Department of Infection, Immunity and Cardiovascular Disease projects

Intercalated BSc Medical Sciences Research available projects

A skin test conducted by a medical researcher

Projects:

Computational analysis of coronary artery blood flow (2 projects)

Main Supervisor:

Professor Julian Gunn

J.Gunn@Sheffield.ac.uk

Second Supervisor:

Dr Paul Morris

Paul.morris@sheffield.ac.uk

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

To process the angiograms of patients with coronary artery disease through our VIRTUheart workflow and determine how patient management will change

Research Methodology:

You will learn about assessing patients with coronary artery disease, become expert at interpreting a coronary angiogram, discover coronary physiology and fractional flow reserve (FFR), learn how to use our own state-of-the art software to apply computational fluid dynamics to the angiogram images and calculate 'virtual' FFRs. This will enable you to solve real research questions posed by our patient data, such as: 'Can vFFR help in assessing bystander disease?' and 'How do different systems of vFFR compare?'.

Expected Outcome:       

Like the majority of our 25 BMedSci/BSc students over the last 10 years, we hope you will gain a first. You will learn critical evaluation skills, data handling, relevant statistics, data analysis, report writing and good research teamwork with our team of PhD, MD and BSc students. You will achieve your research objectives while enjoying yourself in a flexible and friendly work environment.

Additional Training:

We will teach you a lot about the correct management of patients experiencing the most prevalent major morbidity of our time - coronary artery disease. We will teach you interpretation of a coronary angiogram, the place of FFR, how to undertake image analysis, use a novel workflow, critical assessment of your results and how to place your findings in correct context.

Ethical Approval:

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

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

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims 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 in the same larvae to assess outcomes of both processes. 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.

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.

Ethical Approval:

Non-human tissue - no ethics approval required

Viral sensors in pulmonary hypertension

Main Supervisor:

Dr Roger Thompson

R.Thompson@sheffield.ac.uk

Second Supervisor:

Professor Allan Lawrie

a.lawrie@sheffield.ac.uk

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

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

Objectives

Determine if changes in expression of viral sensors can alter cell phenotypes Determine whether viral stimuli alter key proliferative pathways

Research Methodology:

The student will learn to isolate and culture human blood outgrowth endothelial cells from healthy donors and PAH patients and to culture pulmonary artery smooth muscle cells. The project will involve analysis of mRNA (qPCR) and protein expression (Western blot/ELISA), cell phenotypes (apoptosis, proliferation and migration assays) and gene knockdown (transfection of siRNA).

Expected Outcome:       

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

Additional Training:

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

Ethical Approval:

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

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

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims 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.

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.

Ethical Approval:

Non-human tissue - no ethics approval required

Discovering whether the human brain contains endothelial kugeln 

Main Supervisor:

Professor Tim Chico

t.j.chico@sheffield.ac.uk

Second Supervisor:

Dr Emily Noel

e.s.noel@sheffield.ac.uk

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

To perform a range of histological examinations on human brains donated to the Sheffield brain bank to determine whether these brains contain endothelial kugeln

Research Methodology:

This project will examine human brain tissue stored in the Sheffield brain bank for evidence of endothelial kugeln, using histological techniques frequently used in clinical pathology (such as immunohistochemistry).

Expected Outcome:       

We have discovered a unique behaviour of the endothelial cells in the brain of lower organisms. These cells develop transient spherical structures which we have named "kugeln" (German for sphere). Such structures have never been previously observed on any cell type, and they are never observed on blood vessels other than in the brain. We think they may have relevance to human cerebrovascular diseases including dementia and stroke, so we now want to examine human brains to see if these contain kugeln.

Additional Training:

The student will be trained in general lab skills, imaging, immunohistochemistry, statistical analysis, scientific writing and presentation, critical analysis of scientific and clinical literature, and clinical cerebrovascular and cardiovascular medicine.

Ethical Approval:

Non-human tissue - no ethics approval required, Secondary data or tissue samples - UREC or NHS REC ethics approval already received for the intended research project

Better understanding the post-partuum health experience of women living with HIV to improve engagement in care

Main Supervisor:

Dr Paul Collini

p.collini@sheffield.ac.uk

Second Supervisor:

Dr Julia Greig

julia.greig1@nhs.net

Other Supervisor(s):

Sarah Birch

Type of Project:

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

Aims and Objectives:

Aim: Understand and describe the post-partuum experience of women living with HIV

Objectives:

  1. Perform a database and case note review to summarise the HIV-related health outcomes and associated factors for these women.
  2. Describe the wider post-partuum experience while living with HIV.
  3. Present these findings in the BHIVA conference in 2021

Research Methodology:

This is a mixed methods study. First the student will design and perform a database search and retrospective case note review of the Sheffield Teaching Hospitals' HIV service for HIV-related health outcomes for women in the postnatal period and look for associated factors. We manage between 7 and 14 such cases a year and records available from 2012. The student will also undertake a literature review. They will use the data they generate to inform the design of in-depth qualitative investigation of the post-partum experiences of a sample of 5 to 10 of these women from the last 3 years who continue to attend for HIV care in STH. The student will be trained to apply qualitative research techniques and software to perform semistructured interviews and thematic analysis. Through this their research will explore and summarise the experience of living in Sheffield with HIV infection and a young baby, what problems these women face and the impact on their mental and physical health and ability to engage in health care. The student will have full access to the HIV clinic, clinical records and the clinical and academic departmental research team support. The student will join and be encouraged to take part in our infection research meetings IICD.

Expected Outcome:       

The results from this work will provide a better understanding of the drivers of positive and negative HIV related health outcomes for these women. It will enable us to develop strategies to better support women and families affected by HIV. Specific outcomes will be:

  1. Submission of an abstract at the British HIV Association annual conference in Spring 2022
  2. Submission of a manuscript for peer review publication
  3. Presentation of the findings to the STH HIV directorate to inform service improvements.

Additional Training:

The student will be trained in Good Clinical Practice and qualitative research techniques and NVivo qualitative data analysis software.

Ethical Approval:

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

Mechanical or Biological, Does it really matter? - the NECTARINE Study

Main Supervisor:

Mr Norman Briffa

n.briffa@sheffield.ac.uk

Second Supervisor:

Mr Neil Cartwright

neil.cartwright@nhs.net

Type of Project:

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

Aims and Objectives:

The aim of this study is to compare early and late outcomes in younger patients who have undergone surgical aortic valve replacement with either a mechanical or a tissue prosthesis.

Research Methodology:

The student will extract data variables from the Sheffield Adult Cardiac Surgery Database over 20 years to identify the patients who fit the criteria for entry into the study - aged 50-70 undergoing isolated aortic valve replacement. Propensity scoring will be used to construct 2 matched groups which differ only by the type of prosthesis implanted. Outcomes measured will be early death, late death/survival, hospital admission (via HES - Hospital Episode Statistics) with diagnoses of heart failure, aortic valve disease, endocarditis, stroke, and bleeds. T-Tests for independent samples and Kaplan Meier for longitudinal freedom data.

Expected Outcome:       

Young patients who receive a mechanical aortic valve prosthesis survive longer and are less likely to require hospital admission.

Additional Training:

Extraction of data from a SQL database, working with Excel, observing aortic valve surgery, learning about aortic valve disease and surgery from the evidence

Ethical Approval:

Service Evaluation - NHS Service Evaluation number required - UoS Ethics will additionally be required

New ePAQ-CARDIAC, a New Tool on the block

Main Supervisor

Mr Norman Briffa

n.briffa@sheffield.ac.uk

Second Supervisor:

Mr Stephen Radley

stephen.radley@nhs.net

Other Supervisor(s):

Professor Georgina Jones

Type of Project:

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

Aims and Objectives:

The aim of the study is to determine whether ePAQ cardiac, a recently developed online tool to remotely monitor symptoms of patients with heart valve disease is:

  1. acceptable to patients and
  2. accurately detects symptom improvement or deterioration.

Research Methodology:

Face validity, feasibility and utility of the tool will be measured using the QQ-10 questionnaire. This will be done online. Both quantitative analysis using the Likert scoring method described by the developers of the questionnaire, as well as Qualitative thematic analysis using comments received in response to the free-text questions at the end of the QQ-10 will be used. The performance of the tool will be used to test change in QoL (paired T test), construct validity with ANOVA and Kruskall Wallis , Concurrent Validity with the Spearmann Correlation Coefficient, Predictive Criterion using the Spearmann Correlation Coefficient,Reliability using Cronbach's Alpha, Responsivelness using the Cohen effect and sensitivity by assessing floor and ceiling effects. Factor Analysis will be used to modify the tool at the end.

Expected Outcome:       

e-PAQ CARDIAC will be acceptable to patients using the tool. The tool will be useful in detecting changes in patient's health and will prove to be sensitive, valid and responsive making it very suitable to use for long term surveillance of patients with heart valve disease.

Additional Training:

Training in PROMS and questionnaires as well as in techniques and tools of qualitative research (working with Professor G Jones at Leeds Beckett university)

Ethical Approval:

Service Evaluation - NHS Service Evaluation number obtained - UoS Ethics will additionally be required

Prevalence of Functional Gastrointestinal Disorders in patients with Coeliac Disease

Main Supervisor:

Dr Imran Aziz

imran.aziz1@nhs.net

Second Supervisor:

Professor David Sanders

david.sanders1@nhs.net

Other Supervisor(s):

Dr Matthew Kurien

Type of Project:

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

Aims and Objectives:

To determine the prevalence of functional gastrointestinal disorders in patients with coeliac disease

Research Methodology:

This study has already had ethics and the data has been collected from ~1000 patients with coeliac disease! This large amount of data has all been entered into a database. It requires the student, under supervision, to become familiar and deal with a large dataset using a statistical package like SPSS. The student will then start writing abstracts and papers looking at the prevalence of functional gastrointestinal disorders in Coeliac disease and how this prevalence is affected by duration of a gluten-free diet.

Expected Outcome:       

Learning to deal with a large clinical relevant dataset on SPSS under the supervision of Dr Aziz. Then learning how to analyse the date, create tables/figures and learn the art of writing abstracts/papers for scientific publication. We envisage that scientific paper(s) will be published.

Additional Training:

Regular mentoring, teaching the student how to analyse data, prepare tables/figures, writing abstracts/scientific papers. The student will also attend regular gastroenterology teaching sessions and hopefully get their work accepted to attend national conferences. The student will also be encouraged to apply for local grants

Ethical Approval:

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

Breaking Down the Barrier: Using new imaging techniques to phenotype gas exchange pathology in pulmonary fibrosis.

Main Supervisor:

Dr Nicholas Weatherley

n.weatherley@sheffield.ac.uk

Second Supervisor:

Professor Jim Wild

j.m.wild@sheffield.ac.uk

Type of Project:

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

Aims and Objectives:

Aim

  • To help develop multinuclear magnetic resonance imaging as a clinical imaging biomarker for gas diffusion limitation in idiopathic pulmonary fibrosis by examining physiology and imaging mechanisms in patients with this condition.

Objectives

  • To gain an understanding of research techniques in a clinical trial involving patients
  • To assist in the practical aspects of conducting cardiopulmonary exercise testing and intra-scan Xenon gas delivery to study subjects.
  • To correlate measures for exercise physiology with magnetic resonance imaging metrics in a cohort of patients with IPF.
  • To present findings at a national or international conference

Research Methodology:

The researcher will join a team of doctors, physiologists, physicists and engineers to help carry out a clinical study. They will help to conduct a study visit and after training, assist in scanning 8-10 patients with idiopathic pulmonary fibrosis. They will help to guide the subject through a cardiopulmonary exercise test. The data from exercise testing and MRI scanning will be compared using quantitative statistical methods to help understand how imaging findings and exercise physiology in IPF are linked.

Expected Outcome:       

The outcomes from this study will be used to help further the imaging as a novel biomarker in interstitial lung diseases. They will inform further studies in patients with incidental lung parenchymal disease identified in lung cancer screening trials and are envisaged to be useful in early pharmaceutical intervention studies. We expect the findings to be written up as an abstract to a national meeting and likely also a research paper.

Additional Training:

We will provide training in delivery of hyperpolarised xenon gas to study participants in the magnetic resonance imaging scanner and teaching on interstitial lung disease physiology and imaging, as well as the role of cardiopulmonary exercise testing in diagnosis of respiratory disease. Training in specific IT software packages will be provided in order to facilitate analysis of the data.

Ethical Approval:

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

Infection prevention and control measures to reduce the in-hospital transmission of influenza in vulnerable patient groups

Main Supervisor:

Dr Thushan de Silva

t.desilva@sheffield.ac.uk

Second Supervisor:

Dr Cariad Evans

cariad.evans1@nhs.net

Other Supervisor(s):

Dr. Mohammed Raza

Type of Project:

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

Aims and Objectives:

  1. To determine the potential causes of in hospital influenza acquisition and identify measures to address these.
  2. To explore the acceptability and barriers to delivering an inpatient influenza vaccination programme.

Research Methodology:

The project will have two main phases. The first phase will use retrospective data available from 3 influenza seasons at Sheffield Teaching Hospitals NHS Trust, to carry out a detailed hospital epidemiology study to identify the potential reasons for in-hospital influenza cases. Research methods will include large data handling and statistical analysis. The second phase will include a prospective study evaluating the inpatient influenza vaccination programme during the 2020-2021 season. Reasons for vaccine refusal or omission will be evaluated, with a view to informing NHS policy to improve programmes in subsequent years.

Expected Outcome:       

  1. A detailed analysis of factors leading to missed influenza diagnoses on presentation to hospital and/or reasons for in-hospital acquisition of influenza. A manuscript will be drafted for publication in a peer reviewed journal (e.g. Journal of Hospital Infection).
  2. A report evaluating the in-hospital influenza vaccination programme (as per new Public Health England guidance) and barriers to delivery. This will be presented to STH to improve future programmes.

Additional Training:

  1. Working with databases and data analysis in the R statistical package.
  2. Training in clinical data collection and mixed-methods analysis during evaluation of the inpatient influenza vaccination programme at STH.

Ethical Approval:

Service Evaluation - NHS Service Evaluation number required - UoS Ethics will additionally be required

Understanding the impact of error on clinicians

Main Supervisor:

Professor Ian Sabroe

i.sabroe@sheffield.ac.uk

Second Supervisor:

Dr Chris Millard

c.millard@sheffield.ac.uk

Type of Project:

Medical Humanities

Aims and Objectives:

To understand the landscape of clinician error

To explore how clinicians have written about the experience of making mistakes

To explore whether fear of regulation causes difficulties reporting error

Through these studies to transform the public dialogue around clinical error

Research Methodology:

A contemporary historical approach will explore clinician writings and scientific sources that address physician error. The student will work with the supervisors to identify places that error is described as a personal experience. Paralleling these searches, how error is described in medical publications will be identified, and changes in described duties of doctors to disclose error will be studied. Putting these together, the student will form a new understanding of the clinical experience of error.

Expected Outcome:       

We aim that the student will be able to generate a new description of the experience of error, which is not well explored in medical literature. We hope that publications deriving from this work will facilitate a new discussion of error that will help clinicians come to terms with difficult experiences in their careers, and facilitate a better public debate around error.

Additional Training:

Training in methods relating to contemporary historical approaches will support the students writing skills and skills in critical appraisal

Ethical Approval:

Non-human tissue - no ethics approval required

Ventilation MRI in patients with asthma; changes due to bronchodilation and lung inflation level

Main Supervisor:

Dr Helen Marshall

h.marshall@sheffield.ac.uk

Second Supervisor:

Professor Jim Wild

j.m.wild@sheffield.ac.uk

Type of Project:

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

Aims and Objectives:

To analyse magnetic resonance images of lung ventilation acquired from patients with asthma in order to obtain quantitative metrics To investigate the effect of bronchodilator therapy and lung inflation level on the ventilation distribution in patients with asthma, for example, are regions of the lung which open up after deep inspiration the same as those which become ventilated after bronchodilator administration? To explore the relationships between MRI ventilation metrics, pulmonary function tests and other clinical metrics

Research Methodology:

MRI ventilation images are routinely acquired from patients with asthma, before and after bronchodilator therapy and at two different lung inflation levels. The student would be using semi-automated software to segment these images (create representations of which parts of the lungs are ventilated) and derive quantitative metrics from them. The student would compare these MRI metrics to other clinical metrics such as spirometry and symptom score, and investigate the relative effects of bronchodilator administration and lung inflation level on the distribution of ventilation in these patients.

Expected Outcome:       

The student would obtain a good working knowledge of ventilation MRI and quantitative scientific research, and experience of working in a multi-disciplinary research environment. Publication of a conference abstract for the European Respiratory Society International Congress and an original research paper would be expected as a result of this research project.

Additional Training:

Training in lung MRI segmentation using semi-automatic software developed in-house (a graphical user interface, Matlab and ITK-snap) Training in the use of the GraphPad Prism for statistical analysis (correlation, difference testing, Bland-Altman) Teaching in the interpretation of MR images The opportunity to observe lung MRI scanning and pulmonary function testing, and to administer the inhaled contrast agent to patients as part of the scanning team The opportunity to attend weekly image review meetings lead by consultant radiologists and multi-disciplinary team meetings on the use of ventilation MRI in the care of patients with asthma

Ethical Approval:

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

Mycophenolate mofetil, a tool for personalised immune suppression in the age of chronic inflammation and autoimmunity

Main Supervisor:

Dr Simon Johnston

s.a.johnston@sheffield.ac.uk

Second Supervisor:

Dr Phil Elks

p.elks@sheffield.ac.uk

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

Mycophenolate mofetil (MMF) is a common component of immunosuppressive regimens. MMF is used as a lymphocyte anti-proliferative agent but has shown in efficacy in a number of conditions not classically associated with lymphocytes.

My lab has shown how MMF has a specific effect on macrophages and neutrophils independent of lymphocytes. This effect has positive implications for the treatment of e.g. chronic inflammation and atherosclerosis but will increase susceptibility to opportunistic infection in lymphocytic suppression.

By examining the specific mechanism of MMF we now believe we can separate these activities of MMF. This means that we may be able to tailor immunosuppression to different at-risk groups. Therefore, in this project will aim to confirm our findings on the separate activities of MMF and obtain pre-clinical data to support potential clinical trials.

Research Methodology:

You will use isolated human immune cells and mouse models to understand the separate activities of MMF. You will use genetic and pharmacological approaches to dissect the disruption of macrophage and neutrophil function during MMF treatment. You will learn the microbiology techniques needed for handling a human pathogens and how to perform infection studies. You will use high-end microscopes for collecting your data and you will use statistical techniques to analyses your data and how this correlates with our clinical understanding of disease aetiology.

Expected Outcome:       

You will generate pre-clinical data testing the prediction that MMF treatment can be modified preferentially to target lymphocyte versus myeloid effects. You will achieve this by performing experiments that test dose response effects of MMF on immune cells under different challenges (e.g. infection or inflammation) and combining MMF with other modifying treatments. You will then have the opportunity to understand how your data generated fits with existing experimental and clinical data, and how this might be taken forward to clinical studies.

Additional Training:

You will acquire a high level of laboratory training in a range of techniques. You will work in a highly motivated and successful research laboratory that is committed to performing scientific research with clinical relevance. You will generate data that we will make every effort to ensure is published in a reasonable time frame and you will have the opportunity to attend a research conference. This project represents an ideal opportunity to explore your potential for a clinical academic career and we will make every effort to support your future career choices.

In addition to the techniques outlined above you will use a wide variety of analysis techniques for microscopy methods and will learn to put your statistical knowledge into practice. We will aim to train you to be able to generate and test hypotheses relevant to the research question and to move you towards being an independent researcher. You will gain direct experience of how fundamental research can be translated into changing clinical practice.

Ethical Approval:

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

Investigating interactions between the malaria parasite and the human host

Main Supervisor:

Dr Ruth Payne

r.o.payne@sheffield.ac.uk

Second Supervisor:

Dr Simon Johnston

s.a.johnston@sheffield.ac.uk

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

The most severe form of human malaria is caused by the Plasmodium falciparum parasite. Despite recent and encouraging advances in malaria control measures, current estimates suggest that, in 2015, there were still over 200 million clinical cases leading to 438,000 deaths. Consequently, the development of effective treatments and vaccines remain a key strategic goal to aid the control, local elimination, and eventual eradication of this disease.

The mainstay approach is to target the blood-stage of malaria infection, against the merozoite form of the parasite that invades erythrocytes. Recent advances in our molecular understanding of invasion of red blood cells (RBCs) by malarial parasites has stimulated several new therapeutic and vaccine strategies. However, our mechanistic understanding of invasion still limits the development, testing and implementation of new treatments and vaccines.

In this project we aim to understand two key features of RBC invasion by malaria:

The number and spatial organisation of protein complexes required for internalisation The mechanical requirements for invasion

Both these features are poorly understood but are vital in our understanding of invasion, how this can be targeted by drugs and/or vaccine antibodies.

Research Methodology:

The project will use human RBCs infected with Plasmodium falciparum parasites to understand the invasion process. The experimental samples will provided through a long standing collaboration between the Payne lab and the Jenner Institute (Oxford). Infected RBCs will be labelled and imaged in Sheffield to understand the molecular and mechanical details of invasion. We will use state of the art fluorescence imaging techniques (Stochastic Optical Reconstruction Microscopy). Sheffield university has world leading expertise in these techniques, and you will learn how to use them to study malaria infection biology.

Expected Outcome:       

You will acquire a high level of laboratory training in a range of techniques. You will work in a highly motivated and successful research laboratory that is committed to performing scientific research with clinical relevance. You will generate data that we will make every effort to ensure is published in a reasonable time frame and you will have the opportunity to attend a research conference.

Additional Training:

In addition to the techniques outlined above you will use a wide variety of analysis techniques for microscopy methods and will learn to put your statistical knowledge into practice. We will aim to train you to be able to generate and test hypotheses relevant to the research question and to move you towards being an independent researcher. This project represents an ideal opportunity to explore your potential for a clinical academic career and we will make every effort to support your future career choices.

Ethical Approval:

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

Qualitative evaluation of a pilot and feasibility trial of a mindfulness intervention for young people with Inflammatory Bowel Disease

Main Supervisor:

Dr Alenka Brooks

alenka.brooks@nhs.net

Second Supervisor:

Dr Rowse Georgina

g.rowse@sheffield.ac.uk

Other Supervisor(s):

Prof Alan Lobo

Type of Project:

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

Aims and Objectives:

The study will assess participants view on a mindfulness intervention for young people with IBD in order to adaptations to future trial design in a larger cohort.

Research Methodology:

This is a qualitative study using thematic analysis. This methodology is not tied to a particular theoretical position, but offers a systematic approach to discerning themes in participant's accounts of their experiences.

Expected Outcome:       

We aim to assess the acceptability of a mindfulness intervention to ascertain its value to participants and seek service-user views on any adaptations that would need to be made prior to a larger evaluation of the intervention. One-to-one interviews will be conducted with a sample of participants by the BMeSci student guided by an interview-schedule, designed to explore participant’s experience of the intervention in an open non-directive manner. Data will be transcribed and will be analysed using thematic analysis, which focuses on eliciting themes from participants' description of their experiences.

Additional Training:

The student would receive training on thematic analysis and systematic reviews. The student will part of an IBD MDT and have significant patient contact.

Ethical Approval:

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

Understanding the informational needs of pregnant women with inflammatory bowel disease (IBD)

Main Supervisor:

Dr Thean Soon Chew

t.s.chew@sheffield.ac.uk

Second Supervisor:

Professor Alan Lobo

Other Supervisor(s):

Professor Georgina Jones, Dr Matthew Lee

Type of Project:

Clinical project - based in the clinical environment with patients/including service evaluation, Qualitative Project/non-lab based - primarily using qualitative methods

Aims and Objectives:

To synthesise the existing information on the informational and decision support needs of female patients with IBD who are considering becoming pregnant To measure using questionnaires the informational and decision-support needs and preferences of pregnant women with IBD To understand in-depth through semi-structured interviews the informational and decisional support needs and preferences of pregnant women with IBD

Research Methodology:

The BMedSci student will start with a systematic review of the available literature to evaluate the informational needs of female patients with IBD who are considering becoming pregnant and the possible factors involved in voluntary childlessness. The candidate will then design, disseminate, collate and evaluate the results of a questionnaire study (n= 30-50) as well as conduct semi-structured interviews of women with IBD planning a pregnancy, currently pregnant or who have been pregnant (n=10-15 depending on thematic saturation). Recruitment in clinic will be supported by 2 specialist IBD consultants (Dr Chew and Professor Lobo) who run one of the largest IBD clinics in the UK. Support for the qualitative work will be from Prof Georgina Jones, who is an international expert in the field and has supported 2 B Med Sci students fro the Department recently. The BMedSci student will therefore be trained in both quantitative research methods (data collection and analysis) using a survey design and basic statistical analysis and qualitative research methods (data collection and analysis) such as semi-structured interviewing and thematic analysis.

Expected Outcome:       

The BMedSci student will be able to describe the information needs and key decision points of patients with IBD who are pregnant as well as have an in-depth understanding from the narratives of women living with IBD about their fertility and pregnancy experiences. The BMedSci student will be expected to attain skills in evaluating available research literature, designing questionnaires and conducting interviews to obtain qualitative data pertaining to the informational needs of pregnant patients with IBD. The data obtained will facilitate analysis using qualitative research methods to identify and inform key decision points which may possibly inform the development of a new patient decision aid. The BMedSci student will be expected to produce a dissertation at the level of a scientific bachelors degree and attend an oral viva assessment.

Additional Training:

The BMedSci student will be trained in skills pertaining to discovery and evaluation of background scientific literature, questionnaire and interview design and delivery, analysis using qualitative research methodologies, and basic statistics.

Ethical Approval:

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

Identifying changing patterns of disease response in lung cancer

Main Supervisor:

Dr Chris Johns

c.johns@sheffield.ac.uk

Second Supervisor:

Dr Andy Swift

Other Supervisor(s):

Dr Sue Matthews

Type of Project:

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

Aims and Objectives:

  1. To identify the different patterns of response to therapy in lung cancer treated with new immunomodulators
  2. Identify whether these patterns are associated with different disease outcomes

Research Methodology:

All patients with lung cancer treated using the new immunotherapy drugs will be identified from the lung cancer MDT.

The images of the patients on CT at baseline and at follow up will be reviewed to identify different patterns in treatment response. The patterns of response will be either reduction or increase in size or number of the lesions at each time-point. The image review will be based upon qualitative and quantitative measures of change. These patterns of response will be compared to the known patterns of response in solid cancers (using the RECIST criteria).

Once the different patterns have been identified, outcome data and MDT opinion will be used to find those that are clinically important as markers of response to therapy.

The cohort will be identified from the Weston-Park cancer treatment database - this will be done ready for the student starting.

We anticipate that there should be around 75 patients (approximately 1 year ago there were 60 cases on the list).

Expected Outcome:       

We hypothesize that there will be a difference in the treatment response for the new immunotherapy treatments for lung cancer, that are not accurately reflected by the normal measures of treatment response.

Additional Training:

  1. Students will be given training in the use of of the PACS system to review imaging.
  2. Students will be given training in the assessment of thoracic computed tomography in malignancy and assessment of treatment response
  3. Student will be given training in the statistical methods to appraise medical tests.

Ethical Approval:

Secondary data – new ethics approval being sought as the data is being used as part of a different research project to that for which the original ethics was sought.

Machine learning to improve heart disease diagnosis on cardiac MRI

Main Supervisor:

Dr Andew Swift

a.j.swift@sheffield.ac.uk

Second Supervisor:

Haiping Lu

Type of Project:

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

Aims and Objectives:

This project aims to determine the capability of machine learning to make better diagnoses and make more accurate prediction of mortality. The project will utilise the Sheffield 3D lab database of cardiac magnetic resonance imaging (MRI) and computed tomography studies. The ambition is to determine the added value of a machine learning over standard imaging measurements such as ventricular volume mass and function. The study will involve a close collaboration with, Radiologists, Cardiologists and Computer Scientists.

Research Methodology:

Identify cases from large 3D lab image repository Record diagnosis and Radiological reports Perform pre-processing steps on MRI and CT Undertake statistical analysis of machine learning data outputs Determine the diagnostic and prognostic accuracy of the tool

Expected Outcome:       

Develop a tool to improve diagnosis of cardiac disorders Improve diagnostic confidence reporting cardiac MRI and CT studies

Additional Training:

Cardiac MRI and CT image analysis

Machine learning tool

SPSS analysis

Ethical Approval:

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

Role of the HIF2A gene in heart attack and stroke

Main Supervisor:

Professor Paul Evans

paul.evans@sheffield.ac.uk

Second Supervisor:

Dr Maria Fragiadaki

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

Atherosclerosis is a disease of arteries characterised by the build-up of fatty plaques, leading to angina, heart attack or stroke. It is the leading cause of death in the UK. Branches and bends of arteries are prone to atherosclerosis because complex patterns of blood flow at these sites generate frictional forces that trigger disease. Blood flow patterns also regulate the progression of atherosclerosis into dangerous plaques that can rupture triggering catastrophic heart attack or stroke. The Evans lab recently identified a gene called TWIST1 that is expressed in arteries at sites of disturbed blood flow. TWIST1 switches on several sets of disease-causing genes and is a driver of early atherosclerosis. It is also produced in highly diseased arteries and we propose that it may contribute to disease progression and plaque rupture. The proposed studies will investigate whether removal of TWIST1 from vascular cells can slow the build-up of dangerous plaques that can trigger heart attack or stroke. The proposed research may identify TWIST1 as a target for the development of new drugs to treat atherosclerosis and therefore prevent angina, heart attack and stroke.

Research Methodology:

The student will join the Evans Laboratory which is a thriving community of Fellows, Post-doctoral scientists and students studying the molecular basis of atherosclerosis. He/she will receive training in several techniques related to mouse models of atherosclerosis, and will also master several molecular biology techniques. The student will attend weekly lab meetings to present and discuss recent data, and regular 1:1 meetings to discuss progress with the project.

Expected Outcome:       

training in conducting laboratory-based science and specialised training in various in vivo and in vitro techniques, generation of high quality data which can be published in a high-ranking journal authorship on paper(s)

Additional Training:

In vivo techniques - mouse breeeding and husbandry, surgery, intraperitoneal injections, perfusion fixation and dissection of the aorta, en face immunostaining, confocal microscopy.

Molecular biology techniques including PCR of genomic DNA, gene silencing using siRNA, quantitative RT-PCR, Western blotting, flow cytometry.

Ethical Approval:

Non-human tissue - no ethics approval required.

Effects of antiplatelet therapy in patients undergoing percutaneous coronary intervention

Main Supervisor:

Professor Robert Storey

r.f.storey@sheffield.ac.uk

Second Supervisor:

Dr William Parker

Type of Project:

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

Aims and Objectives:

Aims:

Develop a thorough understanding of the pathophysiology of thrombosis and its pharmacological management. Gain skills in laboratory and clinical research within a supported environment. Complete a novel and reportable clinical project within the fields of antithrombotic pharmacology and cardiology.

Objectives:

Review the literature to gain knowledge of the stages of thrombosis, mechanisms and clinical uses of antithrombotic drugs, and dose-dependent effects of aspirin. Train in techniques of assessment of platelet function and inflammation, for example light transmittance aggregometry, ELISA and bleeding time. Identify suitable patients for an exploratory studies of different antiplatelet regimens in patients undergoing percutaneous coronary intervention. Obtain blood samples from the study patients at timepoints required by the study design. Perform laboratory tests on blood obtained from the study patients. Record and analyse the data using a statistical software package. Complete a dissertation detailing the findings.

Research Methodology:

The student will lead the day-to-day running of an exploratory study of different antithrombotic regimens in patients undergoing PCI, under close supervision of the Cardiovascular Research Unit Doctors and Co-ordinators. Our team has access to patients within the South Yorkshire Cardiothoracic Centre. Specifically, this project will involve identifying potential participants, carrying out study sample collection and using laboratory methods (eg. light transmittance aggregometry, ELISA) to generate study data. The student will then complete statistical analysis of data and produce a comprehensive report. For the motivated student, there will be ample opportunity to become involved in other research projects within our busy and productive team of doctors and scientists.

Expected Outcome:       

The student will gain a broad range of transferrable skills relevant to laboratory and clinical research, including critical review of the literature, sample collection and preparation, protein assay, statistical analysis, and scientific writing. It is anticipated that recruitment of patients and study sample analysis will be completed within the course of the studentship. This will allow robust data to be obtained, and it is expected that this will have considerable wider scientific impact, facilitating presentation and publication. It is also expected that they will become familiar with the relevant scientific literature relating to cardiovascular disease, thrombosis, inflammation, antithrombotic pharmacology and relevant areas of cardiology.

Additional Training:

The student will receive training and supervision in the following areas:

General laboratory skills such as pipetting and plasma/serum preparation. Laboratory assessment of platelet function and inflammation (eg. light transmittance aggregometry, ELISA). Venepuncture and bleeding time measurement. Conduct of clinical research (including obtaining Good Clinical Practice certification and maintenance of study documents). Statistical analysis, drawing on the techniques learnt on the BMedSci statistical module. Health & safety training within the laboratory and clinical environment.

Ethical Approval:

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

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

Main Supervisor:

Miss Catherine Loynes

c.loynes@sheffield.ac.uk

Second Supervisor:

Professor Stephen Renshaw

s.a.renshaw@sheffield.ac.uk

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims 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 removal of these cells is critical for successful inflammation resolution. In our lab we are interested in neutrophil removal from inflammatory sites. It is increasingly recognised that neutrophils are able to migrate away from inflammatory sites once they have completed their role. Our laboratory has published in high impact journals our findings that neutrophil reverse migration is tightly regulated in the zebrafish inflammation model. This process can be manipulated both genetically and pharmacologically 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 generate a transgenic CRISPR-interference system in zebrafish to screen through all candidate GPCRs. You will sequentially knock out expression of each GPCR specifically in neutrophils and study their roles in retention signalling during inflammation caused by local tissue injury. Dissecting the molecular mechanisms involved in inflammation resolution will ultimately allow for new target discovery for therapeutic intervention. We have established a model of spontaneously resolving inflammation using the zebrafish. Zebrafish are an excellent model, since their genes are easily manipulated, which allows the genes controlling resolution of inflammation to be identified. Their transparency leads to easy visualisation of neutrophils during development. We have generated a transgenic zebrafish expressing green fluorescent protein (GFP) specifically in neutrophils making them easily identifiable. Moreover, CRISPR-interferencing is working in this system making this approach realistic for the first time.

Research Methodology:

Using new CRISPR interference (CRISPRi) technology, we will manipulate inflammatory genes in the zebrafish. CRISPRi allows for sequence-specific repression or activation of gene expression specifically in neutrophils. 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:       

Validate and test neutrophil-specific zebrafish transgenic repressor CRISPRi lines, already made using cloning techniques and microinjection into one cell stage zebrafish. Generate new and improved transgenic lines, including genetic activator lines and super-repressor lines. Become proficient in live imaging methodology, including using the spinning disk confocal, a Nikon inverted fluorescent microscope and the new Lightsheet microscope. Refine reverse migration assays in transgenic lines following tail fin injury, and optimize analysis using NIS elements tracking software. Identify function of interesting GPCRs during inflammation resolution

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.

Ethical Approval:

Non-human tissue - no ethics approval required.

Identifying new antibiotics

Main Supervisor:

Professor Jon Sayers

j.r.sayers@sheffield.ac.uk

Second Supervisor:

Dr Patrick Baker

Type of Project:

Lab/Bench Project - primarily working in a lab environment

Aims and Objectives:

The rise in reports of bacteria resistant to a range of antibiotics has triggered the WHO to call for new medicines targeting e.g. drug-resistant tuberculosis. Development of new antibiotics had been a low priority for the pharmaceutical sector until very recently. New classes of antibiotics, acting via novel biological pathways, need to be identified. Recent advances in microbial genetics have identified bacterial flap endonucleases as possible targets for novel antimicrobial agents. This project will apply structure-based drug design to engineer novel molecules as inhibitors of these crucial enzymes, an important first step along the drug development pathway.

Research Methodology:

You will be trained in genetic engineering and protein biochemistry techniques. You will then produce recombinant flap endonuclease enzyme from Mycobacterium tuberculosis for inhibitor screening and structure determination. Using a state-of-the-art semi-automatic robotic-screening facilities, you will set up crystallisation and fluorescence-based inhibitor trials. You will screen a library of compounds supplied from a collaborating pharmaceutical company for their ability to inhibit your flap endonuclease. You will also be trained in structure-based drug design and structure determination as well as basic microbiological procedures. You will be integrated into a small team of Ph.D. students and postdoctoral researchers tackling this challenge.

Expected Outcome:       

Data on inhibition of the mycobacterial enzyme and human enzymes will be gathered allowing quantitative structure activity relationships to be built. Building and testing of various computer models and comparison with real-world data. Crystal structure data allowing a 3D atom structure to be built. Also, basic biophysical characterisation of the enzyme activity of the enzyme (e.g. reaction rate and substrate specificity will be determined.

Additional Training:

You will be trained to use drug docking and design software (e.g. Autodock, Swissdock), molecular graphics packages (Pymol, VMD) and enzyme analysis (Graphpad Prism). Wet-lab techniques including cloning, protein purification, micro titre-plate based high throughput enzyme/inhibitor assays, robotic screening techniques and structure determination. Possibility of access to national research facilities such as the Diamond Light Source (Oxford) depending on results. Training in in silicon or virtual high throughput computer based drug screening/design.

Ethical Approval:

Non-human tissue - no ethics approval required.

A world-class university – a unique student experience

Sheffield is a research university with a global reputation for excellence. We're a member of the Russell Group: one of the 24 leading UK universities for research and teaching.