well-being in real-time this may be used to personalise therapy and conduct streamlined experimental medicine studies.

Pulmonary arterial hypertension (PAH) is a devastating disease in which remodeling of the small pulmonary arteries increases pulmonary artery pressure leading to right heart failure. All current therapies are known to improve outcome by dilatation of the pulmonary vasculature and reduction in pulmonary vascular resistance which is measured by invasive right heart catheterisation.

We have developed a cohort of patients with PAH in whom implanted sensors provide remote assessment of pulmonary artery pressure, cardiac output, heart rate and rhythm, and physical activity daily. Patients from this cohort will be enrolled into an MRC funded experimental medicine study that aims to determine if devices provide an early indication of clinical efficacy in patients with pulmonary arterial hypertension.

Aims:
To evaluate the acceptability of the implantable technology in this patient group
To determine the capacity for determination of therapeutic efficacy compatred to established clinical study endpoints

Objectives:
Enrol patients from the cohort in an MRC-funded experimental medicine study
To evaluate the usability of technology within this patient group
Evaluate the capacity of technology to detect change with addition of therapy

Research Methodology

NIHR good clinical practice training for research – online course.
Data analysis study using remote monitoring and clinical data already available from patients recruited into FIT-PH and implanted with remote monitors.
Patient data relayed to an online portal – data will be exported and added to an existing database of clinical parameters, drugs and investigation results.
Statistical analysis undertaken to related changes in therapy to changes in remote monitoring parameters.

Expected Outcome

From early participants in the study it is expected that technology is usable and accurately detects change following addition of therapy. The study will contribute to an ongoing, funded study which aims to repurpose imatinib for the treatment of PAH

Type of Project

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

Additional Training

Outline: Good clinical practice (for research)
Remote monitoring
Data extraction and curation
Statistical analysis

The 'Health of Sheffield' in Context: 1893-1973

Main Supervisor

Dr William Parker (w.parker@sheffield.ac.uk)

Second Supervisor

Dr Victoria Parker (v.parker@sheffield.ac.uk)

Aim and Objectives

1. Extract data on health outcomes from an extensive and important historical series of reports on our city's health from 1893 to 1973.
2. Analyse and plot the data to establish key trends in health outcomes in Sheffield over the period, backed up by robust statistical analysis.
3. Compare Sheffield's data to available national data from the period and with data from our own time.
4. Contextualise and rationalise the findings considering local and national medical, social and political factors, identifying case studies and delving into personal stories to illustrate these.
5. Draw conclusions regarding the relationship between past and current healthcare needs and provision.

Research Methodology

This project would suit someone interested in the history of medicine and social change but who also wishes to gain experience of data handling and scientific methods. Western Bank Library contains in its archives a large series of yearly Medical Officer's reports on the 'Health of Sheffield' from 1893 to 1973. These include detailed mortality statistics, developments in the city's provision of health services and other important observations. The period in question was clearly a time of great medical, social and political change. You will initially digitise mortality data from these reports then use this to study changes in health outcomes over time, including using detailed statistical analysis. You will then reflect on your findings by placing these in the context of medical, social and political change, conducting additional research into this as needed, including using local and national archives where appropriate. Detailed research into several key 'case studies' will involve finding and analysing primary sources that illustrate themes through personal testimony.

Expected Outcome

The student will obtain definitive data on local mortality trends relating to a significant historical period that saw many changes including the boom and bust of the industrial age, war, key developments in medical treatments and the establishment of the National Health Service. They will perform a robust analysis of this data to draw firm conclusions on how health outcomes changed in our city over the period. They will explore these further through historical research with significant flexibility to delve into areas of the findings that particularly interest the student. The student will have the tools to produce a dissertation that is unique, vibrant and thoughtful, yet contains rigorous scientific analysis of data.

Type of Project

Medical Humanities

Additional Training

You will gain training in electronic data handling, searching and using archive material. You will develop skills in critical appraisal and integration of sources. Training in statistical analysis and graphical presentation of data, applicable to all scientific study, will be provided. There will be the opportunity to hone your skills in writing, reflection and oral presentation. It is anticipated you will gain good grounding in medical and social history, with the opportunity for further areas of study as these arise.

Therapeutic targeting of hypoxia signalling in TB

Main Supervisor

Dr Philip Elks (p.elks@sheffield.ac.uk)

Second Supervisor

Dr Simon Johnston (s.a.johnston@sheffield.ac.uk)

Aim and Objectives

Mycobacterium tuberculosis, the causative bacteria of TB, has specialised to survive and proliferate within our immune cells (leukocytes), disarming bacterial killing mechanisms. One such mechanism is hypoxia signalling (mediated by the Hif-alpha transcription factor), a pro-inflammatory signal that is initially activated upon infection but is then dampened by TB. We have shown that stabilising the Hif-alpha signal is beneficial to fight infection, but can have the negative impact of prolonging inflammation.
The aim of this project is to determine whether Hif-alpha can be modulated in a beneficial way during infection without causing negative effects on inflammation outcomes.

Research Methodology

In the lab we use the zebrafish embryo as an in vivo model to understand host-pathogen interactions. Zebrafish embryos are transparent allowing in vivo timelapse microscopy of host-pathogen interactions. We have previously developed genetic and pharmaceutical tools to manipulate and follow hypoxia signalling within the zebrafish embryo. These will be used in a Mycobacterium marinum (Mm) model of TB infection and a tailfin inflammation model. Infection and inflammatory outputs will be assessed using fluorescent microscopy techniques. The project will give the student broad training in a variety of key techniques including zebrafish husbandry, microinjection, molecular biology, microbiology and fluorescent microscopy.

Expected Outcome

Hypoxia signalling will be modulated during infection and inflammation. Understanding the cellular mechanisms involved will help develop hypoxia signalling as an exciting target for therapeutic intervention against TB, without having negative consequences for inflammation. This work is part of a broader aim of the lab to understand the mechanisms of hypoxia signalling in TB infection and it is likely that data from this project will contribute to publication outputs of the lab. Students will be located in a busy and social lab, and will be well-supervised, learning cutting-edge techniques.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Students will be well trained in lab techniques including molecular biology, zebrafish husbandry and quantitative imaging. The imaging will be both fluorescent widefield and confocal imaging and will involve the use of image analysis software including Leica LASX and ImageJ. Quantitation and graphical representation of results to obtain statistics will be performed in Graphpad Prism.
In addition to lab techniques the students will have access to scientific training via departmental seminars, journal club and regular lab meetings with the group. If successful then there may be opportunities to present their work at local and national meetings.

Using CRISPR to identify new drug targets to treat inflammatory disease.

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

Inflammatory diseases such as emphysema, asthma, heart disease and arthritis cause much illness in the developed world. We have little understanding of how the severe inflammation associated with something like pneumonia can completely resolve, while other sorts of inflammation persist with associated tissue damage. In fact, we know little of the processes that cause resolution of inflammation in any setting. The primary inflammatory leukocyte, the neutrophil, is key to mounting an inflammatory response, however the regulation of these cells is critical for a successful inflammatory response.
In our lab we are interested in genes that regulate neutrophil function and removal from inflammatory sites. Because it is not possible to genetically manipulate human neutrophils, we have developed zebrafish as a model where genes can easily be knocked out and neutrophils can easily be seen throughout inflammation. Our results in fish have always been confirmed in human neutrophils. We have published in high impact journals our findings that neutrophil reverse migration away from wounds is tightly regulated. This process can be manipulated genetically to influence the outcome of inflammation. Neutrophil recruitment to inflammatory sites is regulated in large part by the interaction of chemokines and chemokine receptors. Chemokine receptors are part of the family of G-protein coupled receptors (GPCRs) and are expressed in these cells and play important roles in sensing the presence of chemoattractants, transducing signals that lead to the production of inflammatory cytokines and regulation of intracellular and intercellular communications. In addition to recruiting neutrophils, we have indirect evidence that neutrophils are held at inflammatory sites by signalling through GPCRs but don’t know which ones are important for this process. The aim of this project is to use bioinformatics analysis to generate a list of potential regulatory genes and subsequently generate a transgenic CRISPR-interference system in zebrafish to screen through candidate genes of neutrophil regulation. You will sequentially knock out expression of each gene in the whole organism and specifically, in neutrophils to study their roles in retention signalling during inflammation caused by local tissue injury.

Research Methodology

Readily available datasets will be used to identify candidate target genes involved in neutrophil regulation during inflammation and infection. Using CRISPR/Cas9 technology, we will manipulate these inflammatory genes in the zebrafish. This approach will allow us to identify new phenotypes, and will lead to new understanding of clinically important biological questions. This project will investigate specific candidate GPCRs, to identify essential genes involved in the regulation of inflammation resolution, and elucidate targets for translatable drug therapies. You will monitor neutrophil physical characteristics, behaviours and functionality using specialist cell tracking software. Well-established video microscopy, cell tracking and reverse migration assays will be performed in these newly generated activator or repressor zebrafish lines. Neutrophil physical characteristics, behaviours and functionality can also be assessed in incredible detail leading to new understanding and new drug targets for inflammatory diseases.

Expected Outcome

1. Perform detailed bioinformatic analysis to generate a list of potential candidate genes involved in neutrophil function.
2. Suppress gene expression of these candidate genes by microinjection of guide RNAs and Cas9 protein into zebrafish.
3. Generate new and improved transgenic lines, including genetic activator lines and super-repressor lines for neutrophil-specific knockdown.
4. Become proficient in live imaging methodology, including using the spinning disk confocal, a Nikon inverted fluorescent microscope and Lightsheet microscopy.
5. Refine reverse migration assays in transgenic lines following tail fin injury, and optimize analysis using NIS elements tracking software.
6. Identify function of interesting GPCRs during inflammation resolution.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Thorough training will be given covering molecular biology techniques, handling of zebrafish and larvae, standard tail fin transections, microscopy training, analysis software including NIS and graphpad prism. Scientific papers will be provided for background reading to gain a further understanding of the science relating to the project. This studentship proposal will provide a broad range of project-specific and transferable research skills. The training will build on the scientific methodology in routine use in the Renshaw Laboratory. The experimental techniques and methods outlined are all well established in the Renshaw group.

Comparison of impact on healthy brain aging of common inflammatory conditions: a UK BioBank study

Main Supervisor

Professor Nigel Hoggard (n.hoggard@sheffield.ac.uk)

Second Supervisor

Dr Iain Croall (i.croall@sheffield.ac.uk)

Aim and Objectives

Aims
1. Measure severity of white matter damage in patients with a history of coeliac disease, long term eczema or long term psoriasis
2. Measure cerebral atrophy using voxel based morphometry
Objectives
1. Define and identify patients with severe psoriasis and atopic eczema
2. Define the severity of white matter damage using TBSS analysis of diffusion tensor imaging for patients in the UK BioBank study with a history of coeliac disease, long term eczema and long term psoriasis
3. Definite global and regional brain volumes, normalised to total intracranial volume for patients in the UK BioBank study with a history of coeliac disease, long term eczema and long term psoriasis using voxel base morphometry

Research Methodology

Ethics is in place and the data has already been downloaded from the UK BIoBank study.
Software already available will enable patients in the UK BioBank study to be identified and their imaging and clinical data accessed, including performance on detailed neuropsychology testing.
Image analysis will be used to measure the severity of damage to the white matter of the brain and the degree and distribution of cerebral atrophy. Image analysis skills will be taught that are useful across clinical neuroscience.

Expected Outcome

Inflammation is thought to be generally bad for brain health. The comparative magnitude of this effect for patients who are affected by these common inflammatory conditions is not clear.
We wish to show in comparable groups which of these common conditions causes the greatest cerebral atrophy compared to well match controls and if there are specific patterns of this atrophy.
We wish to show if the integrity of the white matter fibres is more disrupted by greater "small vessel disease" in any of these conditions compared to match controls.
This is expected to result in a scientific publication. We have previously reported similar research from the UK BioBank study for patients with coeliac disease in Gastroenterology (IF22.682).

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

We have user guides and there will be direct supervision of the use of FSL, SPM and other software used for clinical neuroscience image processing analysis.
Students will be supervised and learn a broader range of generic scientific skills eg
Students will be expected to participate and present in lab meetings, learning and improving their presentation skills. Students will be expected to learn to at least contribute to writing scientific abstracts and publications.
These skills will be useful across a wide range of clinical neuroscience that utilises MRI brain imaging and are frequently at the core of many neuroscience PhDs.

Improving detection of pulmonary arterial hypertension in systemic sclerosis patients using hyperpolarised gas magnetic resonance imaging

Main Supervisor

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

Second Supervisor

Professor Jim Wild (j.m.wild@sheffield.ac.uk)

Aim and Objectives

1. Establish Xenon-based MRI (Xe-MRI) indices that differentiate between SSc patients who have PAH (SSc-PAH) and those who do not (SSc-noPH).
2. Assess whether Xenon-based metrics improve the positive predictive value of existing tools.
3. Determine the utility of Xe-MRI metrics for detecting changes in response to treatment in newly diagnosed PAH-SSc patients.

Research Methodology

Students will complete GCP, consent and study-specific training. Working alongside a clinical fellow and/or research nurse, students will identify and recruit study participants, carry out study visit assessments (e.g. clinical assessments, blood samples/processing, lung function testing, imaging scans) and collect and analyse data. Training will be provided in laboratory sample processing, image and activity data analysis and statistics.
 

Expected Outcome

Data collected will contribute to publications and the student would be a co-author of these outputs. The student will gain opportunities to present data at national and international conferences. Experience in advanced imaging would prove particularly useful for future careers in radiology, respiratory medicine or cardiology.

Type of Project

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

Additional Training

Students will gain experience of clinical research with an emphasis on imaging techniques. Students will have the opportunity to attend the pulmonary hypertension and imaging MDT meetings, clinics (to help with recruitment) and weekly clinical and scientific educational meetings.

Gastrointestinal BSc projects in the Academic department of Gastroenterology - Clinical studies in Functional Gastrointestinal Disorders (FGIDs)

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

We wish to give you a broad base of research learning in a friendly department with excellent support. Fantastic research opportunities and exposure to clinical practice. Many students also describe that they gained clinical confidence by talking to and recruiting patients as well as working in endoscopy during their project.

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.

Research Methodology

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 ethics have already been obtained and 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.
 

Expected Outcome

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.

Type of Project

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

Additional Training

You will have excellent in-house methodological support from your supervisor and clinical fellows within the department.

At any given time, there are 2-4 students undertaking BSc projects and up to 5 fellows (doctors who are training to become gastroenterology consultants but undertaking an out of programme experience). This is a close-knit group based on Ward P2 (Royal Hallamshire Hospital) with their own office – which means you have a lot of fun socializing within the department! Every Friday we all have lunch together and presentations at the informal Friday GI Academic Meeting.

The unique clinical studies that you will have the opportunity to undertake often lead to changes in clinical practice. You will be well supported in a thriving NHS GI research environment. You may be taking bloods, putting cannulas in, watching gastroscopies or colonoscopies. There is plenty of patient contact and you will feel that you are contributing to the team. Previous students have loved the friendly clinical environment.

"My confidence has grown throughout this year both personally and professionally. I now feel able to integrate myself into a clinical team to get more out of clinical placements in the future. I also had a whole year to practice taking bloods/inserting cannulas and talking to patients about procedures. This year has given me the ability to be confident working independently and when presenting to large audiences. It has been a lot of fun!” – Emily Greenaway GI BSc 2021-2022

Every September you get to attend our Shef Gastro annual symposium. This is an all-day gastrofest held at the Crowne Plaza Hotel (Sheffield). You get to watch world class speakers in gastroenterology and on top of all of that there is free food throughout the day!

All students have been able to present at our local Friday lunchtime academic meeting, our regional meeting (Bardhan Fellowship, usually held annually in March) and at the British Society of Gastroenterology (BSG) meetings (usually held annually in June).

This means that you are super confident and have overcome the ‘hurdle in our minds’ that presentation can be. This is a medical life skill and being taught presentation skills and presenting in a nurtured environment prepares you for when your own BSc presentation comes around. These opportunities also teach you how to field questions – another valuable medical life skill!

Although whilst you read this you will only be thinking (understandably) of ‘what do I get’ in the short-term by doing this GI BSc project. In the long-term, there is a far greater gain. Most of your medical training is didactic but after this experience you will have a more inquisitive mind and this, we promise, will make you a better doctor. You will not just follow medical protocols, but you will personally be able to understand and weigh up the medical science behind your decision making.

All students within the department receive a 1K bursary for your 12-month period in research. This allows you to pay for registration at the BSG annual conference, plus travel and hotel accommodation and still have plenty of funds left over for non-alcoholic beverages!

Computational modelling of coronary artery blood flow in acute coronary syndromes

Main Supervisor

Professor Julian Gunn (j.gunn@sheffield.ac.uk)

Second Supervisor

Dr Paul Morris (paul.morris@sheffield.ac.uk)

Aim and Objectives

Aim: to determine the impact of modelling coronary blood flow in patients with coronary artery disease (CAD)

Objectives
1. Read about the current management of CAD.
2. Learn about coronary angiography and fractional flow reserve (FFR).
3. Learn about our computer model systems of flow, based upon the angiogram.
4. Screen the angiograms.
5. Run the systems and work out the virtual FFRs.
6. Determine how virtual FFR can change treatment decisions.

Objectives
1. Apply data analysis tools to relate pulmonary artery pressure waveform and cardiac haemodynamics in patients with pulmonary hypertension
2. Determine the accuracy of methods for determining cardiac output from pressure waveform using an existing large set of data collected from clinical practise
3. Determine the relationship between remote monitor measured cardiac haemodynamics and physical activity in patients with pulmonary hypertension following treatment change and clinical worsening

Hypothesis - cardiac output can be derived from pulmonary artery pressure waveform

This is not service evaluation and we have REC approval already in place.

Research Methodology

* Reconstruct the study vessels
* Run the 3 software packages
* Determine the vFFR values (FFR > or < 0.80)
* Compare the performance of the 3 systems
* compare actual angiographic-based management (stent or not) with vFFR- based management

Expected Outcome

We have supervised 28 BMedSci/BSc students over the years and the vast majority have got a first. You will obtain a publication in a Cardiology journal and a presentation at a conference

Type of Project

Lab/Bench Project - primarily working in a lab environment (mostly virtual)

Additional Training

a) The data will be ready for you.
b) The software licences will be available.
c) We can train you in interpreting angiograms.
d) We will train you in using the software.
d) All ethical approvals are in place.
e) You will be supervised to analyse the data and write a report.
f) The 'lab work' mentioned above can be remote, on a laptop, in your own time.

Modelling in Pulmonary Hypertension

Main Supervisor

Dr Alex Rothman (a.rothman@sheffield.ac.uk)

Second Supervisor

Dr Jennifer Middleton (j.middleton@sheffield.ac.uk)

Aim and Objectives

Aims: To assess the feasibility of using pulmonary artery pressure monitor derived pressure waveforms to determine cardiac output and evaluate change with therapeutic escalation and clinical worsening.

Objectives
1. Apply data analysis tools to relate pulmonary artery pressure waveform and cardiac haemodynamics in patients with pulmonary hypertension
2. Determine the accuracy of methods for determining cardiac output from pressure waveform using an existing large set of data collected from clinical practise
3. Determine the relationship between remote monitor measured cardiac haemodynamics and physical activity in patients with pulmonary hypertension following treatment change and clinical worsening

Hypothesis - cardiac output can be derived from pulmonary artery pressure waveform

This is not service evaluation and we have REC approval already in place.

Research Methodology

You will learn about the invasive and non-invasive assessment of pulmonary hypertension, and how clinical decisions are made. You will also learn about using tools to perform waveform analysis and remote monitoring technology. You will learn how to critically appraise evidence and how to write a scientific report. You will work under close supervision from motivated members of the research group.

Expected Outcome

You will gain an excellent BMedSci dissertation, contribute data toward publication, and insights into cutting edge interventional cardiology clinical research and remote monitoring.

Type of Project

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

Additional Training

Statistical analysis in SPSS, prism and R. Exposure to clinical studies and clinical practise.

Tackling infectious disease prevention and diagnosis using a data driven approach

Main Supervisor

Dr Tom Darton (t.darton@sheffield.ac.uk)

Second Supervisor

Dr Farah Shahi (f.shahi@sheffield.ac.uk)

Other Supervisors

Dr Thushan de Silva, Prof Sarah Rowland Jones

Aim and Objectives

Recognising exposure to infectious pathogens is critical to the control of communicable disease transmission and prevention of illness. Data derived through analysis of pathogen isolates and immune correlates from individual patient samples provide a rich source of information to understand the dynamics of exposure and transmission.
In this project the student will use existing data collected from individuals during the COVID-19 pandemic and/or patients from the STH latent TB or HIV clinic. Depending on student choice of project, specific objectives might include be 1. To compare traditional measures of LTBI with recently described TB blood RNA signatures 2. To compare serological and cell mediated immune responses to COVID-19 with pathogen strain.

Research Methodology

Observational study using prospectively and retrospectively collected patient and healthy volunteer clinical and laboratory data. The student will be involved in some or all of clinical record data collection, interrogation of clinical and laboratory databases, statistical analyses of the data using R software.

Expected Outcome

The student will produce a distinct piece of research addressing the objective(s) and be the first author on a conference abstract submitted to one or more relevant infection conferences (e.g. ECCMID, BIA, FIS, Union TB conference, BHIVA) and subsequent manuscript submitted to appropriate infection research journal.

Type of Project

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

Additional Training

The student will be working with the wider clinical infectious diseases research group of supervisors, post doctoral research assistants, clinical fellows and post graduate students. They will be trained in Good Clinical Practice and data analysis including the use of statistical techniques, basic epidemiology and data management including an introduction to the R statistical computing and graphics language.

Production & Characterisation of Viral Proteins for Medical Biotech Applications

Main Supervisor

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

Second Supervisor

Dr Pat Baker (p.baker@sheffield.ac.uk)

Third Supervisor

Dr Martin Nicklin

Aim and Objectives

Optimise production of recombinant viral proteins; Characterise viral proteins; Determine molecular structure and interactions of viral proteins.

This project could address many questions e.g.
Research Question example 1: For a project on SARS-CoV-2 Nucleocapsid protein (NCAP, which condenses viral RNA and packages it into the capsid) we can ask how do variations in viral protein sequence impact upon nucleic acid binding? Do these proteins behave differently in diagnostic tests e.g. ELISA or rapid antigen tests?

Research Question example 2: Production of SARS-CoV-2 Spike protein (the active immunogen in most currently used vaccines) is limited by the relatively poor yield of Spike protein. We have engineered recombinant Spike protein that we believe can be made in much larger amounts than any currently produced. We can ask whether these altered Spike proteins are still recognised by commercial antibodies to "natural" Spike proteins? Do these recombinant engineered Spike proteins behave differently in diagnostic tests e.g. ELISA or rapid antigen tests?

Research Question example 3: Recombinant viral nucleases are used in point-of-care diagnostic devices in FDA approved tests for gonorrhoea with other target pathogens under development. The price of the nuclease represents a large proportion of overall cost per test. Can we use protein engineering to make more efficient enzymes and hence reduce the cost per test facilitating better monitoring of infection and targeted use of antimicrobial agents?

For examples 1 and 2 we would make use of sera collected under the "COVID-19 Humoral ImmunE RespOnses in front-line health care workers [The COVID HERO study]" in collaboration with Dr Thushan de Silva, as published doi: 10.1101/2021.07.07.21260151 (Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust
David Hodgson et al, medRxiv. Preprint. 2021 Jul 8.

Example 3 would not require such samples.

Research Methodology

We have been making SARS-CoV-2 (causative agent of covid19) antigens for DoHSC, NIBSC and UKNEQAS for use as standards and have supplied a UK consortium with this protein to develop new diagnostic technologies that do not rely on PCR. You will use our established recombinant DNA technology to optimise production of newly arising variant viral Nucleocapsid proteins and other nucleic-acid binding proteins. You will use biophysical and structural biology techniques to determine the biological activity and 3D structure of the proteins using a range of state-of-the-art technologies available locally. Full training in all laboratory techniques will be given.

Expected Outcome

The student will be trained in laboratory and computer-based 3D structure-determination methods underpinning modern structure-based drug discovery. You will produce useful reagents that we will disseminate to the wider scientific and commercial sector as they are potentially useful for development of diagnostic and molecular biological reagents.
You will produce quantitative data showing the strength of interactions between viral proteins and their interaction partners.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

I run an advanced module in analysis of protein interactions and in silico structural biology. The student could participate in these during semester ( 7 days hands-on workshops) and classes in recombinant protein production and purification.

Discovering new drugs for neglected tropical diseases

Main Supervisor

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

Second Supervisor

Dr Martin Nicklin (m.nicklin@sheffield.ac.uk)

Aim and Objectives

BACKGROUND: We work on flap endonucleases which are essential enzymes that process the branched DNA that accumulates during cell division. We have developed inhibitors of bacterial FEN enzymes that are able to kill bacteria but are relatively non-toxic to human cells. This project aims to African trypanosomiasis, Chagas disease and leishmaniaisis. FEN activity is crucial for the survival of all organisms tested, from mammals to bacteria, making them viable targets for antimicrobials. The project is based on experience from pilot projects and a spin-out company focusing on design of bacterial FEN inhibitors, and overseen by Prof Sayers who has 30 years of experience with nucleases.

Aims & Objectives: You will receive training in structure-based drug design and use that training to answer the following "Research Questions":

i) Can inhibitors with selectivity for parasite over human flap endonuclease enzymes be identified by a combination of fragment library and in silico screening?

ii) do these inhibitors interact with the protein, the DNA or both?

iii) Do these inhibitors kill parasites?

Research Methodology

The student will be trained in laboratory and in silico methods underpinning modern structure-based drug discovery. This multidisciplinary structure-based inhibitor design project involves in vitro and/or in silico screening, hit identification using FRET-based enzyme assays, and protein crystallisation, on top of standard molecular biology techniques, like recombinant protein production and characterisation.
If appropriate, further techniques are available, including biophysical characterisation of protein-inhibitor interactions using our new state-of-the art Bio-Layer Interferometry equipment, or structural biology employing X-Ray crystallography

Expected Outcome

You will produce recombinant protein, check quality and activity and carry out enzyme inhibitor assays on both parasite and human FEN enzymes in order to screen a library of so-called "drug fragments". You will compare the results for the human and parasite enzymes in order to identify molecules which show some level of selectivity (i.e. inhibit the parasite but not human enzyme). You will also generate a computer-based model and attempt to refine it in the light of the data you acquire. You will then use these data to carry out a "hit expansion" in an attempt to identify more potent but selective inhibitors.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

I run an advanced module in analysis of protein interactions and in silico structural biology. The student could participate in these during semester (7 days hands-on workshops).

Virus exposure and pulmonary hypertension

Main Supervisor

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

Second Supervisor

Professor Allan Lawrie (a.lawrie@sheffield.ac.uk)

Aim and Objectives

Pulmonary arterial hypertension (PAH) is a devastating condition characterised by progressive pulmonary vascular remodelling. Patients with PAH develop right heart failure and have a prognosis worse than many cancers. Inflammation plays an important role in driving vascular remodelling but the mechanisms linking inflammation and remodelling are poorly understood. Remodelling in PAH involves proliferation of vascular smooth muscle and endothelial cells. This project aims to assess whether exposure to viral stimuli changes how cells respond to pro-proliferative stimuli.

Objectives:
1. Determine if changes in expression of viral sensors can alter cell phenotypes
2. Determine whether viral stimuli alter key proliferative pathways

Research Methodology

The student will learn to isolate and culture human blood outgrowth endothelial cells from healthy donors and PAH patients and to culture pulmonary artery smooth muscle cells. The project will involve analysis of mRNA (qPCR) and protein expression (Western blot/ELISA), cell phenotypes (apoptosis, proliferation and migration assays) and gene knockdown (transfection of siRNA). If laboratory work becomes restricted due to COVID, the student will use clinical data from the pulmonary vascular diseases unit and the post-COVID respiratory clinic to assess whether viral exposure increases the risk of pulmonary vascular complications.

Expected Outcome

The project will provide important information about potential drivers of vascular remodelling in pulmonary hypertension. The student should expect to collect sufficient data for presentation at a national/international conference.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

The student will gain experience of obtaining samples from PAH patients and should become proficient in a variety of laboratory assays and in recording and analysis of results. The student will have the opportunity to attend PAH MDT meetings and weekly clinical and scientific educational meetings.

Staphylococcus aureus and Streptococcus pyogenes carriage in low- and middle-income countries: a systematic review and meta-analysis of risk factors and prevalence

Main Supervisor

Dr Thushan de Silva (t.desilva@sheffield.ac.uk)

Second Supervisor

Dr Alex Keeley (a.keeley@sheffield.ac.uk)

Other supervisors

Dr. Tom Darton

Aim and Objectives

The aims of this systematic review is to:

  1. Identify all data where a microbiological sample was taken that would detect S. aureus and /or S. pyogenes that were collected from asymptomatic human subjects in a community environment in LMICs, with an assessment of prevalence of carriage.
  2. Determine the prevalence of S. aureus (inc MRSA) and S. pyogenes carriage in a community environment in LMICs.
  3. Assess the associations of study site (country, urban, rural), body site, gender, age, poverty indicators, impact of pneumococcal conjugate vaccine with carriage and where data available to undertake a meta-analysis.
  4. Determine the prevalence of antibiotic resistance in colonising isolates of S. Aureus and S. pyogenes where data are available.

Research Methodology

Students will assist in systematic review in accordance with PRISMA guidelines and will reported using PRISMA checklist. The study has been submitted for registration with Prospero. Students will the systematically review and include studies with extractable data relating to a human group or subgroup of subjects in a community environment that determine the prevalence of S. aureus and/or S. pyogenes carriage from a low or middle income setting. Students will extract data pertaining to prevalence of, and risk factors for, community colonisation with S. Aureus and S Pyogenes. Students will perform a risk of bias assessment with a validated tool built into the data extraction proforma.

Expected Outcome

  1. Determine the prevalence of S. aureus (inc MRSA) and S. pyogenes carriage in a community environment in LMICs
  2. Perform meta analysis of risk factors for colonisation
  3. Lead the preparation of a manuscript for submission to Lancet Global Health Journal

Type of Project

Qualitative Project/non-lab based - primarily using qualitative methods

Additional Training

We will provide supervision in the performance of systematic review searches and data collection.

Investigating novel tissue resident macrophage populations in vivo

Main Supervisor

Dr Iwan Evans (i.r.evans@sheffield.ac.uk)

Second Supervisor

Dr Martin Zeidler (m.zeidler@sheffield.ac.uk)

Aim and Objectives

The white blood cells known as macrophages play an essential role in development, homeostasis, immunity and repair. The macrophage lineage is highly heterogeneous owing to the existence of tissue-resident populations alongside the ability to become activated to a range of states (termed macrophage polarisation).

Our lab used the genetically-tractable model organism Drosophila melanogaster (fruit flies) to understand regulation of macrophage function in vivo. We have recently discovered, for the first time, the existence of developmentally-regulated macrophage subpopulations in this organism. Fruit flies have been extensively utilised to understand immunity, not least in its role in the discovery of the immunoregulatory role of Toll receptors, for which Hoffmann received the Nobel Prize for Medicine.

This project aims to understand the function of these subpopulation macrophages and their relationship to vertebrate macrophages in more detail.

In order to understand the importance of these subpopulations the student will use genetic strategies to ablate subpopulation macrophages at various stages of the fly life cycle and examine the consequences for development, survival and immunity. In particular the student will examine the ability of the organism to fight off infections and repair damage when the macrophage subpopulations are removed. We will also address the effects of expanding these subpopulations.

Genes that are differentially expressed between subpopulations will also be investigated to understand the contributions that they make to immune responses in vivo.

Research Methodology

This project involves genetics, molecular biology, in vivo imaging, microscopy, image processing and analysis and statistical analysis. The student will take charge of their own Drosophila stocks and conduct genetic crosses to generate progeny in which subpopulation macrophages have been manipulated or candidate genes removed/overexpressed. The resulting fly embryos, larvae and adults will be analysed in a range of assays to understand the role of these subpopulation macrophages. Live imaging will then be analysed using software including Fiji and quantitative data obtained from these images. Other non-microscopic data will also be collected (e.g. survival of flies following infection/injury).

Expected Outcome

This project will enable us to understand the role of Drosophila macrophage subpopulations in response to infection, during development and during aging.

We will assess the role of candidate genes differentially expressed between subpopulations in these responses.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Full training in all techniques will be provided by my lab. This will include fly genetics, fly husbandry, dissection techniques, in vivo imaging, microscopy, image processing and analysis, statistical analysis in Prism.

We have weekly lab meetings and also take part in bimonthly fly meetings with groups in BMS. We have an annual lab retreat with other immunity-focused groups in IICD/BMS and are part of the Bateson Centre.

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