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(MRC CASE) Aptamer biosensors to measure health via PAR dynamics in living cells


Project Description

We live in an era of ‘precision health and wellness’. Each and every one of us are different and the manner in which we age, live or become ill is unique, but predicting an individual’s fate is notoriously difficult. However, nature offers us a possible solution: by accurately and precisely measuring enzymatic activity or biomolecular modification, it may be possible to provide a ‘way in’ to quantifiably profiling the underlying biochemistry of health and aging.
A class of enzymes receiving intense scrutiny in pathophysiological processes are those involved in polyADP-ribosylation, a post-translational modification whereby chains of poly ADP-ribose (PAR) are assembled on acceptor proteins such as histones and other DNA-associated proteins. Parylation regulates various fundamental cellular processes including chromatin organisation, DNA repair, transcription and replication, processes that are frequently involved in chronic and acute diseases, such as cancer or those associated with aging. PAR chains are assembled by PAR polymerases, PARPs, and catabolised by the glycohydrolase PARG, and the balance between the two classes of enzymes is required to carefully regulate PAR dynamics. However, we currently lack the ability to measure PAR dynamics in living cells.
Our aim is to explore fluorescent or other chemically modified and measurable aptamers as ‘PAR biosensors’ capable of binding to PAR chains in living cells. With our industrial partner, Aptamer Group, we will generate new tools to study parylation and its role in DNA replication and damage repair in the context of normal cellular physiology and pathological states such as aging and in particular ovarian cancer.
The student will generate synthetic PARylated peptides; create aptamer beacons and evaluate the PAR biosensor(s) in living cells. The student will receive a broad interdisciplinary skills training in chemical biology; in particular they will be trained in state-of-the-art aptamer technology aimed at developing novel biosensors. In addition, via the validation steps, they will learn in vitro analytical techniques and cell biology methods including cell culture, time-lapse and immunofluorescence microscopy, as well as functional assays e.g. apoptosis, replication stress. They will also gain a strong intellectual training in the relevant background (i.e. cell cycle, DNA replication and cancer), and in experimental design and strategic multidisciplinary approaches.
Together, this project will provide the student with a body of work suitable for a high-quality thesis, a high impact publication, and an invaluable interdisciplinary skill set, thus making them extremely competitive for posts in either academic institutions or the biotech/pharma sector.
1. Nelson L, Tighe A, Golder A, Littler S, Bakker B, Murtuza Baker S, Donaldson I, D.C. S, Desai S, Winter-Roach B, Edmondson RJ, Clamp A, Jayson G, Morgan RD, Hayes A, Foijer F and Taylor SS. "A living biobank of ovarian cancer ex vivo modesl reveals profound mitotic heterogeneity". Under revision at Nature Comms.
2. Pillay N, Tighe A, Bah N, Nelson L, Golder A, Littler S, James DI, Ogilvie DJ, Bakker B, D.C. S, Foijer F, Jackson DA and Taylor SS. (2019) "DNA replication stress vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors". Cancer Cell. 35:519-533.e8.
3. Paige, JS, Wu, KY, and Jaffrey, SR. (2011) “RNA mimics of green fluorescent protein”. Science 333:642-6.
4. Strack, RL, Song, W, and Jaffrey, SR. (2014) “Using Spinach-based sensors for fluorescence imaging of intracellular metabolites and proteins in living bacteria”. Nat Protoc 9:146-55.
5. Truong L, Ferré-D’Amaré AR. (2019) “From fluorescent proteins to fluorogenic RNAs: tools for imaging cellular macromolecules”. Protein Sci. 2019 Apr 24. doi: 10.1002/pro.3632

• Taylor lab website - http://www.bub1.com
• Townsend lab website - https://www.research.manchester.ac.uk/portal/paul.townsend.html
• MCRC Gynae cancer website - http://www.mcrc.manchester.ac.uk/Our-Research/Disease-Sites/Gynaecology
• Manchester Cancer Research Centre - http://www.mcrc.manchester.ac.uk
• Aptamer Group Website - http://www.aptamergroup.co.uk

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This is a CASE studentship in partnership with Aptamer Group and will be funded under the MRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Supervisor to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found here View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Nelson L, Tighe A, Golder A, Littler S, Bakker B, Murtuza Baker S, Donaldson I, D.C. S, Desai S, Winter-Roach B, Edmondson RJ, Clamp A, Jayson G, Morgan RD, Hayes A, Foijer F and Taylor SS. "A living biobank of ovarian cancer ex vivo modesl reveals profound mitotic heterogeneity". Under revision at Nature Comms.
Recent, relevant and high impact manuscript, describing the ovarian cancer models available for this proposed project.
2. Barnes, ET, Bunka DH, Tolly A and Townsend PA. “Development of Novel Aptamer Technology for stratifying and detecting prostate cancer stage”. Under preparation.
Recent, relevant and high impact manuscript, describing the design generation, and use of novel aptamers for use in interrogating prostate cancer biology from the Taylor lab collaborating with Aptamer Group.
3. Pillay N, Tighe A, Bah N, Nelson L, Golder A, Littler S, James DI, Ogilvie DJ, Bakker B, D.C. S, Foijer F, Jackson DA and Taylor SS. (2019) "DNA replication stress vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors". Cancer Cell. 35:519-533.e8.
Recent, relevant and high impact publication, describing a novel PARG inhibitor in the context of ovarian cancer.
4. Simoes-Sousa S, Littler S, Thompson S, Minshall P, Whalley H, Bakker B, Belkot K, Moralli D, Bronder D, Tighe A, Spierings D, Bah N, Graham J, Nelson L, Green C, Foijer F, Townsend P and Taylor SS. (2018) "The p38α stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1α". Cell Reports 25:749-760.e6.
Recent collaborative and high impact publication from the Taylor and Townsend labs.
5. Topham C, Tighe A, Ly P, Bennett A, Sloss O, Nelson L, Ridgway RA, Huels D, Littler S, Schandl C, Sun Y, Bechi B, Procter DJ, Sansom OJ, Cleveland DW and Taylor SS. (2015) "MYC Is a Major Determinant of Mitotic Cell Fate". Cancer Cell 28:129-140.
Recent and high impact publication from the Taylor lab.

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