Details
We are looking for a highly motivated graduate with a strong interest in nucleic acid-processing enzymes and mRNA therapeutics for a 4-year full-time BBSRC iCASE studentship in partnership with AstraZeneca. The studentship will be based within the teams of Dr Barbara Ciani (Chemistry), Prof Jane Grasby (Chemistry), Dr Izzy Jayasinghe (Biosciences), with a minimum placement of 6 months at AstraZeneca (Cambridge) to provide exposure to both academic and industrial environments.
Double-stranded RNA (dsRNA) impurities are a barrier for therapeutic use of mRNAs. DsRNA structures, present in RNA therapeutics, can induce a strong inflammatory response that limits the drug’s efficacy, and this is especially true for therapeutics for chronic diseases. There is an increasing interest from regulatory agencies to demonstrate adequate dsRNA level control and current immunoassays used for dsRNA quantification show limited correlation between dsRNA structure detection and immunogenicity.
In this project, the student will repurpose natural dsRNA sensors to establish an in-vitro/in-vivo assay for the quantitation of immunogenic dsRNA. The student will be trained on techniques and approaches to address structure-activity relationships of nucleic acid processing enzymes combining chemical biology and biophysical chemistry methods in solution with advanced imaging methods to quantify innate immune signalling activation in cells.
About the DTP
This studentship is offered as part of the White Rose BBSRC Doctoral Training Partnership (DTP) in Mechanistic Biology, which brings together the research of the world-class molecular and cellular bioscience centres at the White Rose universities of Leeds, Sheffield and York.
Our mission is to train excellent bio-scientists who understand how living systems work and can innovate to address global challenges, such as the impact of climate change, a healthier old age, sustainable food production, land use and energy production.
What is on offer?
This is an i-CASE (industry partnership) studentship for entry in October 2024.
Join us and you will receive a 4-year, funded PhD programme of research and skills training, with cross-disciplinary supervision, plus a structured programme of cohort-wide training and networking events. A highlight is the annual symposium, which is planned and delivered by students.
A unique part of your training will be a fully-funded placement of at least 3 months with the industry partner.
How to apply – Expression of Interest
Students may apply for up to three projects anywhere in the Doctoral Training Partnership (DTP). Applications will be to the DTP centrally, using an online Expression of Interest (EoI). The EoI will include:
§ CV information; not submitted separately
§ Equality, Diversity and Inclusion (EDI) data
§ Names of two referees
Deadline for EoIs is midnight Sunday 7th January 2024.
Submit EoIs using this link: https://leeds.onlinesurveys.ac.uk/white-rose-bbsrc-dtp-expression-of-interest-form
Shortlisted candidates will be required to make formal applications to the Graduate School at each institution, supplying the necessary paperwork.
Details of the interview process will be decided by the academic and industry partners for this project
Website: https://www.whiterose-mechanisticbiology-dtp.ac.uk/
Funding Notes
Appointed candidates will be fully funded for 4 years:
Tax-free annual stipend at the UKRI rate. The rate for starters in 2023/24 was £18,622. (Rates for 2024/25 starters are not yet available).
UKRI tuition fees – These are paid directly to the host institution.
A Research Training and Support Grant
An allowance for Fieldwork/Conference/Travel
A fully funded placement with the industry partner
The industry partner may also make an additional contribution to the research costs and, in some cases, they may offer an uplift to the stipend.
References
1. D Thaller, D Tong, CJ Marklew, S Borah, B Ciani, P Lusk. Direct PA-binding by Chm7 is required for nuclear envelope surveillance at herniations. J Cell Biol. 2021;220(3): e202004222.
2. A Booth, CJ Marklew, B Ciani*, PA Beales*. in-vitro membrane remodelling by ESCRT-II/ESCRT-III is regulated by negative feedback from membrane tension. iScience. 2019 15, 173-184.
3. Willan J*, Cleasby AJ*, Flores-Rodriguez N*, Stefani F, Rinaldo C, Pisciottani A, Grant E, Woodman P, Bryant HE & Ciani B. ESCRT-III is necessary for the integrity of the nuclear
envelope in micronuclei but is aberrant at ruptured micronuclear envelopes generating damage. Oncogenesis. 8(5):29, 2019.
4. Mark J Thompson, Victoria Gotham, Barbara Ciani and Jane A Grasby (2018). A conserved loop-wedge motif moderates reaction site search and recognition by FEN1. Nucleic Acids Research. 46, 7858-7872.
*co-corresponding authors
1. Hunter AK, Rezvani K, Aspelund MT, Xi G, Gadre D, Linke T, Cai K, Mulagapati SHR, Witkos T. (2022) Identification of compendial nonionic detergents for the replacement of Triton X-100 in bioprocessing. Biotechnol Prog., 38(2):e3235.
2. Wehrle A, Witkos TM, Unger S, Schneider J, Follit JA, Hermann J, Welting T, Fano V, Hietala M, Vatanavicharn N, Schoner K, Spranger J, Schmidts M, Zabel B, Pazour GJ, Bloch-Zupan A, Nishimura G, Superti-Furga A, Lowe M, Lausch E. (2019) Hypomorphic mutations of TRIP11 cause odontochondrodysplasia. JCI Insight, 4(3):e124701.
3. Witkos TM, Chan WL, Joensuu M, Rhiel M, Pallister E, Thomas-Oates J, Mould AP, Mironov AA, Biot C, Guerardel Y, Morelle W, Ungar D, Wieland FT, Jokitalo E, Tassabehji M, Kornak U, Lowe M. GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation. (2019) Nat Commun., Jan 10;10(1):127
4. Witkos TM, Krzyzosiak WJ, Fiszer A, Koscianska E. (2018) A potential role of extended simple sequence repeats in competing endogenous RNA crosstalk. RNA Biol., 15(11):1399-1409.
1. Sally B Morton, L David Finger, R van der Sluijs, William D Mulcrone, Michael J Hodskinson, Christopher L Millington, C Vanhinsbergh, KL Patel, Michael J Dickman, Puck Knipscheer , Jane A Grasby and David M Williams (2023). Efficient synthesis of DNA duplexes containing reduced acetaldehyde interstrand cross-links. Journal of the American Chemical Society, 145(2), 953-959.
2. Mark J Thompson, Victoria Gotham, Barbara Ciani and Jane A Grasby (2018). A conserved loop-wedge motif moderates reaction site search and recognition by FEN1. Nucleic Acids Research. 46, 7858-7872.
3. Ian A Bennet, L David Finger, Nicola J Baxter, Benjamin Ambrose, Andrea M Hounslow, Mark J Thompson, Jack C Exell, Nur Nazihah B Md Shahari, Timothy D Craggs, Jonathan P Waltho, Jane A Grasby (2018). Regional conformational flexibility couples substrate specificity and scissile phosphate diester selectivity in human flap endonuclease 1. Nucleic Acids Research 46, 5618–5633.
4. Steven J. Shaw, L. David Finger, and Jane A. Grasby (2017). Human Exonuclease 1 Threads 5′-Flap Substrates through Its Helical Arch. Biochemistry, 56, 3704-3707.
1. Sheard, T.M.D. #, Hurley, M.E. #, White, E., Colyer, J., Norman, R., Pervolaraki, E., Narayanasamy, K., Hou, Y., Kirton, H., Yang, Z., Hunter, L. #, Shim, J., Clowsley, A.H., Smith, A.J., Baddeley, D., Soeller, C., Colman, M.A., Jayasinghe, I.; Three-dimensional and chemical mapping of intracellular signalling nanodomains in health and disease with enhanced expansion microscopy. ACS Nano. 2019. DOI: 10.1021/acsnano.8b08742
2. Jayasinghe, I.*, Clowsley, A.H.* #, Green, E., Harrison, C. #, Lutz, T.#, Baddeley, D., di Michele, L., Soeller, C. True molecular scale visualisation of variable clustering properties of ryanodine receptors. Cell Reports. 2018; 22(2) 557-567. * Equal contributors
3. Hurley, M.E.H. #, White, E., Sheard, T.M.D. #, Kirton, H.M., Steele, D., Jayasinghe, I. Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease. Open Biology. 2023. 13: 230045230045
4. Suen, K. Sheard. T.M.D., Lin, C., Jayasinghe, I. Ladbury, J., Expansion microscopy reveals subdomains in C. elegans germ granules. Life Science Alliance. 2023. DOI: 10.26508/lsa.202201650
# postgraduate co-authors