VACANCIES
Prof P Genever, Dr O Davies
Sunday, December 17, 2023
Competition Funded PhD Project (Students Worldwide)
About the Project
This PhD project combines cutting edge science with innovative therapeutic development, under the supervision of two experts in the field, Professor Paul Genever (York) and Dr Owen Davies (Loughborough). The promise of mesenchymal stem cell (MSC) therapies to offer a solution to regenerate tissue lost to damage or disease has been limited by a lack of understanding of their mechanism of action (i.e. how they achieve their therapeutic effect) and an inability to reproducibly manufacture enough MSCs to meet clinical demand. Recent evidence has suggested that stem cells, at least in part, achieve their therapeutic effects through the secretion of bioactive nanoparticles called exosomes.
In many ways, exosomes can be viewed as the body’s postal service, enabling the safe transport of biological factors essential for tissue development, homeostasis and repair. Exosomes have potential therapeutic advantages over cells in that they are comparatively safe, stable and potentially more cost-effective. As such, exosomes are increasingly viewed as an exciting new biotherapeutic paradigm. However, several key challenges currently prevent promising exosome therapies from reaching a global market and benefitting patients. Importantly, we need to address exosome identity, consistency, mechanism of action and strategies for their isolation.
This PhD is designed to tackle these challenges by identifying the most potent tissue-forming exosomes derived from immortalised clonal MSC lines, underpinned by mechanistic biology. The focus will be on bone regeneration to address tissue loss caused by trauma, tumour resections and major global diseases such as osteoporosis.
To achieve this, you will isolate exosome subtypes from different immortalised MSC clonal lines, which we have already generated and characterised in the lab. You will test the exosome subtypes using in vitro and ex-vivo bone-forming assays, including rapid osteogenic reporter screens. You will characterise the pro-osteogenic exosome subtypes by nanoparticle tracking analysis, western blotting and multi-omic analyses and test candidate mechanisms of action by pathway targeting and genetic modification. Collectively, your research will accelerate the preclinical development of a novel biotherapeutic for an important and unmet clinical need.
You will be based in the Department of Biology at the University set in the beautiful, historic city of York. You will join a vibrant community of like-minded biomedical research scientists and fellow PhD students. You will have access to state-of-the-art equipment through our renowned Technology Facility and the opportunity to develop your scientific and transferable skills through a comprehensive training programme. Unique to this project, you will also benefit from the expertise and facilities for exosome characterisation and analysis available at Loughborough University. We have excellent industrial collaborators including our own spin-out company, Mesenbio, which will provide exposure to commercial development and a genuine route for the clinical translation of your research.
Sunday, December 17, 2023
Competition Funded PhD Project (Students Worldwide)
About the Project
This project offers a PhD student the opportunity to work with Professor Adele Fielding, a clinician-scientist who studies leukaemia in the lab and in the clinic together with a Professor Paul Genever, a biologist who focuses on mesenchymal stromal cell and skeletal biology. The student will help to unpick how stromal cells become ‘cancer-associated fibroblasts’ (CAF), support leukaemia cells and afford them protection from chemotherapy1. The overall goal in understanding this relationship is to interrupt the connections between cancer cells and their cellular support systems in order to treat leukaemia without chemotherapy.
The scientific aim of the project offered is to define the distinct genetic and functional identity of the mesenchymal stromal cell subpopulation(s) which support leukaemia. Modelling the stromal cell to CAF transition is well-established in the Fielding lab using chemotherapy-exposure, co-culture with leukaemia cell lines, patient-derived xenografts and primary patient leukaemia cells. In order to determine which from among a number of distinct MSC subpopulations previously identified by the Genever lab2 can become CAF after exposure to ALL cells, the student will use immunofluorescence microscopy, cytokine bead arrays and RQ PCR as read-outs. Next, to understand the genetic determinants of which subpopulations of MSC can become CAF, the student will analyse bulk and singe cell RNA sequencing data generated by both labs to correlate the functional characteristics determined above with relevant gene expression profiles. Finally, in order to dissect the precise mechanisms by which subpopulations of MSC support leukaemia, the student will design mechanistic studies to confirm the findings e.g. CRISPR-Cas9 knockouts, antibody blocking experiments. A bone marrow organoid model3 is also available within Fielding lab for the mechanistic work.
The research question in this project is embedded within the Fielding team’s overall goal of ensuring that patients with acute lymphoblastic leukaemia receive ‘precision medicine’ treatment approaches relevant to their age and the genetic subtype of disease, ultimately substituting ‘chemotherapy for all regardless of age/disease subtype’ with a more nuanced approach which will involve interrupting the connections between cancer cells and their support systems.
The student will benefit from an extremely positive, collaborative research culture primarily based in the Centre for Blood Research at the University of York and close supervision by two experienced supervisors with overlapping but distinct skills and interests. Career progression and acquisition of generic skills of students is taken very seriously within a supportive but professional environment. Students play a full role in the labs including presentations to team members, writing manuscripts and conference attendance to present data. Day-to-day help and supervision from experienced post-doctoral scientists is available. The renowned Bioscience Technology Facility at the University of York provides access to and training on a wide number of state-of-the-art technologies to be used in the project (e.g. imaging and cytometry, genomics, molecular interactions, protein work). The facility is run by experts who offer wonderful courses and specific training to allow the student to achieve competence to use the equipment without supervision.
Prof Adele Fielding, Prof P Genever
Sunday, December 17, 2023
Competition Funded PhD Project (Students Worldwide)
About the Project
This project offers a PhD student the opportunity to work with Professor Adele Fielding, a clinician-scientist who studies leukaemia in the lab and in the clinic together with a Professor Paul Genever, a biologist who focuses on mesenchymal stromal cell and skeletal biology. The student will help to unpick how stromal cells become ‘cancer-associated fibroblasts’ (CAF), support leukaemia cells and afford them protection from chemotherapy1. The overall goal in understanding this relationship is to interrupt the connections between cancer cells and their cellular support systems in order to treat leukaemia without chemotherapy.
The scientific aim of the project offered is to define the distinct genetic and functional identity of the mesenchymal stromal cell subpopulation(s) which support leukaemia. Modelling the stromal cell to CAF transition is well-established in the Fielding lab using chemotherapy-exposure, co-culture with leukaemia cell lines, patient-derived xenografts and primary patient leukaemia cells. In order to determine which from among a number of distinct MSC subpopulations previously identified by the Genever lab2 can become CAF after exposure to ALL cells, the student will use immunofluorescence microscopy, cytokine bead arrays and RQ PCR as read-outs. Next, to understand the genetic determinants of which subpopulations of MSC can become CAF, the student will analyse bulk and singe cell RNA sequencing data generated by both labs to correlate the functional characteristics determined above with relevant gene expression profiles. Finally, in order to dissect the precise mechanisms by which subpopulations of MSC support leukaemia, the student will design mechanistic studies to confirm the findings e.g. CRISPR-Cas9 knockouts, antibody blocking experiments. A bone marrow organoid model3 is also available within Fielding lab for the mechanistic work.
The research question in this project is embedded within the Fielding team’s overall goal of ensuring that patients with acute lymphoblastic leukaemia receive ‘precision medicine’ treatment approaches relevant to their age and the genetic subtype of disease, ultimately substituting ‘chemotherapy for all regardless of age/disease subtype’ with a more nuanced approach which will involve interrupting the connections between cancer cells and their support systems.
The student will benefit from an extremely positive, collaborative research culture primarily based in the Centre for Blood Research at the University of York and close supervision by two experienced supervisors with overlapping but distinct skills and interests. Career progression and acquisition of generic skills of students is taken very seriously within a supportive but professional environment. Students play a full role in the labs including presentations to team members, writing manuscripts and conference attendance to present data. Day-to-day help and supervision from experienced post-doctoral scientists is available. The renowned Bioscience Technology Facility at the University of York provides access to and training on a wide number of state-of-the-art technologies to be used in the project (e.g. imaging and cytometry, genomics, molecular interactions, protein work). The facility is run by experts who offer wonderful courses and specific training to allow the student to achieve competence to use the equipment without supervision.
Prof Victor Chechik, Prof P Genever, Prof Daniel Ungar, Dr G Vallejo Fernandez
Sunday, December 17, 2023
Competition Funded PhD Project (Students Worldwide)
About the Project
A major challenge for drug delivery is in ensuring that the active agent is delivered to the correct cell types in the correct quantities to induce the desired therapeutic effect. Working closely with our industrial partner Liquid Research Ltd, we will address this challenge by designing magnetic nanoparticles (MNPs) with a thermally-responsive shell for targeted delivery and release of drugs. The idea behind our method is that protein-based drug molecules can be encapsulated in the nanoparticle shell at human body temperature, where their release is triggered by application of an alternating magnetic field which heats the nanoparticles and disrupts the shell. We recently demonstrated the feasibility of our approach [1]. In this project, we aim to develop a new MNP system based on elastin-like peptides (ELPs) [2]. These thermally-responsive materials have much more clinical potential than synthetic polymers used in our previous work. Functional groups at the surface of ELP-coated MNPs will be used for chemical functionalisation, e.g., attachment of an antibody. This exciting new MNP modification will allow us to target delivery of the encapsulated protein to specific tissues. The new MNP system will be applied to the delivery of therapeutic proteins, focusing on bone morphogenetic protein 2 (BMP2) for the treatment of bone disease, an urgent global healthcare need.
Experimental approach
We will synthesise and characterise ELP-coated MNPs using chemical and biochemical methods established in our laboratories and by our industrial partner. Encapsulation and magnetic release of proteins (e.g., BMP2) by these MNPs will be studied in buffers and cell cultures. Bringing chemistry and biology together will help us understand the nature of protein-nanoparticle interactions, which is an important part of the project.
Collaboration with industry
The project is supported by Liquids Research Ltd who is a major supplier of magnetic nanoparticles. The company will fully fund a 3-month placement at their site, will contribute to student training and conference allowance, and will allow us to use their protocols and equipment for nanoparticle synthesis and characterisation.
How the project will be supervised
This is a highly interdisciplinary project and in order to provide expertise in all areas of the project, it will involve four supervisors: Victor Chechik (nanoparticle synthesis, chemical modifications), Paul Genever (cell biology, regenerative medicine), Dani Ungar (biochemistry, ELP expression) and Gonzalo Vallejo Fernandez (magnetic properties). We have a strong track record of working together and will ensure that the student is actively interacting with at least one supervisor at all times, while having fortnightly meetings with all supervisors. You will join a vibrant, cross-departmental community of chemists and biochemists, and will have access to state-of-the-art equipment.
Training
The project will suit students interested in (bio)chemistry, biophysics, nanomaterials, drug delivery and related areas. Training in all aspects of the project will be provided. The project offers a great opportunity to consolidate ideas and expertise of different disciplines in order to develop new methodologies.
Liquids Research Limited (www.liquidsresearch.com) has provided a letter of support for the project.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog
Further information on the programme and how to apply can be found on our website: