Clinical Medicine projects

Intercalated BSc Medical Sciences Research available projects

A skin test conducted by a medical researcher
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Projects:

Viral inflammatory memory in respiratory epithelial stem cells

Main Supervisor

Professor Colin Bingle (c.d.bingle@sheffield.ac.uk)

Second Supervisor

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

Other Supervisors

Dr Ben Lindsey

Aim and Objectives

Aim: To quantify the rate and magnitude of interferon stimulated genes in basal cells that have recently been exposed to Human Rhinovirus (HRV) and Influenza A infection (IAV) and determine the duration of transcriptional memory.

Objectives:

1. Culture basal cells from previous in vitro infected respiratory epithelium.
2. Quantify expression of specific interferon stimulated gene mRNAs, pre and post stimulation with recombinant interferon-ɑ (IFN-ɑ) at several time points (3 days, 7 days, 14 weeks) post viral infection.
3. Compare magnitude and rate or mRNA expression between HRV and IAV exposed cells.

Research Methodology

The student will be trained to independently carry out cell culture which will include counting, seeding and splitting cells. Previously infected and uninfected cultured cells will then be stimulated with varying concentration of IFN-ɑ (Month 0-3). They will undertake RNA extraction and polymerase chain reaction (PCR) experiments to quantify the mRNA expression under the various conditions outlined above (Month 3-6). After generating the data they will be supported in analysing and interpreting the data (Months 6-8).
 

Expected Outcome

We hypothesise that expression of certain interferon stimulated genes (ISGs) will continue for at least 14 days post infection with HRV and IAV. It is anticipated that the rate and magnitude of ISGs will be greater in cells that have recently been exposed to viral infection. The effect size may differ between the two viruses and the overall effect will persist for at least 2 weeks.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Cell culture (counting, seeding, splitting cells)
Light microscopy
RNA extraction
PCR
Data analysis
Opportunity to learn about high fidelity respiratory epithelial cell culture and transcriptomic methods

Measuring change In MSA (MINIM study)

Main Supervisor

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

Second Supervisor

Professor Marios Hadjivassiliou (m.hadjivassiliou@nhs.net)

Other Supervisors

Dr I Croall

Aim and Objectives

(i) Does MR volumetry and MR spectroscopy show progressive declines in patients with probable and possible MSA-C, the rate of which will reflect the clinical state of the patients and their survival.

(ii) Will MR imaging of patients with probable and possible MSA-C reflect the underlying neuropathology causing changes in myelination of the brainstem-cerebellar pathways be demonstrable with MR diffusion tensor imaging (DTI) and magnetisation transfer imaging (MTI) and be reflective of the clinical state of the patient.

(iii) Will FDG PET imaging of patients with probable and possible MSA-C detect metabolic changes in brain function that correlate with measureable anatomical changes on MR imaging and the clinical state of the patient.

(iv) Will FDG PET imaging of patients with severe and aggressive ataxia help differentiate early MSA-C from autoimmune ataxia.

Research Methodology

Work Package 1
Observational, retrospective study of the natural history MSA-C in the Sheffield cohort of around 140 people. This is an opportunity to learn image processing skills such as voxel based morphometry (VBM). Ethics is in place, this will be the main focus of the project.
Work Package 2
We have commenced recruitment to a single centre pilot study evaluating the use of a range of imaging biomarkers for use in future therapeutic trials. This will be an opportunity to learn PET data analysis skills. Students will not be expected to play a central role in recruitment.
 

Expected Outcome

WP 1: The rate of change in atrophy and MR spectroscopy will be determined in relation to clinical severity and the date of death/disease duration in deceased patients.
WP 2: Comparison of PET imaging with magnetisationisation transfer and DTI to determine the best outcome measures for trial use.

Type of Project

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

Additional Training

This is an opportunity to undertake image processing in the context of neurodegenerative disease, such as voxel base morphometry (VBM) but there will be an opportunity to gain experience with analysis of PET imaging data, diffusion tensor imaging and magnetisation transfer imaging. These generic skills are widely used across the spectrum of neurodegenerative disease. The soft ware platforms used will mainly be SPM and FSL.

Investigating the causal impact of mildly elevated IGF-1 on metabolism using Mendelian randomisation studies

Main Supervisor

Professor John Newell-Price (j.newellprice@sheffield.ac.uk)

Second Supervisor

Dr Alan Kelsall (a.kelsall@sheffield.ac.uk)

Aim and Objectives

Aims

To investigate the causal effects of genetically determined IGF-1 in influencing cardiometabolic parameters

Objectives

To conduct a literature review to detect conditions associated with elevated growth hormone/ IGF-1

To use Mendelian randomisation studies to analyse the causal relationship between IGF-1 and cardiometabolic parameters

Research Methodology

Acromegaly is rare endocrine disorder of growth hormone excess, associated with a wide range of cardiometabolic disorders. Growth hormone stimulates the secretion of insulin-like growth factor 1 (IGF-1) from the liver. IGF-1 correlates with growth hormone and is used in the diagnosis of acromegaly and for monitoring treatment effects. In otherwise healthy individuals a causal relationship between prevailing levels of IGF1 and cardiovascular disease is not fully established, and data associative.

Genetic variations occur commonly throughout the genome and can lead to altered gene expression. Within a normal population, some people will have a relatively elevated IGF-1 without having classical phenotypic features of acromegaly. Mendelian randomisation is a technique that allows the association of these common genetic variations, with a measured value, such as IGF-1. These genetic variants associated with elevated IGF-1 can then be used as an instrument to assess against other phenotypes. As genetic variations are randomly distributed through a population, environmental confounding is reduced and the methodology can be used to assess for causal relationships, rather than just associations. As such it is powerful approach that compliments other experimental paradigms.

Expected Outcome

Project Outcomes

The student will learn how to synthesise relevant literature and conduct a literature review

The student will gain confidence in writing code in the statistical software package R which will be significantly beneficial throughout their research career. In addition they will have exposure to high performance computing and parallel computing. The skills gained will be highly transferable to assessment of many disease states and physiology.

Summary statistic data for IGF-1 from the UK Biobank that has data on around 500,000 individuals will be used to find genetic variants associated with varying IGF-1 levels and assess against other databases of phenotypes to investigate causality.

This project will involve in-silico research with analysis conducted using R and high performance computing networks. There will be no laboratory studies. We are currently using Mendelian randomisation studies to assess the wide ranging effects of cortisol and have discovered several novel results.

The student will become proficient in conducting Mendelian randomisation techniques including:
• Accessing and formatting large data sets from online databases
• Performing quality assurance of both the IGF-1 dataset and metabolic traits
• Ensuring that the correct alleles are compared between datasets
• Performing a range of MR analyses and robust tests to consolidate findings
• Producing high quality figures in R as well as being comfortable performing more basic statistical analysis/ data interpretation which will have significant carry over to other research projects

Supervision

Hands on teaching and support will be provided throughout the project particularly in the initial phases when learning how to code with R and MR techniques. Meetings with supervisors will be held at least weekly and there will be regular opportunities to attend specialist endocrine clinics and see patients with rare disorders such as Cushing’s disease and acromegaly.

Type of Project

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

Additional Training

As above

What is the frequency of incidentally detected Renal Cancer in South Yorkshire? Do these tumours behave differently to those tumours that present symptomatically in terms of survival and other outcomes?

Main Supervisor

Professor Janet Brown (j.e.brown@sheffield.ac.uk)

Second Supervisor

Mr Marcus Cumberbatch (M.G.Cumberbatch@sheffield.ac.uk)

Aim and Objectives

Identify from histology records and medical records patients who have had a new diagnosis of localised or metastatic renal cancer in our region and link to presentation if symptomatic or incidental on imaging for other purposes. To look at a particular time period ie 2018-2020 to also allow investigation of survival and other outcome data

Gain experience in research methods such as literature review techniques as well as auditing NHS data.

Develop data collection skills and recommendations for service improvement.

Research Methodology

This is a clinical non-lab based project.

Review of the existing literature on incidentally detected renal cancers. .

Deciding which data fields would be sensible to collect from clinical records and designing an excel spreadsheet to collect that data..

Experience on using NHS electronic records to search pathology and other data.

Producing a report including basic statistics on things like numbers of incidentally detected , stage and histology and also developing stats and presentation skills to show the data and do basic survival curves etc.

Drafting with support a publication on the findings in our region and also including up to date published literature at other centres and gaining skills in summarizing this information.

Setting up the data fields also to continue this project beyond this BMedsci.

Gaining experience in presenting data at national meetings and making posters as well as drafting papers.

Expected Outcome

Produce a detailed write up on modern day numbers of incidental tumours diagnosed with renal cancer in our region and describe their stage compared to those who present with symptoms as part of the study. Write up to provide an up to date publlshable review in this area as well as ideas for service improvements that can be made to improve patient care.

Type of Project

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

Additional Training

Teaching in good clinical practice.

Database creation.

Basic stats training.

Teaching on how to write a research report and publication and present at national meetings.

Opportunities to also attend clinics urology and or oncology clinics with renal cancer patients.

The strong combination of an academic urologist in renal cancer working with an academic oncologist makes this a very strong project in terms of outcomes.

Artificial Intelligence in Medical Education: Impact on Student Assessment Preparation and Performance in Clinical and Academic Settings?

Main Supervisor

Professor Chris Roberts (chris.roberts@sheffield.ac.uk)

Second Supervisor

Professor Pirashantie Vivekananda-schmidt (p.vivekananda-schmidt@sheffield.ac.uk)

Aim and Objectives

There are two linked research aims for this project depending on the research interests and capabilities of the student 1) To develop and validate a quantitative scale for use in surveys that determines the readiness of medical students for AI-assisted assessment in medical education? Alternatively 2) Using an interview based study, to explore the perceptions and experiences of students which influence their use of AI technologies in preparing for their academic and clinical assessments.

Research Methodology

Study 1 Items will be generated for an questionnaire measuring AI readiness based on the relevant domains derived from the Technology Acceptance Model (TAM) and review of relevant literature. An item quality process, including expert reviews and pilot testing will be undertaken to refine and finalize the scale items. Following data collection from implementation within the Sheffield Medical School, statistical analysis will be undertaken to determine the factors impacting readiness.
Study 2 Qualitative interviews or focus group discussions with with a sample of volunteer students will explore students perceptions, experiences, and insights regarding their readiness for AI-assisted assessment. Qualitative data analysis techniques will determine rigor of the study.

Expected Outcome

The validated scale and qualitative findings will contribute to the field of medical education by providing a reliable and valid tool to assess medical students' readiness for AI-assisted assessment. Alternatively, a qualitative interview based study will provide an in depth understanding of the main factors. These findings will inform both students, faculty and administrators in curriculum and assessment development, instructional design, and policy making regarding better and informed integration of AI technologies in medical education programs.

Type of Project

Medical Humanities

Additional Training

Project 1) Use of SPSS for questionnaire analysis. Project 2 Basic qualitative research methods .

Immune long term toxicities or late effects in patients on Cancer immunotherapy: a Sheffield led national data base to improve patient outcomes.

Main Supervisor

Professor Janet Brown (j.e.brown@sheffield.ac.uk)

Second Supervisor

Dr Joanne Bird (joanne.bird4@nhs.net)

Aim and Objectives

To help review and understand what late effects data should be collected as part of this important project and contribute to a review publication in this area. Also possible publication on creation of this national data base and research evidence for decisions on fields collected

for student to gain knowledge on immunotherapy toxicity, literature reviewing and designing core data set to collect together with Prof Brown Dr Jo Birds and staff at Data collect in the university.

To gain experience working in a multidisciplinary research team.

This project is very clinically orientated and will also allow attending cancer immunotherapy late effects clinics.

For candidate to have opportunities to also present at UK and possibly international meetings on this area.

To develop an understanding of how such national data bases contribute to identification and treatment of patient late effects

This project is ideal for a student who is interested in Oncology, endocrinology or indeed other areas of medicine such as respiratory, gastro, renal, Hepatology in view of long term toxicities involved also those who want to understand the increasing role of big data and developing national protected research environments

This is also likely to be a very active area going forward that Sheffield is leading that could late form basis for a PHD project

Research Methodology

This project is largely clinical and also linked to data

Review of existing literature to home down on fields to collect this is likely to include a modified Delphi exercise with clinicians which student would not be expected to run alone but take part in will also involve university ethics for discussions with staff and qualitative methods regarding input into what data to collect

Expected Outcome

Review with significant guidance of literature of chosen late effects to include within the data set and to lead in writing a publishable review in this area with guidance.

To have played a significant role in the early identification via literature discussion with clinicians what data might contribute to data base going forward.

Type of Project

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

Additional Training

Clinical training in immunot6herapy and toxicity scoring, learning about cancer late effects in the clinic.

How to write a relevant review.

How to work with digital teams and learn about protected research environments and research ethics.

Principles of qualitative research and Delphi exercise, how to create a research national data base.

Research university ethics and Good clinical practice.

How to present information at an invited talk and how to make and present a poster at a national meeting.

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

Main Supervisor

Dr 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.
A similar project completed by the lead supervisor won poster prize at a national conference, was presented as an oral presentation in an international conference and was published in a peer reviewed journal- see link https://bjgpopen.org/content/6/2/BJGPO.2021.0224

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.

International medical graduates and their postgraduate career paths in general practice

Main Supervisor

Dr Laura Emery (l.j.emery@sheffield.ac.uk)

Second Supervisor

Dr Ben Jackson (ben.jackson@sheffield.ac.uk)

Other Supervisors

Dr Caroline Mitchell

Aim and Objectives

To identify what factors influence career decisions for general practitioners and whether factors differ between UK graduates and international graduates.

Research Methodology

The student will be an integral member of the research team for this project. October to December- Student will co-design an electronic survey with the lead supervisor to be disseminated to postgraduate general practitioners across Yorkshire and the Humber. January to April- Student will be supported in analysis of the quantitative and qualitative data generated by the survey. May to July- Time to write up project. Student will have the opportunity to present findings and co-author on any resulting papers.

Expected Outcome

This issue of differential attainment between international graduates and their UK trained colleagues is of great importance in postgraduate medical education and especially in primary care, but the research in this area is significantly lacking. So far most research has been focused around postgraduate exam outcomes, but it is likely that there is also an effect on long term career trajectories. Any research which provides concrete data on this issue is likely to be very well received.

A similar project completed by the lead supervisor won poster prize at a national conference, was presented as an oral presentation in an international conference and was published in a peer reviewed journal- see link https://bjgpopen.org/content/6/2/BJGPO.2021.0224

Type of Project

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

Additional Training

Design of an online survey, introduction to qualitative data analysis and basic training in use of NVivo software for qualitative analysis.

Karonudib: a novel treatment for myeloma

Main Supervisor

Dr Alanna Green (a.c.green@sheffield.ac.uk)

Second Supervisor

Dr Helen Bryant (h.bryant@sheffield.ac.uk)

Aim and Objectives

The goal of this project is to validate Karonudib as a treatment for myeloma, using patient cells to confirm data in cell lines and animal models.
The specific aims are to:
1) Determine whether Karonudib kills myeloma patient cells
2) Identify if a dormant cell population can be detected in patient samples, and if so whether Karonudib kills these dormant cells
3) Validate the mechanism of Karonudib in patient cells

Research Methodology

The student will isolate CD138+ myeloma cells from patient bone marrow (or plasma cells from healthy donors) using magnetic bead separation. Patient cells will be cultured with Karonudib (or vehicle) and full spectrum flow cytometry will be used to measure apoptosis, cell cycle phases, reactive oxygen species (ROS), DNA damage, MTH1 and AXL (dormancy marker) simultaneously in each sample.
Samples will also be taken for qPCR, to correlate Karonudib sensitivity with gene expression, to help validate biomarkers of sensitivity and resistance (which are currently being identified through a Karonudib genome-wide CRIPR screen) to guide a precision medicine approach.

Expected Outcome

We expect that patient cells will respond to Karonudib similarly to cell lines, whereby induction of ROS causes apoptosis. Our data have led to a phase I trial in myeloma patients, and our goal is to progress to phase II. The data generated in this project will help facilitate translation to a phase II trial.
If we can identify a dormant cell population in patient cells, and Karonudib can kill these cells, this may also guide treatment strategies. For instance, whether Karonudib should be given as a maintenance therapy to eradicate minimal residual disease, which persists after chemotherapy.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Lab techniques: cell culture, 2D/3D multicellular models, magnetic bead purification, large-panel full spectrum flow cytometry, apoptosis assays, cell cycle assays, ROS assays, measuring DNA damage markers.
Analysis of flow cytometry data in FlowJo and statistical analysis is GraphPad Prism.

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

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

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.

Research Methodology

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

Expected Outcome

Clinical series in a peer-reviewed journal
Methylation episignature for HNRNP-related disorders
Conference abstracts

Type of Project

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

Additional Training

Variant interpretation; clinical phenotyping; lab work if interested

Regenerative strategies for the treatment of human osteoarthritis.

Main Supervisor

Professor Christine Le Maitre (c.lemaitre@sheffield.ac.uk)

Second Supervisor

Professor Claire Brockett (c.brockett@sheffield.ac.uk)

Other Supervisors

Professor Mark Wilkinson, Professor Endre Kiss-Toth

Aim and Objectives

This project aims to provide Proof of Concept data supporting the use of a novel injectable hydrogel for repair and restoration of damaged cartilage.
Specifically it will address a number of key objectives:
1) Does the biomaterial integrate with local cartilage tissue following application.
2) Do articular chondrocytes migrate into the biomaterials within an ex vivo culture system.
3) Biomechanical assessment of biomaterial induced repair.

Research Methodology

The student will investigate the application of a novel biomaterial on models of osteoarthritis using a combination of waste animal tissues and human tissue from surgery. They will perform ex vivo culture of living osteochondral explants treated with biomaterials. Following culture samples will be investigated with a variety of downstream analysis including micro-CT, histology and immunohistochemistry to understand the ability of the biomaterial to induce repair and potential regeneration. In addition biomaterials will be biomechanically characterised including testing following application to whole joints.

Expected Outcome

This project will establish important proof of concept data, as to whether our injectable biomaterial system supports tissue repair, cellular migration and biomechanical restoration of osteoarthritic tissues as a pre requisite for future development for clinical application.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Issolation of tissues from surgical samples, Ex vivo culture within physiologically relevant conditions, biomaterial handling, biomechanical testing, histology, immunohistochemistry, QPath automated analysis software, Graph Pad Prism and statistical analysis.

Investigating barriers and drivers using Quality Improvement methodology to support implementation of the NHS Green Plan

Main Supervisor

Dr Helen Crimlisk (helen.crimlisk@shsc.nhs.uk)

Second Supervisor

Ms Parya Rostami (Parya.Rostami@shsc.nhs.uk)

Other Supervisors

Sarah Ellison, Jo Hardwick, Dr Jaimee Wylam, Dr Dasal Abayaratne

Aim and Objectives

The student will work with the Quality Improvement Team and Trust Sustainability Lead and Corporate and Clinical staff working with the team including Consultant Psychiatrist and Hon SL, Dr Helen Crimlisk who is leading elements of this work in her role as Deputy Medical Director.

The student will identify barriers and drivers in clinical and corporate teams using a quality improvement approach outlined in the SusQI Framework https://sustainablehealthcare.org.uk/susqi.

They will go on to test some of their ideas in conjunction with the QI team measuring outcomes and impact using data collection methods as appropriate to the project.

Research Methodology

This will be a mixed methods approach. The student will use quantitative and qualitative methods including focus groups, literature exploration and data collection through routine quality improvement processes to demonstrate outcome of interventions chosen. It is anticipated that the range of options will include improvements based around individual behaviour, service models and delivery and corporate procurement themes.

Expected Outcome

The student will gain experience at an organisational level in the speciality of mental health of the challenge of implementing transformation to meet challenging targets and the methodologies needed to enable this within an organisation which include a focus on quality and experience of individuals and looking at drivers and barriers and addressing some of these through systems orientated change and leadership.

There will also be the opportunity to understand and participate in specific Quality Improvement projects identified and learn about the system leadership and partnership approach which is necessary to drive change. There is organisational (and indeed NHS) commitment on this strategic aim which will support the project

Type of Project

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

Additional Training

Training will be offered in SusQI methodology through https://sustainablehealthcare.org.uk/courses/sustainability-quality-improvement and also via the Sheffield Microsystems Academy https://www.sheffieldmca.org.uk/ or other appropriate QI Academy.
There is also the opportunity to link with the RCPsych who offer networking and CPD on Sustainability https://www.rcpsych.ac.uk/improving-care/sustainability-and-mental-health.

The student will have the opportunity to link with this group through the support of one of the previous College Sustainability Fellows, Dr Dasal Abayaratne and understand the links to Public and Population Health through the support of Public Health Registrar, Dr Jaimee Wylam and Head of Population Health, Jo Hardwick. The student will also be supported by SHSC Sustainability Lead, Sarah Ellison.

Equitable bereavement care for all - An inclusive, qualitative study to improve
bereavement services for those from ethnically diverse communities

Main Supervisor

Dr Catriona Mayland (c.r.mayland@sheffield.ac.uk)

Second Supervisor

Ms Emily Fisher (e.fisher1@sheffield.ac.uk)

Aim and Objectives

This study aims to understand the needs and experiences of bereavement support services for people from ethnically diverse (ED) communities and begin to identify solutions to better meet current needs.

Objectives:
1. To explore awareness, accessibility, and experiences of bereavement support services for people representing specific ED communities.
2. To investigate barriers and facilitators to improving accessibility, acceptability, and appropriateness of bereavement support services from the perspective of bereaved people
3. To investigate barriers and facilitators to improving accessibility, acceptability, and appropriateness of bereavement support services from the perspective of service providers
4. To understand good practice in how bereavement support services advertise their services, adapt services for diverse communities, and widen access to their support.
5. To engage with potential service users, providers and key stakeholders to collate research findings, and together design appropriate, acceptable resources and policy-relevant recommendations to help services develop and deliver culturally sensitive bereavement support services which are accessed by all who need them.
6. To develop a logic model of factors required for culturally sensitive bereavement support services, including adaptations to be more accessible, acceptable, and appropriate.
7. To disseminate findings in a broad, diverse way, using multi-media methods, to policymakers, professionals, key community and charitable stakeholders.

Research Methodology

As part of a larger funded qualitative study, incorporating principles of experience-based co-design, the student will conduct a qualitative study with a specific ethnically diverse community to:


1. Explore awareness, accessibility, and experiences of bereavement support services for people representing specific ED communities.
2. Investigate barriers and facilitators to improving accessibility, acceptability, and appropriateness of bereavement support services from the perspective of bereaved people

Design: Concurrent focus group and individual interviews targeting bereaved individuals from a specific community. We will aim to achieve representation of different ages and genders to address intersectionality. The student will potentially work with community researchers, multi-lingual researchers, and interpreters where needed.

Specific skills obtained: Training in NVIVO (specific qualitative research package) and qualitative analysis.

Expected Outcome

1. Description of the facilitators and barriers for awareness, acceptability, accessibility, and
‘appropriateness’ of bereavement support services within a specific ethnically diverse community.

2. Data regarding contexts and mechanisms of action to improve bereavement support services

3. Outputs will include an abstract and publication. In addition, the student will gain insight into the production of a short film of participant narratives, that will form one of the outputs within the larger study.

Type of Project

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

Additional Training

Introduction to qualitative research methods.

How can learning about health inequalities in community placements be supported by co-created learning experiences and knowledge exchange.

Main Supervisor

Dr Joanne Thompson (j.thompson1@sheffield.ac.uk)

Second Supervisor

Dr Ben Jackson (Ben.jackson@sheffield.ac.uk)

Other Supervisors

Dr Andy Douglas

Aim and Objectives

Aim:
To explore and understand the impact of community based placements on the learning experience of medical students
Objective:
By using questionnaires and focus groups we will consider the co-creation process and how this promotes learning for student doctors.

Research Methodology

Students will undertake qualitative research through focus groups and semi-structured interviews with medical students who have completed a community based student selected component during their studies. A short questionnaire may be used to help inform the qualitative work. Students will lead the research project and develop skills in creating a research proposal and research ethics application, as well as developing skills in collating, analysing and presenting qualitative data qualitative data.

Expected Outcome

Students will complete a research project that develops new knowledge in the emerging medical education field of co-creation and student knowledge exchange. We anticipate that this project will generate sufficient new knowledge for publication in a peer reviewed journal.

Type of Project

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

Additional Training

Students will receive training in qualitative research methods. Students will also be invited to our departmental medical education scholarship forum as well as any relevant GP and/or health inequity events that will support their work.
If more than one student opts for the project, a peer learning group will be supported.

A paediatric reference range study for non-invasive screening and diagnostic tests of Adrenal Insufficiency.

Main Supervisor

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

Second Supervisor

Dr Neil Wright (N.P.Wright@sheffield.ac.uk)

Other Supervisors

Professor Richard Ross

Aim and Objectives

To construct age, sex and pubertal-stage reference centiles for awakening salivary cortisol and cortisone (ASCort - screening test for adrenal insufficiency)
To construct age, sex and pubertal-stage reference centiles for salivary cortisol and cortisone using the Nasacthin Test at the 60-minute timepoint.
To explore the acceptability and usability of ASCort and Nasacthin Tests in participants and healthcare staff.

The research question for this work is “What are the normal salivary glucocorticoid (cortisol & cortisone) ranges (awakening, afternoon and bedtime) and in response to ACTH stimulation in healthy children? Are the reference ranges impacted by age, sex and pubertal stage?

Research Methodology

The BSc student will be part of a team delivering a clinical study defining the normal reference range data in neonatal and paediatric healthy children for novel screening and diagnostic tests evaluating adrenal function. Our group has been developing novel tests of adrenal function for a number of years. We use awakening salivary glucocorticoids (cortisol and cortisone) collected by the patient/healthy volunteer at home to screen for adrenal insufficiency and have reformulated synacthen (ACTH analogue) for nasal administration for a novel invasive Short Synacthen diagnostic test.
The study is an open-label normative data study of healthy children (0-18 years). On day 1 participants will collect an awakening salivary sample, then at 2pm and on retiring for bed. On day 2 participants will produce another awakening sample and bring all four samples to the study visit where a baseline salivary sample will be taken and immediately afterwards Nasacthin (novel formulation of Syancthen) will be administered nasally followed by a 60-minute salivary sample. After their visit the participant/carer will complete a questionnaire to assess the acceptability/usability of both tests. At the end of the study staff will fill in a questionnaire exploring their experience of the Nasacthin Test.
The student will be involved with the recruitment, clinical visits and post-visit surveillance for the study. They will get experience of setting up, running and monitoring of a clinical study with some exposure to basic results analysis.

Expected Outcome

Overall experience of running a clinical study for novel endocrine tests in children of all ages.
Specifically:
Assist the research team in recruitment and study visits in 210 healthy children.
Upkeep of research database and clinical research forms
Analysis of some of the study data (a statistician will construct the normal ranges)
Analysis of questionnaires to determine acceptability/tolerability of the participants.

Type of Project

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

Additional Training

The student will be part of successful research team who work to improve adrenal function testing and treatment using novel diagnostic and therapies in children and adults. The student will receive close supervision and exposure to clinical trial methodologies, statistics, laboratory methods (this is NOT a laboratory study), presentation and paper writing skills.

How does cartilage respond to mechanical loading?

Main Supervisor

Professor Mark Wilkinson (j.m.wilkinson@sheffield.ac.uk)

Second Supervisor

Professor Endre Kiss-Toth (e.kiss-toth@sheffield.ac.uk)

Aim and Objectives

To determine: 1) how the human chondrocyte transcriptome responds to mechanical loading
2) whether disease and normal chindrocytes differ in their responses

Research Methodology

The student will lead the project and will be supported by the supervisory team and the lab PhD students and post-docs.
The student will attend theatre to collect the tissue from the patients, will prepare the tissue for culture and loading using our dedicated mechanical testing jig.
The student will also take the lead role in the downstream processing of the tissues, including tissue and RNA extraction and in analysing the experimental outputs.

Expected Outcome

Expected outcomes will include:
1) Enthusiasm and confidence in laboratory skills, understanding scientific writing, and a passion for musculoskeletal research! 2) Oral and poster presentations at relevant local, national and international musculoskeletal meetings
3) Prominent authorship positions on manuscript outputs that will be submitted to leading journals in the field
4) A successful research dissertation
Previous intercalating students in our group have won local, national and international awards for meeting presentations and had their work published in leading journals including Lancet Rheumatology and Journal of Bone and Joint Surgery.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

This project will expose the student to many clinical and laboratory skills.
The student will learn about the ethics and consent process around biobanking of human tissue samples. The student will interact with the patient in the consent process.
The student will learn about tissue culturing and mechanical loading of cells and tissues, and how to extract cells from cartilage and RNA from the cells. The student willl also learn how to assess RNA quality and run PCRs for various genes.
The student will also be trained in research methodology and in cartilage and osteoarthritis biology.

Role of NBAS in human disease beyond bone fragility

Main Supervisor

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

Second Supervisor

Professor Steve Renshaw

Aim and Objectives

- Analyse in-depth the skeletal, liver and immune abnormalities of homozygous mutant NBAS fish.
- Recapitulate human phenotype, by generating disease-specific mutant zebrafish using CRISPR-Cas9.
- Drug screening assay to identify potential therapeutics.

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

Research 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 (SOPH syndrome, Short stature; Optic atrophy; 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 done in my lab as well as others suggests that NBAS may play a role in the secretion of collagen.

Expected Outcome

Analyse skeletal and liver abnormalities in NBAS mutant zebrafish
Compare 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

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.

Lung MRI for Risk Stratification to select non-small cell lung cancer patients for radical treatment (LUMRIS)

Main Supervisor

Dr Bilal Tahir (b.tahir@sheffield.ac.uk)

Second Supervisor

Professor Matthew Hatton (matthewhatton@nhs.net)

Third Supervisor

Professor Jim Wild

Aim and Objectives

The objective of this study is to clinically evaluate the feasibility of introducing advanced functional MRI techniques into the current lung cancer diagnostic pathways across a cancer network and to assess its impact on multi-disciplinary team (MDT) decision-making for risk stratification of non-small cell lung cancer patients.

Primary Objective
To assess the feasibility of adding functional lung MRI to the diagnostic MDT pathways for radically treatable lung cancer.

Secondary Objectives

1. To assess the impact of introducing this technology on MDT decision-making for risk stratification.
2. To assess the accuracy of functional MRI for predicting post-treatment lung function measurements.
3. To investigate if functional MRI can detect early and late post-treatment changes in lung function.
4. To develop a robust and repeatable functional and structural lung MRI protocol that can be implemented on any MRI scanner in the region.

Research Methodology

The student will be responsible for the following:
- Applying image analysis techniques, including lung segmentation. This includes developing robust pipelines for image and data analysis techniques.
- Providing patient support and being present at patient imaging procedures. They will also be involved in administrating Xenon gas to the patient and coach the patient in performing breathing manoeuvres required for imaging.
- Assisting with integrating images for patients in the radiotherapy arm with a commercial radiotherapy treatment planning system (Varian Eclipse) to facilitate planning and assessment of radiation dose effects on functional tissue.
- Maintaining an up-to-date spreadsheet of clinical and imaging data for all patient visits.
- Assisting the investigators with data analysis and report writing for conference abstracts and peer-reviewed journal articles.

Expected Outcome

Lung cancer is the most common cancer in Yorkshire, with over 4,500 new cases diagnosed annually. Survival rates in the UK lag behind those seen in Europe and are greatly influenced by numbers able to undergo curative treatment with surgery or radiotherapy. Survival in Yorkshire is sadly currently below the UK average as high levels of respiratory co-morbidities reduce lung function and significantly increase the risk of serious adverse effects from either treatment. This study investigates whether more accurate, reproducible and regionally quantifiable MRI measures of lung function and structure, developed and translated in Sheffield, can be incorporated into current NHS diagnostic pathways and if the additional information gained alters treatment choice. These techniques will be focused on patients with borderline function where better selection for radiotherapy/surgery, potentially increases the number offered curative rather than palliative treatment and reduces the treatment risks, thereby improving survival and quality of life. It is also expected that the work will lead to conference proceedings at major national and international conferences and publications in reputable oncology and radiology journals.

Type of Project

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

Additional Training

The student will be trained in medical image acquisition and analysis, specifically in the context of functional lung imaging. They will also be trained in the use of advanced software and programming and use of statistical software.

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

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

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.

Research Methodology

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

Expected Outcome

Clinical series in a peer-reviewed journal
Methylation episignature for HNRNP-related disorders
Conference abstracts

Type of Project

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

Additional Training

Variant interpretation; clinical phenotyping; lab work if interested

Cone beam computed tomography for the diagnosis of scaphoid fractures in children

Main Supervisor

Professor Amaka Offiah (a.offiah@sheffield.ac.uk)

Second Supervisor

Dr Sanjeev Madan (s.madan@sheffield.ac.uk)

Aim and Objectives

To determine whether the current patient pathway for children with suspected scaphoid fracture can be improved. The hypothesis is that CT on Day 0 will be sufficiently accurate to allow confident discharge of those patients with negative findings. This will avoid unnecessary casts and further hospital attendances and thus result in improved patient outcomes and a reduction in costs.

Research Methodology

This is a randomized test-treatment trial directly comparing diagnostic strategies and using patient relevant outcomes. This design provides the best evidence for whether a new strategy leads to benefits for patients and/or the healthcare system.
An alternative design would be to perform both radiography and computed tomography in all patients. However this approach increases radiation exposure, which was the major concern for the 27% of surveyed families who would not have entered the trial.

Expected Outcome

• Non-inferiority analysis of patient reported outcomes for CT compared to radiographs
i. Need for and duration of cast
ii. Number and types of imaging examinations
iii. Duration of hospital interaction
iv. Overall radiation dose
v. Complication rate (avascular necrosis of the scaphoid)
• Comparison of false negative rate of CT
• Cost effectiveness analysis

Type of Project

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

Additional Training

Interpretation of radiographs

The impact of obesity on testicular function in boy and young men

Main Supervisor

Professor Nils Krone (n.krone@sheffield.ac.uk)

Second Supervisor

Dr Neil Wright (n.p.wright@sheffield.ac.uk)

Aim and Objectives

1. To assess adrenal and gonadal steroid hormone synthesis in obese boys aged 8-18 years.
2. To define the interaction between insulin resistance and altered adrenal and gonadal hormone synthesis
3. To identify treatment targets` to improve testicular function

Research Methodology

The student will join a well-established clinical and academic team under the joint supervision of two senior Paediatric Endocrinologists. The student will be involved in patient recruitment, study coordination, data collection and data analysis. The recruitment of patients is ongoing before the student will join the research team. This will, however, continue after the start of the student. Patients will be recruited from the specialised tertiary weight management service. This will provide the student with clinical experience and critical insights into recruitment of patients. The involvement of the student into coordination of sample collection and analysis will provide a vital training element for conducting future clinical studies. The student will also collect clinical data and link them biochemical investigations. In addition, the student will under supervision conduct the statistical analysis of collected data. Overall, this project will provide training of transferable skills relevant to clinical research.

Expected Outcome

We anticipate to identify a dysregulation of steroid hormone biosynthesis that can be specifically targeted in future studies to improve testicular function and future fertility in males. It is highly likely that results will be presented at national and international meetings and will lead to at least one significant research publication.

Type of Project

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

Additional Training

In addition to the clinical research training, clinical skills and training in standard statistical packages, the students have the chance to get involved in novel approaches to statistical modelling, which is highly relevant to a broad variety of fields in clinical research.

Qualitative study of the impact of different levels of health literacy on consultations within a Symptoms Clinic

Main Supervisor

Professor Christopher Burton (chris.burton@sheffield.ac.uk)

Second Supervisor

Dr Catie Nagel (c.nagel@sheffield.ac.uk)

Third Supervisor

Professor Gill Rowlands (Newcastle University)

Aim and Objectives

Aim: to understand the way that complex consultations reflect / adapt to / are limited by different levels of health literacy.

Objectives:
1. transcribe a selected set of consultation transcripts from a special clinic for people with multiple persistent physical symptoms (already recorded)
2. Apply a framework of health literacy (the ability to access, understand, evaluate and implement information to take more control of ones health) to the transcripts.
3. Describe how clinicians adapt to different levels of health literacy in consultations
4. Identify particular problems or successes in consultations reflecting this
 

Research Methodology

Materials: consultation recordings (some transcribed) will be made available from Multiple Symptoms Study 3, a trial of extended role GP consultations. Trial participants completed a measure of health literacy at enrolment and this will be used to select cases for analysis,
Data preparation: you will transcribe some of the consultations (others will be ready-transcribed)
Analysis: you will conduct a qualitative analysis of the consultation content. The specific approach is still to be decided.

Expected Outcome

1. Literature review specifically focusing on health literacy in relation to persistent physical symptoms.
2. Project report describing the qualitative analysis
3. A conference poster (probably regional academic primary care, possibly the year after BSc)
4. There should be sufficient material (review or analysis) to write a peer reviewed publication following the BSc. You will have the option of this as first author but will be fully supported to publication.
5. You will understand the principles of qualitative research, and be able to critically appraise qualitative research.

Type of Project

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

Additional Training

You will learn and use qualitative research skills through a combination of guided reading and practical supervision.
We will provide expert input relating to the concept of health literacy.

International medical graduates and their postgraduate career paths in general practice

Main Supervisor

Dr Laura Emery (l.j.emery@sheffield.ac.uk)

Second Supervisor

Dr Ben Jackson (ben.jackson@sheffield.ac.uk)

Third Supervisor

Dr Caroline Mitchell

Aim and Objectives

To identify what factors influence career decisions for general practitioners and whether factors differ between UK graduates and international graduates.

Research Methodology

The student will be an integral member of the research team for this project. October to December- Student will co-design an electronic survey with the lead supervisor to be disseminated to postgraduate general practitioners across Yorkshire and the Humber. January to April- Student will be supported in analysis of the quantitative and qualitative data generated by the survey. May to July- Time to write up project. Student will have the opportunity to present findings and co-author on any resulting papers.

Expected Outcome

This issue of differential attainment between international graduates and their UK trained colleagues is of great importance in postgraduate medical education and especially in primary care, but the research in this area is significantly lacking. So far most research has been focused around postgraduate exam outcomes, but it is likely that there is also an effect on long term career trajectories. Any research which provides concrete data on this issue is likely to be very well received.

A similar project completed by the lead supervisor won poster prize at a national conference, was presented as an oral presentation in an international conference and was published in a peer reviewed journal - see here

Type of Project

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

Additional Training

Design of an online survey, introduction to qualitative data analysis and basic training in use of NVivo software for qualitative analysis.

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.

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.

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.

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).

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.

Four students laughing while sat at a bench, outside the Students' Union

International Merit Scholarships

We offer a generous package of financial support for international students including 75 undergraduate scholarships worth £10,000 towards the annual tuition fee and 125 postgraduate taught scholarships worth £5,000 towards the tuition fee. Applications are now open for existing offer holders.