Department of Infection, Immunity and Cardiovascular Disease projects

Intercalated BSc Medical Sciences Research available projects

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Projects:

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.

Computational modelling of coronary artery blood flow in acute coronary syndromes

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

The aim is 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.

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.

Prevalence of Functional Gastrointestinal Disorders (FGIDs) in subjects with Non-coeliac gluten sensitivity (NCGS)

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

This clinical project in gastroenterology will determine the prevalence of functional gastrointestinal disorders (FGIDs) and general health impairment in subjects with non-coeliac gluten sensitivity (NCGS). This data will subsequently be compared against a) individuals with coeliac disease and b) healthy matched individuals within the general population.

The student is expected to present their work at (inter)national meetings and also write original articles as first author for subsequent publication in journals.

Research Methodology

The ethics and dataset have already been obtained and the student will learn how to analyse this and write up as presentations and papers. They will learn how to perform case-control matching and compare the prevalence of FGIDs and other health impairment in subjects with NCGS against subjects with coeliac disease and population controls.

Expected Outcome

Previous student has published original articles as first author, presented the work at international meetings, and submitted a thesis culminating in a first. We therefore envisage a successful outcome.

Type of Project

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

Additional Training

Learning how to analyse datasets using SPSS, present work orally and as poster presentations at conferences, write original articles, submit papers, and address reviewers comments. The student will also have the opportunity to attend clinical gastroenterology sessions and weekly departmental lectures. The student will be expected to submit their work to conferences and attend these (likely virtually for the foreseeable future). Finally, the student will have the opportunity to collect data for other ongoing clinically-based projects culminating in co-authorship in future papers.

Chronic wounds in Diabetes – using zebrafish to explore the hold-up in inflammation.

Main Supervisor

Dr David Gurevich (d.b.gurevich@sheffield.ac.uk)

Second Supervisor

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

Aim and Objectives

Clinical investigations show that dysregulated inflammation is a crucial factor in the establishment of chronic, non-healing wounds, particularly in diabetes. Understanding these defects at the genetic, cellular and tissue level will help inform future therapeutic approaches, as current strategies struggle to effectively treat these compromised wounds. Improving these wound healing interventions is vital, as 15-25% of the nearly 500 million diabetes sufferers worldwide develop non-healing wounds such as foot ulcers, many requiring amputation. These wounds represent a significant reduction in quality of life, increased morbidity and mortality rates, and are a huge burden on health services.

Zebrafish have essentially all components of mammalian tissue but with the added advantage of being translucent and genetically tractable. They are therefore ideal for non-invasively live imaging tissue repair processes, as well as rapidly screening candidate genes for their role in regulating inflammation. Our preliminary proteomics data performed on recently established zebrafish diabetes mutants reveals numerous promising and novel targets underlying inflammation dysregulation. Through this project, we aim to identify key genes that are disrupted in diabetic wounds, knocking them down with CRISPR mutagenesis and examining how this affects inflammation and, consequently, tissue repair.

Research Methodology

The first step in this project will be identifying key targets, using proteomics data from wounded diabetic zebrafish. Once you’ve decided on targets, you will perform CRISPR mutagenesis on transgenic zebrafish with fluorescent reporters of immune cells. You will then injure these fish and use advanced fluorescence microscopy to live image the immune cells response to wounding, defining in real time how these genes impact on wound inflammation. Using FACS sorting and quantitative PCR, you will determine the mechanisms of how these CRISPR mutations affect the gene expression profiles and subsequent behaviours of immune cells.

Expected Outcome

At the end of this project, you will have gained a deeper understanding of wound healing biology, identifying novel candidates that are key in regulating inflammation. The mechanistic insight gained from this work will directly contribute to unravelling how diabetic wounds fail to heal in this highly publishable sphere of research, as well as defining new targets that may be used in drug discovery and other therapeutic interventions. The supervisory team has a strong track record of delivering first class degrees to committed students, and this is also an expected outcome.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

Students will be trained to mine proteomics datasets with “Proteome Discoverer” software and pathway analysis using string-db.org. They will be trained in zebrafish husbandry, genotyping, sorting for fluorescent markers, CRISPR mutagenesis, and wound induction methods to generate the appropriate fish for investigating candidate genes. They will also be instructed in FACS sorting, RNA extraction, cDNA synthesis and quantitative PCR for subsequent cellular interrogation.

Adaption of a protein microarray to detect influenza specific antibodies against multiple strain specific antigens within dried blood spots

Main Supervisor

Dr Benjamin Lindsey (b.lindsey@sheffield.ac.uk)

Second Supervisor

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

Aim and Objectives

  • Design a protein microarray against strain specific influenza Haemagglutinin and Neuraminidase proteins.
  • Compare the microarray on serum and dried blood spots.
  • Analyse the resulting data to evaluate the performance of the assay.

Research Methodology

The student’s role will be to select appropriate proteins to include in the assay which match recently circulating influenza viruses. They will use a protein microarray printer to create glass plates that will detect virus specific antibodies. They will then run laboratory experiments to optimise the assay. Once optimised they will test the microarray against serum and dried blood spot samples.

Expected Outcome

The endpoint of the project will be to have a functioning protein microarray which can be applied to a number of scenarios where traditional methods are not suitable. Namely, large population screens of influenza immunity in children, where it is often difficult to take blood samples. It will also facilitate studies in resource limited settings where the infrastructure for sample collection and processing is not always available.

Type of Project

Lab/Bench Project - primarily working in a lab environment

Additional Training

The student will be trained how to work safety in a research lab. They will get the opportunity to engage in lab meetings and present their work to the group. They will be able to apply statistics to a real-world problem and learn how this enables the evaluation of a laboratory assay. This skills will be widely applicable to any future laboratory based work.

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.

Neurological manifestations of Sjogren’s syndrome.

Main Supervisor

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

Second Supervisor

Professor Marios Hadjivassiliou (m.hadjivassiliou@sheffield.ac.uk)

Other Supervisors

Mohammed Akil

Aim and Objectives

Aim: To establish the phenotypic manifestations of neurological involvement by Sjogren’s syndrome beyond peripheral neuropathy

Objectives

  1. Identify the number of cases of ataxia in patients with Sjogren's disease in the Sheffield cohort.
  2. Collate the neuro imaging and clinical findings of patients with ataxia and Sjogren's disease and describe its natural history.
  3. Assessment of the wider health of patients with neurological manifestations of Sjogren's disease (with SF36) compared to patients with Sjogren's disease without neurological complications.

Research Methodology

The clinical records from Dr Akil's Sjogren's clinic will be used to identify patients and seek their consent to participate in the study. The study will be possible even under lockdown conditions. Clinical manifestations will be obtained from clinical records. The brain imaging studies will be a retrospective analysis of the existing clinically acquired scans using FSL and Free Surfer image analysis software to measure cerebellar atrophy and cervical cord atrophy to be supervised within the university MR imaging group. The SF36 will be undertaken by post with telephone support for those patients that request it, or at visits to clinic depending on patient preferences.

Expected Outcome

Several abstracts are expected:

  • Range of neurological findings in a single centre cohort of patients with Sjogren's disease. Impact on health of having neurological complications with Sjogren's disease compared to those patients without neurological complications.
  • Natural history of ataxia in patients with Sjogren's disease.
  • Imaging features of ataxia in patients with Sjogren's disease.

These will likely be published in a single manuscript describing the natural history and impact on health of having neurological complications of Sjogren's disease.

Type of Project

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

Additional Training

We hope the student will take advantage of this opportunity to learn the basics of imaging processing which is applicable across much of neuroscience research. There will be teaching on the clinical assessment and management of patients with long term rheumatological conditions and neurological conditions.

Remote haemodynamic and arrhythmia monitoring of patients with pulmonary arterial hypertension

Main Supervisor

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

Second Supervisor

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

Aim and Objectives

Pulmonary arterial hypertension is driven by small vessel remodelling of the pulmonary arteries and leads to right heart failure. Heart failure causes abnormal heart rhythms and abnormal heart rhythms in patients with heart failure result in an increase in adverse clinical outcomes. The prevalence of abnormal heart rhythms in patients with pulmonary arterial hypertension is unknown as is the relationship to adverse clinical outcomes, pulmonary artery pressure, physical activity and quality-of-life. We have developed a cohort of 60 patients (funding to recruit 80 patients in place from the MRC and Wellcome Trust) with pulmonary arterial hypertension implanted devices that remotely return heart rate, rhythm, physical activity and pulmonary artery pressure, daily and weekly quality-of-life.

Aims:

  1. Determine the prevalence of abnormal heart rhythms in patients with pulmonary arterial hypertension.
  2. Determine the relationship of abnormal heart rhythms to clinical characteristics, MRI parameters, hamodynamcis, physical activity and quality-of-life.

Objectives:

  1. align remote monitoring and clinical data to generate a database.
  2. validate and quantify abnormal heart rhythms reported from approved medical devices.
  3. relate abnormal heart rhythms to clinical characteristics, haemodynamics, pulmonary artery pressures, therapies and clinical worsening events.

Research Methodology

The team run a range of cutting-edge remote monitoring and novel drug studies. A student would join the team and contribute to all aspects of study conduct and data analysis within the remit of their own project.

Specific roles would include:

  • Identification of patients for study recruitment from clinic and patient lists (2-3 months).
  • Participation in study procedures and device implant visits.
  • Extraction of remote monitoring data (ongoing ).
  • Alignment of this data to existing databases which include clinical characteristics and investigation results (add data to established databases).
  • Data analysis (3 months).
  • Report writing for thesis and publication.

Expected Outcome

The study will be the first to determine the prevalence of abnormal heart rhythms in patients with pulmonary arterial hypertension and will inform the diagnosis and management of patients in the future. Due to availability of remote monitoring and clinical data the study will be the first to determine the temporal physiological change of patients preceding clinical worsening events, and the first to demonstrate the response to treatment. Multiple aspects of the project will be highly publishable in both abstract and fully manuscript form.

Type of Project

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

Additional Training

The team run a range of remote monitoring and novel drug studies. A student would join the team and contribute to all aspects of study conduct and data analysis within the remit of their own project.
Specific training would include:

  • Clinical studies training, NIHR good clinical practise course and hands-on clinical studies management.
  • Research training in data extraction tools and statistical analysis using Prism and SPSS.
  • Clinical training in cardiac haemodynamic and cardiac rhythm monitoring.
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.

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)

Aim 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.

Type of Project

Lab/Bench Project - primarily working in a lab environment

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.

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)

Aim 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.

Type of Project

Lab/Bench Project - primarily working in a lab environment

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.

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)

Aim 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.

Type of Project

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

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.

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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