The accumulation of misfolded or otherwise non-native proteins in the cell is linked to an array of ageing-related disorders, including neurodegenerative diseases and cancers1. Healthy cells limit the toxicity of misfolded proteins by promoting their clearance and maintaining proteome balance (“proteostasis”). The importance of discovering the two major pathways for misfolded protein clearance—the ubiquitin-proteasome system and autophagy—was highlighted by Nobel Prizes in 2004 and 2016, respectively. How they are integrated to maintain proteostasis, however, is poorly understood. Addressing this question is the central scientific driver of the Samant Lab at the Babraham Institute. Given that loss of proteostasis—including decline in both proteasomal and autophagic degradation—is a major hallmark of ageing, investigating the co-ordination between protein clearance pathways in young and aged cells will provide insights into improving health and wellbeing across the lifecourse.
We hypothesize that the plasticity of protein clearance pathways (i.e., the ability of misfolded proteins to be re-routed to alternative pathways if one is overwhelmed) declines during ageing, thereby driving ageing-related proteostasis decline. This project will employ a parallel proteomics approach (e.g., mass spectrometry-based ubiquitin remnant profiling combined with ubiquitin linkage-specific enrichment strategies) to test the plasticity of protein clearance pathways in mammalian cell culture models of ageing, using inhibition of the molecular chaperone Heat Shock Protein 90 (HSP90) as an inducer of proteotoxic stress. HSP90 is responsible for the activity and stability of around 300 “clients”, which include many disease-associated signalling proteins. Pharmacologic modulators of HSP90 are being pursued in the clinic, as HSP90 levels decline during ageing and neurodegeneration, but increase in cancers. Importantly, HSP90 inhibition triggers the clearance of its destabilized clients through both the proteasome and autophagy2. The structural and functional determinants of which pathway is employed are currently being defined in the Samant Lab using unique lab-developed tools and assays2,3.
The PhD student will build upon this work, using pharmacologic modulators of each pathway (e.g., clinically-approved inhibitors of the proteasome and autophagy) together with CRISPR/Cas9-based gene editing of individual components of the proteostasis machinery to unravel: (1) the extent to which HSP90 clients that are normally targeted to the proteasome can be re-routed to autophagy (and vice-versa); and (2) how this re-routing goes astray during ageing. We will also manipulate the ubiquitination of clients through recent advances in chemical biology, such as ubiquitin linkage mutants, synthetic ubiquitin attachment strategies, and recently developed targeted degraders (e.g., PROTACs), to test more directly whether cells can be coerced into clearing misfolded proteins—perhaps providing proofs-of-concept for therapeutic interventions targeting such proteins and pathways.
This cross-disciplinary project will combine cutting-edge cell and molecular biology expertise and build an excellent foundation for a career in the biosciences, with an emphasis on proteomics, bioinformatics, and cell-based assays. As pharmacologic modulators of HSP90, the ubiquitin-proteasome system, and autophagy are all being tested clinically for cancers and various neurodegenerative diseases—not to mention the growing therapeutic interest in PROTACs for a host of pathologies—expected results from this project will have broad-spanning implications for both mechanistic biology and translational biomedical research.
cell biology/development; molecular biology
PhD Student Opportunities 2020
The Babraham Institute is a world-leader in fundamental biological research investigating the systems that underpin development and healthy ageing. It is a recognised postgraduate University Partner Institute of the University of Cambridge. Starting October 2020 a number of Studentships will be available leading to a University of Cambridge PhD degree. These studentships can be awarded for up to 3.5 or 4 years. In addition, studentships funded by a range of University of Cambridge funding schemes can be held at the Babraham Institute (see the student pages of our website here - https://www.babraham.ac.uk/vacancies-training/phd-programme
) and for specific funding sources for EU and overseas graduate student at Cambridge, please visit here - http://www.graduate.study.cam.ac.uk/finance/funding
Please see our website (http://www.babraham.ac.uk/
) and the BBSRC website (https://bbsrc.ukri.org/skills/
) for details of eligibility and funding. Non-EU nationals must find funding for academic fees and personal support. In cases where applicants must find their own funding, we will require evidence that the level of funding is at least equal to the standard BBSRC/MRC PhD funding package.
Students will join a thriving scientific community situated on an attractive parkland campus near Cambridge. Our 60 students are all members of Cambridge Colleges and participate fully in University social and academic life - https://www.gradschl.lifesci.cam.ac.uk/
Details of our interactive scientific programmes can be found on the Babraham Institute website - http://www.babraham.ac.uk/
As a student at the Institute, you will have access to all of our outstanding science facilities (https://www.babraham.ac.uk/science-services
), each one providing specialist equipment and expertise to support key research techniques and technologies. In addition to our animal facility, imaging, chemical synthesis and mass spectrometry we are able to offer transgenics services, flow cytometry, lipidomics, next-generation sequencing and a highly specialist team of bioinformaticians. In addition, several of our facilities operate training programmes to help you develop your own skills in these key research areas. The Institute’s research groups also incorporate a selection of other cutting-edge specialties including single-cell and multiomics approaches.
All applications for PhD Studentships at the Babraham Institute need to be made using the University of Cambridge Graduate Application Portal regardless of funding source: https://www.graduate.study.cam.ac.uk/
Please see the “Applying for a PhD” pages on our website for further details of the application process: https://www.babraham.ac.uk/vacancies-training/phd-programme/phd-applications
Short-listed applicants will be invited to attend our Institute Graduate Open Day on Wednesday 22nd January 2020 for a series of interviews. This will give applicants an opportunity to meet Group Leaders and their research groups, as well as receiving a tour of our research facilities. Reasonable travel expenses will be paid to those invited.
Students will not be able to take up an award unless they meet all University eligibility criteria and are successful in securing admission to the University. In addition, they will not be able to apply for a visa (if needed) until they hold an unconditional offer from the University.
The deadline for submission of applications via the Graduate Application Portal is 3rd December 2019. Incomplete applications will not be considered.
If you would like more information, or have any questions not answered on our website or the University of Cambridge Graduate Admission site, please contact us:
Graduate Studies Assistant, Babraham Institute, Babraham Research Campus, CB22 3AT or email to [email protected]
An Equal opportunities employer. An Institute supported by the Biotechnology and Biological Sciences Research Council http://www.babraham.ac.uk
1. Sontag, E. M., Samant, R. S. & Frydman, J. Annu. Rev. Biochem. 86, 97–122 (2017).
2. Samant, R. S., Clarke, P. A. & Workman, P. Proc. Natl. Acad. Sci. U. S. A. 111, 6834–6839 2014).
3. Samant, R. S., Livingston, C. M., Sontag, E. M. & Frydman, J. Nature 563, 407–411 (2018).