PGT to PGR Project List

Infection, Immunity & Cardiovascular Disease

Adhesion platforms organised by tetraspanins account for differences during N. gonorrhoeae infection of males and females

Supervisor: Dr Luke Green

Project Description: Infectious disease is a huge health burden globally and antibiotic resistance is an ever growing problem, currently attributable to ~700,000 deaths per year with projected figures rising to 10 million by the year 2050. For this reason, new therapies to replace antibiotics are crucial. Due to their rapid doubling time, bacteria have the ability to quickly evolve mechanisms to overcome drugs targeted to them, and for this reason, I believe the future for anti-infectives is to target infection at the human cell level.

Neisseria gonorrhoeae is the causative agent of gonorrhoea, the second most common sexually transmitted disease in the UK. In 2016, the World Health Organisation (WHO) estimated the incidence of gonorrhoea at 86.9 million, however, cases are increasing sharply across the world, for example, cases rose by 26% in the UK between 2017-2018. To compound this problem, the WHO global gonococcal antimicrobial surveillance programme (GASP) has highlighted the rise in multidrug resistant gonorrhoea infections around the world. There are increasing reports of clinical isolates demonstrating resistance to the first-line antibiotics, ceftriaxone and azithromycin, with 3 cases recently identified in the UK demonstrating treatment failure with this dual therapy.

Symptoms associated with gonorrhoea are sex specific, however, the reasons behind this are currently unclear. Changes within the protein repertoire and their expression between male urethral cells or cervical epithelial cells are thought to be a major reason for these differences. Our lab has identified a family of human proteins involved in the association of N. gonorrhoeae to human cells. Blockade of these proteins can reduce adherence by almost 50%. These proteins do not appear to act as receptors but instead organise various host proteins at the cell surface into platforms. These platforms are ‘hijacked’ by the bacteria in order to aid adhesion and internalisation. This project will further characterise these ‘adhesion platforms’ across various cell types to elucidate the mechanisms that allow N. gonorrhoeae to produce sex specific differences during infection. Understanding how bacteria hijack these platforms is an essential step leading to the development of new anti-infectives which bypass the need for antibiotics.

The student will join a young and enthusiastic team of researchers in the Department of Infection, Immunity and Cardiovascular Disease. The supervisory team consists of Dr. Green, a Humane Research Trust funded research fellow and Dr. Shaw, a reader in microbiology. Email enquiries to l.r.green@sheffield.ac.uk.

How to apply:

Please complete a University Postgraduate Research Application form available here.
 

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Are macrophages the heroes or villains of infection control?

Supervisor: Dr Simon Johnston

Entry Requirements: Qualifications in mathematical subjects desirable but not essential.

Project Description: The field of host pathogen interactions has never been more important. From the recent Covid19 pandemic to the causes of cancer and neurodegenerative disease host pathogen interactions underpin the pathology of many important diseases. Coupled with the ongoing antimicrobial resistance pandemic, it is vitally important we understand infection in the context of the immune system and how that interaction might be targeted for treatment beyond the use antimicrobials. Macrophages have been studied in detail as effector and regulator cells in the immune response to infection. Despite such detailed investigation the critical aspect(s) of macrophages biology that go wrong in life threatening infection is unknown. For example, numerous studies by ourselves and others have demonstrated that macrophages in vitro are poor effector cells in controlling infection but are known to be essential for control in animal models and human disease.

While genetic and molecular studies have identified many factors that are necessary and/or sufficient for different aspects of macrophage biology how these factors interact with each other and with other elements of the host and pathogen response are rarely reliably testable in current experimental models. A major reason for this is that what we measure as the outcome of infection is the result of many thousands of individual events, most of which are by their nature stochastic (random). Our research group is in a unique position to have comparable experimental model data from multiple different cellular, animal and human clinical models. Therefore, in this project we will use our existing published and unpublished data sets on host pathogen interactions to develop theoretical models of the function of macrophages in the outcome of different infections.

A critical feature is that we have data that demonstrates both the detailed features of the relevant host pathogen interactions and the outcome of the infection. This means we can develop our models using known measurements and relevant biological features but can also test our models against the known outcome of infections, including human clinical trial data.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Qualifications in mathematical subjects desirable but not essential.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Exploiting inflammation-induced damage response to treat atherosclerosis

Supervisor: Professor Sheila Francis

Entry Requirements: Candidates must have, or expect to gain, a Merit or a Distinction in their Masters Course.

Project Description: It is becoming recognised that the connection between inflammation and atherosclerosis is DNA damage. This project hypothesises that the repair response to excess unrepaired DNA damage in a vascular wall cell potentiates inflammation and that this drives atherosclerosis. We therefore also propose that inhibiting the DNA repair response will cause break the feedback-loop and reduce atherosclerosis. In this project, careful examination of the mechanisms involved will enable choice of a suitable inhibitor(s) to be used in vivo in a model of atherosclerosis.

The importance of this work to the scientific field is that the direct connection mechanism between DNA repair and inflammation is not yet known. Intervention with certain types of DNA damage inhibitors may be a useful adjunct to lipid lowering medications such as statins in patients with coronary artery disease.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Candidates must have or expect to gain a Merit or a Distinction in their Masters Course.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Regulation of RNA stability in inflammation - a new route to pro-resolution therapeutics

Supervisor: Professor Stephen Renshaw

Project Description: Uncontrolled inflammation is known to be a major driver of pathology in many common disabling diseases, including common and debilitating lung diseases such as Chronic Obstructive Pulmonary Disease (COPD), which causes over 3 million deaths globally each year (WHO). There is a pressing need for pro-resolution therapies that target persisting inflammatory neutrophils, while leaving circulating neutrophils able to respond to infectious threats. We seek to determine the molecular mechanisms behind regulation of neutrophil function and to identify drug targets to develop their translational potential.

Although neutrophils are resistant to the anti-inflammatory effects of current treatments, our lab has shown that targeting neutrophil phenotype can drive inflammation resolution. Gene transcription, through regulation of RNA stability, is important in controlling neutrophil phenotype. We have shown that the RNA stabilising protein, ELAVL1, controls the inflammatory phenotype of the neutrophil by regulating expression of pro-inflammatory gene products. You will use in vivo (zebrafish) and in vitro (human neutrophils) models to manipulate neutrophil phenotype to reveal the downstream targets of ELAVL1, identifying new drug targets for the treatment of inflammatory disease.
Zebrafish are an excellent model for in vivo studies of neutrophil function, since their genes are easily manipulated, which allows the genes controlling neutrophil recruitment and resolution of inflammation to be identified. Using our model of tailfin transection, we can visualise the behavioural dynamics of neutrophils at wound sites in several transgenic zebrafish lines and various live stains.

Ours is a lively, fun and exciting lab to work in. There are lots of post-docs around to help. We strongly encourage students attendance international conferences, and we operate a publication-focussed lab culture that allows students to publish manuscripts at an early stage.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Neuroscience

A personalised medicine approach to the treatment of low dose interleukin-2 in amyotrophic lateral sclerosis: predicting patients’ response through blood transcriptomics.

Supervisor: Professor Janine Kirby

Project Description: MIROCALS, is a clinical trial of low-dose interleukin-2 (IL-2) in patients with amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disorder. Disease duration is 2-3 years from symptom onset and death is usually due to respiratory failure. Riluzole is currently the only approved drug in the UK and is estimated to extend life by 3-6 months. Patients with high regulatory T cells (Tregs) levels live longer than those with low Treg levels (Source). Therefore, the clinical trial aims to increase Treg levels though treatment with a low-dose of IL-2, as used previously in type 1 diabetes. Longitudinal blood samples have been taken, white cells isolated, and the cells sent to Sheffield for transcriptomic analysis.

Objectives: The primary aim is to establish the changes in transcriptomic profiles in response to both riluzole and IL-2 treatment. Secondary objectives are to establish the gene expression profiles associated with high and low levels of phosphorylated neurofilament light protein (NFL), a proposed biomarker of ALS, and those profiles associated with responders and non-responders to IL-2. Finally, we aim to establish gene expression biomarkers that would predict the patient’s response to IL-2. This would have a significant impact in terms of clinical translation, should low dose IL-2 extend survival in ALS patients in the MIROCALS clinical trial.

The clinical trial is novel because of the science being carried out alongside; blood (serum/plasma/PBMCs/DNA/RNA) and CSF samples are being collected throughout the trial and transcriptomic analysis will be linked with genomic and immunological data being generated by our collaborators. This project is unique in providing a large cohort of longitudinal biosamples from ALS patients treated with riluzole and IL-2.

Experimental Approach: Gene expression profiles have been generated using Clariom D arrays (Affymetrix), which allow us to distinguish not only differential expression of genes but also detect alternatively spliced exons, using the Transcriptome Analysis Console (TAC) (Affymetrix), as in the pilot study IMODALS (Source 1, Source 2). Software such as Metascape and Ingenuity Pathway Analysis will be used to identify significantly enriched biological pathways. The secondary supervisor will input directly into the bioinformatics analysis and teach the student how to write their own scripts in R to analyse the data using known and bespoke software. Once NFL and Treg levels are generated from our collaborators, further analysis and correlations will be determined to complete the secondary objectives and establish whether gene expression profiles at baseline can predict response to IL-2.

For more information, please email Prof Janine Kirby (j.kirby@sheffield.ac.uk).

How to apply:

Please complete a University Postgraduate Research Application form available here.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Understanding the dynamics of microtubule maintenance supporting neuronal longevity

Supervisors: Dr Alison Twelvetrees & Dr Chris Toseland

Project Description: This studentship is focused on understanding the molecular basis of neurodegeneration through the study of microtubules, by applying advanced microscopy approaches (single molecule live-cell imaging) and biochemistry. The project aims to open up new avenues for intervention in disease. You will be part of a new collaboration between the Twelvetrees lab (twelvetreeslab.co.uk) at the Sheffield Institute for Translational Neuroscience (SITraN) and the Toseland lab (toseland-lab.com) in the Department of Oncology and Metabolism, at the University of Sheffield.

Neurons form complex extended cellular structures. For example, motor neurons have cell bodies in the spinal cord, but extend axons down to the muscles of hands and feet. This length presents a problem for neurons, as the majority of newly synthesized protein is made in the cell body and then transported long distances down the axon to its site of use. Axonal transport supports the continuous supply of critical cellular machinery synthesised in the cell body and is essential to neuronal survival. Defects in transport are observed in many neurodegenerative conditions, including Alzheimer’s, Parkinson’s, Huntington’s and Motor Neuron Disease.

Microtubules are platforms for almost all long-distance transport in cells and maintaining microtubules is critical for maintaining healthy neurons. Microtubules are formed from tubulin monomers synthesised in cell bodies and gradually moved to distal axons at ~0.5 mm/day. This creates some of the longest-lived proteins in axons, of the order of several years in the longest axons of the body. How tubulin then contributes to the maintenance of axonal microtubules over the lifetime of a neuron is also unknown.

You will be trained in cutting edge techniques for a quantitative understanding of biology, with training in computational skills applied to analysing real-time imaging data. In parallel you will also receive training in advanced tissue culture techniques and cellular and molecular neurobiology. There is also potential to develop super-resolution microscopy (DNA-PAINT) and CRISPR/Cas9 genome editing approaches to support the project. This research will provide fundamental insights into axonal transport, with translational outcomes for neurodegenerative diseases.

Creative individuals with an eye for detail are encouraged to apply. The successful applicant will be based in the Sheffield Institute for Translational Neuroscience, whilst working closely with both labs involved. You will be supervised by Dr Alison Twelvetrees and Dr Chris Toseland. Applications from a diverse range of scientific backgrounds are welcomed e.g. cell biology, biophysics, neuroscience, biochemistry, chemistry, structural biology and biomedical sciences. Interested applicants should contact Dr Twelvetrees to discuss the project (a.twelvetrees@sheffield.ac.uk) with more details available on our lab website twelvetreeslab.co.uk.

How to apply: 

Please complete a University Postgraduate Research Application form available here.

Candidates must have a first or upper second class honours degree or significant research experience

Developing and validating in silico models of neuropsychological changes seen in amnestic Mild Cognitive impairment (aMCI) based on cellular metabolic parameters

Supervisor: Dr Simon Bell

Project Description: Dysfunctional brain metabolism is common in many neurological diseases, such as Alzheimer’s Disease (AD). Metabolic changes develop early in AD and may lead to the acceleration of other neuropathology such as amyloid or tau accumulations. Brain metabolism is often studied separately either on cellular or clinical scales. The development of whole organ imaging methods such as 18F-FDG-PET or 31P MRS allow for the investigation of metabolism at an intermediate level between the cellular and clinical. However, these different scales of metabolism research have rarely been studied together and systematically integrated in a single individual human subject. This limits the ability to develop prognostic models predicting whether therapeutics developed toward cellular dysfunction can be interrogated with brain imaging and lead to the clinical level outcomes.

Understanding the neural mechanism across modalities and scales is critical for the development of prognostic models but a canonically challenging task. Here, we propose a new computational approach to relate data from different modalities and scales in studying metabolic dysfunctions in Mild Cognitive Impairment (MCI), a precursor to AD.

In this PhD project, we will develop an in silico neuronal network model that allows for the prediction of neuropsychological performance (in particular memory loss in aMCI) based on cellular metabolic limits and imaging biomarkers (18F-FDG-PET and 31P MRS). The model will initially be trained using data sets for neuropsychological scores and brain imaging techniques that are already available such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, and metabolic parameters identified in a literature search based around known markers of neuronal metabolic function. The project will also include an imaging study in which in vivo imaging of glucose uptake and phosphorous spectroscopy will be compared between aMCI and control groups whilst performing memory tasks (18F-FDG-PET and 31P MRS). This project will conclude by using the developed in silico model system to predict the ability of therapeutics, that target metabolic dysfunction, to improve neuropsychological performance in patients with aMCI. This virtual clinical trial paradigm has the potential to screen multiple drugs quickly aiding the discovery of new treatments for AD. By the end of this project an in-depth assessment of metabolic function at the brain and cellular level will have been performed, and an assessment of how these factors effect performance on neuropsychological testing will have been made.

This project will allow the student to gain skills in computer science, neuropsychology and a deep understanding of brain metabolism. By the end of the PhD the student will be able to create virtual clinical trials to test new therapeutics for patients with aMCI and AD.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Oncology & Metabolism

Improving radiation outcomes in NSCLC

Supervisor: Dr Helen Bryant

Project Description: Lung cancer is the leading cause of cancer mortality worldwide, and 85% of lung cancer is non-small cell lung cancer (NSCLC) subtype. Most NSCLC patients benefit initially from radiation treatment; however, even when given with radical intent, radiotherapy survival remains low partially due to intrinsic radioresistance. Thus strategies to improve radiotherapy response are urgently required. A promising approach is to combine molecularly targeted drugs with radiotherapy.

CDK12 and CDK13 are Ser/Thr protein kinases that regulate cell cycle and transcription. Consequently, selective CDK12/13 inhibitors constitute powerful research tools as well as promising anti-cancer therapeutics, either alone or in combination therapy. We have data that CDK12 inhibitors can radiosensitize NSCLC cell lines. Radiosensitization by the closely related CDK13 has not been tested.

Mechanistically CDK12 inhibition causes a BRCAness phenotype by blocking homologous recombination, this is reported due to changes in transcription of DNA repair genes. Thus it is likely due to lack of DNA repair that radiosensitization is seen; though so far this is not proven. The function of CDK13 is less clear but it is known to be required for RNA splicing so we propose that changes in gene expression could be involved.

The hypothesis of the project is that CDK12 and CDK13 inhibitors can radiosensitize NSCLC and therefore could be used to improve therapeutic outcomes.
Specific aims are
1. Test CDK12 and CDK13 inhibitors for radiosensitization of a range of NSLC cell lines in 2D and in 3D models.
2. Determine changes in gene expression (including splicing) with CDK12 and CDK13 in the presence and absence of ionizing radiation. (this will feed into mechanistic studies)
3. Investigate the mechanism of radiosensitization

This industrial linked studentship will provide training in a wide range of techniques from 3D cell culture to bioinformatics and functional assays of DNA damage and repair.

You will be part of the Bryant lab, a supportive, dynamic multidisciplinary team spanning chemists to clinical fellows, who are all working together to develop better treatments for cancer. You will also benefit from being part of the wider research within Sheffield as part of the Sheffield Institute for Nucleic Acids and Sheffield ECMC centers. You will benefit from regular contact and advice from our industrial partners Carrick Therapeutics ensuring you get an in depth understanding of drug development from bench to clinic.
You will join an active, friendly and lively PhD student cohort at the University of Sheffield, which hosts regular social events alongside networking and career development opportunities.
This project is suited to students from a diverse range of backgrounds, e.g. biochemistry, cell biology, biomedical sciences, medical chemistry or related disciplines. Interested applicants should contact Dr Bryant to discuss the project further (h.bryant@sheffield.ac.uk).

How to apply:

Please complete a University Postgraduate Research Application form available here.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Magnetic nanocarriers to enhance oncolytic virotherapy in breast cancer

Supervisor: Dr Munitta Muthana

Project Description: Oncolytic viruses (OV) are fast gaining acceptance as a cancer treatment modality that can activate anti-tumour immunity. However, following intravenous administration OVs are eliminated by the host’s defence mechanisms, limiting the use of OV to accessible tumours where direct tumour injection is necessary. MRI scanners offer new opportunities to magnetically guide OVs to inaccessible (deep) tumours that can’t be reached by direct injection such as metastatic breast cancers (BC).

This multi-disciplinary project aims to create a nanomedicine that chemically combines OVs with biologically derived magnetic nanoparticles called ‘magnetosomes’ synthesised by magnetotactic bacteria (MTB). The magnetosomes provide a metallic shield for the OV so that it is protected in the circulation whilst multiple species of MTB provide a platform of different shape and sized magnetosomes enabling optimisation of drug loading, biodistribution and cellular interaction. Additionally, the ability to steer them to the tumour site using MRI scanners, enhances the pharmacokinetic advantages of the nanomedicine for their enrichment at tumour sites.

We will address the biomanufacture of new MTB species for magnetosome production. After which, chemical cross-linking of OVs with magnetosomes will be assessed for stability and oncolytic potential in a panel of human and murine BC cells. In vivo pharmacokinetics and anti-tumour efficacy will be assessed in-vivo in primary and metastatic mammary tumour models. We will establish how these nanomedicines mediate anti-tumour immunity by profiling immune cells isolated from tumours and corresponding tissues using flow cytometry, qPCR and histology.

Here, we propose that OV and magnetosomes can be integrated into a therapeutic nanomedicine for synergistic combinations that have the potential to tailor their delivery and retention time to specific tissues regardless of the surrounding immune profile, and thereby underpin the development of a new nano-based immunotherapy for the treatment of BC.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Mapping differences in global mRNA splicing patterns in soft tissue sarcomas to improve diagnosis, prognosis and therapy.

Supervisor: Dr Will English

Entry Requirements: Minimum of 2i at undergraduate degree level in relevant subject with distinction preferred. Competitive candidates would normally have an MSc at distinction level or demonstrable relevant experience at postgraduate level. Prior experience with R and Galaxy would be advantageous.

Project Description: Soft Tissue Sarcomas (STS) are rare and difficult to treat solid tumours derived from cells of mesenchymal lineage that can be classified into over 50 histological subtypes. Each has their own genetic heterogeneity, making the development of new therapies challenging. This is complicated by the difficulty in correctly identifying subtypes, which can lead to more than 10% of STS patients receiving inappropriate treatment leading to decreased survival. Although the prognosis for localised, low-grade STS is good, less than 20% of patients with metastatic disease survive beyond five years. Treatment options are currently limited for STS patients and newer methods to aid identification of STS subtypes and the development of new therapies are urgently needed.

One area that has not been explored that could provide novel opportunities improvements in diagnosis, prognosis and novel therapies in STS is understanding how pre-mRNA splicing is altered between STS subtypes. On average each pre-mRNA generates four mRNA isoforms through alternative splicing of exons, which produces proteins with different functions. Isoform switching, a change in isoforms produced, is seen between normal and cancerous cells. Pre-mRNA splicing can be targeted therapeutically, either through the pathways that regulate the spliceosome, inhibitors of the spliceosome or specific splicing events through targeting with RNAi. To date, there has been no whole transcriptome level analysis of the differences in mRNA isoform switching in STS, characterisation of the molecular mechanisms that may regulate them or their prognostic significance.

Using a novel dataset of mRNA isoform expression across the whole transcriptome of STS developed within the group of Dr English, the student will use bioinformatic methods to perform a global analysis of Pre-mRNA splicing across multiple STS histotypes. The student will then explore the impact these have on diagnosis and prognosis, and identify key changes in isoform expression and molecular pathways linked to them that could be targetable. The PhD student will then validate these using a combination of molecular techniques in STS cells and tumour tissues, and explore methods of inhibition of splicing events.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Candidates must have a minimum of 2i (with distinction preferred) at undergraduate degree level in a relevant subject. Competitive candidates would normally have an MSc at distinction level or demonstrable relevant experience at postgraduate level. Prior experience with R and Galaxy would be advantageous.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Targeting mitochondria for treatment of bladder cancer

Supervisor: Dr Helen Bryant

Project Description: Non-muscle invasive bladder cancer (BC) constitutes 75% of all bladder cancer cases. It has very high recurrence rates of 60-70% with a progression rate of 20-30%. Only three drugs have been approved in the last 30+ years for this entity: Bacillus Calmette–Guérin (BCG), Thiotepa, and Valrubicin. To date, there are no standard therapies for patients after BCG failure, other than radical cystectomy. Novel therapies are therefore urgently required.

Mitochondria play a key role in cell metabolism and mitochondrial studies is an emerging area of cancer research. However, the role of mitochondrial function in BC has been scarcely investigated. A deeper understanding of mitochondrial function and/or active targeting of mitochondria in BC could therefore provide novel opportunities for targeted therapeutic strategies.

We have developed novel duel imaging and photodynamic therapy (PDT) Ir(III)-containing agents that specifically localise to mitochondria.
The broad aims of this project are to further investigate the use of these novel agents for BC therapy and understand the mechanism of action in mitochondria. It is also envisioned that the project will provide important insights into the role of mitochondrial function / dysfunction in BC.

Photodynamic agents are compounds which are non-toxic, but become toxic when exposed to light, when they generate reactive oxygen species (ROS), which kill cells. Thus, local irradiation specifically kills the tumour leaving non-irradiated healthy cells unharmed, reducing toxic side-effects. To date all approved PDT agents are organic molecules, but the light-induced properties of many transition metal complexes make them ideal PDT candidates. Their key advantage over organic molecules is the heavy atom effect, which favors population of a long-lived so-called triplet excited state which has orders of magnitude longer lifetimes than excited states in organic molecules. Longer lifetime means much higher yields of 1O2 and/or other ROS, and more efficient light treatment. The ease of chemical modification, increased bioavailability and their photostability adds to the appeal of these complexes.

In this interdisciplinary project you will test our novel agents in bladder cancer cells, and 2D- and 3D- bladder cancer tissue models. You will also investigate the mechanism of action using molecular techniques and cutting edge imaging technologies. Uniquely you will spend time at the UK science and technology central laser facility, Octopus Imaging (https://www.clf.stfc.ac.uk/Pages/home.aspx, and https://www.clf.stfc.ac.uk/Pages/Octopus.aspx) where you will help develop the next generation of mitochondrial function assays and use these to examine how mitochondria can be targeted to beat cancer.

The project therefore provides a world-class training in cross-disciplinary research.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Towards understanding the immunological mechanisms of preterm birth – the functional role of pro-inflammatory and anti-inflammatory cytokines in the placental features of spontaneous preterm birth.

Supervisor: Professor Dilly Anumba

Entry Requirements: Candidates must have a first or upper second class honours degree or significant research experience.

Project Description: We are seeking an ambitious and enthusiastic person with a good Bachelors and masters honours degrees in a biological science discipline to join a team of researchers investigating the mechanisms of premature birth in humans towards the award of a PhD. More than 15 million premature births occur annually globally. Over a million premature babies die as a consequence and many of those who survive are left with long term health conditions. This is the tip of the iceberg in that placental dysfunction also causes stillbirth of fetal growth retardation. The placenta is a key organ for a healthy pregnancy outcome and several of its processes can be impaired leading to stillbirth, growth restriction or preterm birth.

This project will provide an opportunity for the student to study key molecular events in the placenta that are associated with preterm birth, the prevention of which holds great promise for improved birth outcomes and the survival of the babies. Using a range of laboratory techniques the student will explore placental inflammation in various pregnant tissues including the placenta.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Candidates must have a first or upper second class honours degree or significant research experience.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

School of Clinical Dentistry

Developing a novel mode of anti-cancer drug delivery using a tissue engineering and mass spectrometry imaging approach

Supervisor: Professor Craig Murdoch

Project Description: There is increasing interest in the development of needle-free drug delivery systems for a number of diseases. A multidisciplinary team at The University of Sheffield, in collaboration with AFYX Therapeutics, have developed a polymer-based patch that can adhere tightly to the oral epithelium that lines the inside of the mouth and deliver drugs (corticosteroids, anaesthetic, peptides) directly to oral lesions (Colley 2018, Clitherow 2020, Said 2021). The patch has successfully completed phase 2 clinical trials. This project aims to incorporate anti-cancer agents into these novel patches for the treatment of oral cancer, the incidence of which has risen by 60% in the UK in the last decade.

To progress further, the oral patch technology requires fine-tuning in terms of controlled drug delivery and understanding drug absorption, distribution in tissues, as well as drug metabolism and excretion. In this project you will produce oral patches to contain anti-cancer drugs at therapeutically relevant concentrations and determine the drug release profiles from the patch over-time using a number of analytical techniques (Franz Chamber/HPLC). We have previously developed tissue-engineered in-vitro models of human oral cancer (Colley 2011) that accurately mimic cancer in vivo. You will adhere patches to oral cancer models and visualise drug permeation through the 3D tissue using Mass Spectrometry (MS) Imaging, a powerful label-free analytical technique that allows visualisation and spatial location of any specific molecule within tissues (Russo 2018, Handler 2021). You will also measure oral cancer cell death and rates of drug metabolism as the anti-cancer drug is de-activated by enzymes within cancer cells. The use of MS imaging combined with tissue-engineered oral cancer to develop oral patch-delivered drugs has not been performed previously. In addition, the data produced will be used by mathematicians at the University of Liverpool to develop an in silico predictive model of drug delivery as part of an NC3R-sponsored project.

This project will deliver extensive training in cell culture, tissue-engineering and 3D biology, a rapidly expanding area that aligns with NC3R principles. This will be combined with training in advanced tissue imaging and analytical techniques. Complementing these core techniques, the student will also obtain training in biomaterial fabrication using polymers (University of Sheffield) and network with mathematical modelers that make-up the wider multidisciplinary team, allowing first-hand insight into other disciplines and how these interact at the cutting edge of science.

Click here to view video presentation

How to apply:

Please complete a University Postgraduate Research Application form available here.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

ScHARR

Exploration of equality, inclusivity and diversity in children’s health research

Supervisor: Professor Cindy Cooper

Project Description: Exploration of equality, inclusivity and diversity in children’s health research.
This project aims to explore the challenges of ensuring inclusivity and diversity of participants in children’s health and healthcare research to address the following hypotheses:
It is recognised that there is under investment in research involving children and that further high quality paediatric research is needed.1 Providers of children’s health care are often reliant on evidence that has been derived from studies on adults and the findings may not be appropriate to children. 2 Initiatives are being developed to ensure standards for research in children.1 Although these standards give consideration to issues of vulnerability and explore ethical issues related to recruitment of children into research studies, they do not address issues of inclusivity and diversity of study participants.3
Diversity and inclusivity of participants involved in research studies is essential to ensure that the research participants in studies are representative of the people who are intended to benefit from the healthcare being evaluated. If the participants in a study are not representative of the target population then the findings of the research may not be valid and may not be generalisable to those who could benefit. It is well established that in adult trials participants tend to be healthier, older and more affluent than the general population. People from Black and Minority Ethnic Communities and people with multiple health problems are also under-represented.4 It is therefore important that the focus is not only on increasing the amount of research in children but also on facilitating the diversity and inclusivity of the children involved.

This PhD project will therefore aim to explore the challenges of ensuring inclusivity and diversity of participants in children’s health and healthcare research. It will take a mixed method approach to address a number of objectives such as:-

1. Undertaking a review of the literature to understand the evidence about the representativeness of children in health research
2. Identifying factors which act as barriers and facilitators to the recruitment and retention of children and challenges related to socio-economic, ethnicity, cultural and health issues.
3. Qualitative research with researchers, parents and/ or children to explore issues related to involvement of children in research focussing on recruitment, retention and issues of diversity and inclusivity.
4. Development of guidance on ensuring equality, diversity and inclusivity in children’s research.

Applicants will be required to develop the research questions and methodology further and will be encouraged to develop the ideas in line with their own interests.

Refererences
1. Klassen TP, et al (2008) Children Are Not Just Small Adults: The Urgent Need for High-Quality Trial Evidence in Children. PLoS Med 5(8): e172. 
2. Cramer K, et al. (2005) Children in reviews: methodological issues in child-relevant evidence syntheses. BMC Pediatr 5: 38.
3. Patrina H. Y.etal . Standard 1 . Consent and Recruitment. Pediatrics June 2012, 129 (Supplement 3) S118-S123.
4. Bartlett, C.,. et al. (2005), ‘The causes and effects of socio-demographic exclusion from clinical trials’, Health Technology Assessment, 9, 38.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Exploring the use of meta-epidemiological analysis and expert elicitation to gain scientific consensus on methods that affect evidence synthesis

Supervisor: Dr Lesley Uttley

Entry Requirements: Candidates must have a proven record of competency with modules in statistics from their Masters degree. Candidates should ideally have experience in conducting analyses such as linear regression and generalised linear regression. Candidates should have a good understanding of the main principles and purposes of systematic reviews and meta-analyses.

Project Description: Systematic reviews that include meta-analyses, are the gold standard for combining evidence from multiple studies. However, increasing research documents flaws in the conduct of systematic reviews which could potentially affect the reliability or validity of their conclusions. These problems include, a lack of prespecification of primary outcome, conflicts of interest of review authors, exclusion of unpublished studies, data extraction errors, and many more. Several meta-research studies have tried to demonstrate the potential impacts to pooled treatment effects when such problems are noted in published systematic reviews. However, existing statistical methods may not be able to correct for the full range of problems that systematic reviews are at risk of. In order to understand which particular biases are the most fatal to meta-analytical results, consultation with methodological experts from the wider scientific community may be preferable.
This project involves engagement with two existing funded projects in ScHARR. The first, funded by the MRC (awarded to Lesley Uttley), is to understand the full range of problems with systematic reviews. This has resulted in a living systematic review which will inform the proposed postdoctoral study. The second, funded by NIHR (awarded to Kate Ren), is to improve the robustness of decision making when evidence from RCTs are not available. This includes incorporation of experts' opinion using ‘expert elicitation’. The aim is to apply this novel approach to gain consensus from international collaborators about non-negotiable requirements for best-practice systematic review conduct to inform medical decision making.

Knowledge and application of standard statistical techniques used to derive conclusions in medical decision making, such as meta-analysis, will be extended to understand different quantitative methods employed by the various ‘meta-research’ studies of systematic reviews. The proposed postdoctoral research will firstly involve examination of studies which take a quantitative approach to analysing groups of systematic reviews to assess the robustness of their conclusions. The aim is to review and present the variety of methodological approaches used in meta-research studies of systematic review problems and outline the heterogeneous nature of the quantitative methods employed. This challenging and innovative research will examine whether it is feasible to conduct a formal quantitaive analysis of the ‘meta-variables’ identified from the living systematic review in order to assess whether interpretations given in systematic review conclusions can be considered robust.

This research will involve working closely with supervisors as well as international methodological experts to assess the implications of these findings. This project aims to gain scientific consensus with collaborators internationally. The project has a steering panel of experts that represent key global methodological bodies for good practice in systematic reviews including Cochrane and the PRISMA guidelines. Project collaborators include representation from the leading Universities in Canada, the United States, Europe and Australia.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Candidates must have a proven record of competency with modules in statistics from their Masters degree. Candidates should ideally have experience in conducting analyses such as linear regression and generalised linear regression. Candidates should have a good understanding of the main principles and purposes of systematic reviews and meta-analyses.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.

Promotion of dietary fibre intake in UK children.

Supervisor: Dr Sam Caton

Entry Requirements: Due to the multidisciplinary nature of this project, candidates from a variety of disciplines will be considered including (but not limited to): psychology, human nutrition, public health, human geography, or any other related social/ behavioural sciences. Candidates must hold a Masters degree or be close to completing at the time of interview. Students from diverse backgrounds are encouraged to apply.

Project Description: Intake of dietary fibre is less than optimal in children and adults. Epidemiological evidence demonstrates that optimal dietary fibre intake is associated with reduced risk of chronic diseases such as cardiovascular diseases, certain cancers, type 2 diabetes, and all-cause mortality. Despite the reported health benefits of diets high in dietary fibre many individuals do not consume enough, which might be due to the taste, texture, appearance, availability and accessibility. The overarching aims of this project are to understand why dietary fibre intake is low in UK children and how intake can be improved.

Using a mixed-methods, interdisciplinary approach spanning public health, psychology and nutrition this PhD will develop an understanding of 1) why children (and parents) do not consume sufficient amounts of fibre: what are the main barriers to sufficient dietary fibre intake? This will be addressed via a systematic review and interviews with parents. 2) How much dietary fibre is being consumed by children, and who is consuming the least: analysis of secondary data sets such as the National Diet and Nutrition Survey will allow researchers to explore the amount, sources of dietary fibre and determine which groups are consuming the least. 3) How can we encourage children (and their families) to increase their dietary fibre intake? and what methods are feasible and effective? This will be explored via a pilot/ feasibility study in the home environment.

The supervisors combine expertise in psychology, nutrition, and public health (Dr Sam Caton, Public Health, School of Health and Related Research, University of Sheffield, and Professor Louise Dye as external advisor, Schools of Psychology/Food Science & Nutrition, University of Leeds), sustainable food systems and human geography (Prof. Peter Jackson, Geography, University of Sheffield). Due to the multidisciplinary nature of this project, candidates from a variety of disciplines will be considered including (but not limited to): psychology, human nutrition, public health, human geography, or any other related social/ behavioural sciences. Candidates must hold a Masters degree or be close to completing at the time of interview. Students from diverse backgrounds are encouraged to apply.

How to apply:

Please complete a University Postgraduate Research Application form available here.

Due to the multidisciplinary nature of this project, candidates from a variety of disciplines will be considered including (but not limited to): psychology, human nutrition, public health, human geography, or any other related social/ behavioural sciences. Candidates must hold a Masters degree or be close to completing at the time of interview. Students from diverse backgrounds are encouraged to apply.

Please clearly state the prospective main supervisor in the respective box and select (department name) as the department.