Department of Infection, Immunity and Cardiovascular Disease projects

Intercalated BSc Medical Sciences Research available projects

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Projects:

Modelling in Pulmonary Hypertension

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

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

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

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

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

Research Methodology

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

Expected Outcome

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

Type of Project

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

Additional Training

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

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

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 experimental medicine study which aims to determine the optimal dose of imatinib in the treatment of patients with pulmonary arterial hypertension.

Aims:
To evaluate the acceptability of the implantable technology in this patient group
To determine the haemodynamic effect of imatinib in an dose escalation study

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

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 repurpse imatinib for the treatment of PAH.

Type of Project

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

Additional Training

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

AI system to detect cardiac pathology diseases

Main Supervisor

Dr Michail Mamalakis (mmamalakis1@sheffield.ac.uk)

Second Supervisor

Dr Andy J Swift (a.j.swift@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.

Tackling infectious disease prevention and diagnosis using a data driven approach

Main Supervisor

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

Second Supervisor

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

Other Supervisors

Dr Thushan de Silva, Prof Sarah Rowland Jones

Aim and Objectives

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

Research Methodology

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

Expected Outcome

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

Type of Project

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

Additional Training

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

Production & Characterisation of Viral Proteins for Medical Biotech Applications

Main Supervisor

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

Second Supervisor

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

Third Supervisor

Dr Martin Nicklin

Aim and Objectives

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

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

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

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

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

Example 3 would not require such samples.

Research Methodology

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

Expected Outcome

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

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

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

Discovering new drugs for neglected tropical diseases

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

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

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

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

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

iii) Do these inhibitors kill parasites?

Research Methodology

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

Expected Outcome

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

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

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

Virus exposure and pulmonary hypertension

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

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

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

Research Methodology

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

Expected Outcome

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

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

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

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

Main Supervisor

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

Second Supervisor

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

Other supervisors

Dr. Tom Darton

Aim and Objectives

The aims of this systematic review is to:

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

Research Methodology

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

Expected Outcome

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

Type of Project

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

Additional Training

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

Investigating novel tissue resident macrophage populations in vivo

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

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

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

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

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

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

Research Methodology

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

Expected Outcome

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

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

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

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

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

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