Background
There is a lot more to DNA than the Watson-Crick double helix. As a flexible polymer, it folds in different ways adopting many different secondary structures. Much less is known about these structures – how and when they form, what they do and how their structure relates to their role. Even so, such “alternative” structures have been linked to switch on/off of genes, and thus to genetic diseases: understanding them is vital to development of new therapies and diagnostics. i-Motif (iM) DNA – the focus of this project – is an exciting current topic as its existence in organisms was only proven in 2018. Consequently, while iM containing sequences have been linked to diabetes and cancer, little is known about their biological structure/function relationships, and research is held back by a lack of effective detection methods that can be applied to live cells and organisms.
This project, aimed at developing metal-based small molecule iM probes compatible with live cells, tissues and organisms, is led by Dr John Fielden, who joins the Chemistry Department at the University of Lancaster at the end of January 2023. Research in the Fielden Group is focused on the synthesis, photophysical and electrochemical properties of new molecular inorganic compounds, and their application in fields ranging from non-linear optics, to biological imaging and detection.
Project description
A 3.5 year Faculty of Science funded PhD position is available at Lancaster University, focused on design, synthesis and testing of new ruthenium-based small molecule probes for i-Motif DNA (iM). The project is in collaboration with Dr. Zoë Waller (School of Pharmacy, University College London), and follows up our recent discovery of a ruthenium complex that can, in vitro, detect iM in the presence of other DNA forms (J. Am. Chem. Soc. 2020, 142, 13856) through observation of a phosphorescence lifetime increase.
Existing means of detecting iM are only compatible with fixed, dead cells, whereas ruthenium complexes have demonstrated uptake, and tolerance by live cells and organisms. Thus, our discovery has potential to enable detection and study of the role of iM in living systems, and ultimately inform development of diagnostics and treatments for iM-linked genetic diseases. The studentship will take key steps towards this goal by synthesing new analogues of our lead compound, designed to have stronger and more specific responses to iM. It will also improve our understanding of the phosphorescence switch-on, and begin the work of translating the research from the test tube to cells.
The project will provide training in ligand and metal complex design and synthesis, including handling of air and moisture sensitive reagents (Schlenk technique), and a full range of molecular characterisation techniques (NMR & IR spectroscopy, mass spectrometry, X-ray crystallography). You will learn photophysical characterisation methods (UV-vis, fluorescence/phosphorescence, circular dichroism) and their application to biophysical chemistry, and be involved in the first studies of these compounds in live cells. Biophysical and biological work will be conducted in collaboration with the Waller group, and is expected to include short visits or secondments to UCL.
Requirements
Applicants will hold, or expect to receive, a 1st class or 2:1 UK Masters-level or BSc degree (or equivalent) in Chemistry, or a closely related discipline and possess theoretical and practical skills commensurate with a science-based undergraduate degree programme. Candidates with a 2:2 may be considered if they can demonstrate excellent research skills in their application and references.
The successful candidate will combine a strong interest in synthetic coordination and organometallic chemistry with curiosity about the interaction of small molecules with biological systems, and the willingness to learn and apply multiple photophysical and biophysical techniques. They will also have enthusiasm for work in a laboratory environment, a collaborative attitude, and excellent written and oral communication skills in English.
How to apply (Please read carefully)
Dr John Fielden encourages informal email enquiries before submitting an application ([Email Address Removed]). Please note that we cannot receive applications by email as they must be processed centrally.
Applications should be made via Lancaster University’s online application system (http://www.lancaster.ac.uk/study/postgraduate/how-to-apply-for-postgraduate-study/).
Please indicate on your application that you are applying for this funded PhD project by declaring the title of the advertisement where prompted. You may use the project description as your research proposal to apply for this studentship.
Funding Details
The studentship will cover fees at the UK rate plus the standard maintenance stipend (this was raised to £17668 tax free in Oct 22).
It may also fully or partially contribute to the fees and stipend of a self-funded international candidate, though it is advised that you enquire regarding this before applying.
Deadline: 20th January 2022. Shortlisted candidates will be interviewed in early February.
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