About the Project
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 2023 a Research Studentship will be available leading to a University of Cambridge PhD degree in the laboratory of Dr Della David. This studentship can be awarded for up to 4 years.
Details of our interactive scientific programmes can be found on www.babraham.ac.uk. As a student at the Institute, you will have access to all of our outstanding science facilities, each one providing specialist equipment and expertise to support key research techniques and technologies.
Project Details
Stress granules are transient biomolecular condensates of proteins and RNAs in the cell. These membraneless microcompartments are normally highly dynamic structures that form in response to environmental stress to protect the cell and then rapidly disassemble after the stress has been removed. Recent advances show that stress granules assemble into biomolecular condensates by liquid-liquid phase separation (LLPS). This process of protein de-mixing in a manner similar to oil and water separating in a salad dressing has emerged as a ground-breaking concept supporting intracellular organization. In vitro data and evidence from neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) show that biomolecular condensates can undergo an aberrant phase transition from liquid into solid aggregated structures.
Recently our group discovered that stress granule proteins form solid aggregates in C. elegans during the course of ageing in the absence of disease processes1,2. C. elegans, a small 1 mm long nematode, is an outstanding model for ageing research due to its rapid ageing and well-defined deteriorations in physiological functions. Basic molecular mechanisms such as protein quality control are well conserved between C. elegans and higher organisms. Our lab has generated several C. elegans transgenic models with key fluorescent-labelled stress granule protein markers. The aggregation of these markers reveals that the capacity to undergo LLPS becomes a liability during ageing. We showed that long-lived animals with reduced insulin / IGF-1 daf-2 receptor signaling prioritise the maintenance of dynamic stress granule proteins, mainly through activation of the transcription factor HSF-11. We successfully demonstrated that lipoic acid, a compound found to dissolve stress granules in cell culture, is also active in vivo and strongly prevents stress granule protein aggregation3. Using these models will be a powerful way to gain further understanding into the aberrant liquid-to-solid transition during ageing.
Building on our previous findings and expertise, the goal of the PhD project will be to use C. elegans:
(1) to perform an in-depth characterization of liquid-to-solid phase transition during ageing.
(2) to identify molecular mechanisms that inhibit aberrant stress granule assembly and accelerate disassembly.
(3) to evaluate how mechanisms to keep stress granules dynamic influence the stress response and the organism’s fitness during ageing.
The project will involve using state of the art microscopy analysis, mass spectrometry, screening methods, and assays measuring functional decline in ageing C. elegans.
We expect mechanisms discovered to prevent stress granule protein aggregation will restore stress resistance and contribute to healthy ageing. These mechanisms could also have protective effects in neurodegenerative diseases such as ALS.
Keywords: Ageing, Protein aggregation, Stress granules, C. elegans, Proteomics
If you would like more information, or have any questions not answered on our website or the University of Cambridge Graduate Application Portal, please contact us:
The Graduate Studies Tutor, Babraham Hall, Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT via email [Email Address Removed] .
An Equal opportunities employer. An Institute supported by the Biotechnology and Biological Sciences Research Council.
All applications for PhD Studentships at the Babraham Institute need to be made using the University of Cambridge Graduate Application Portal ( https://www.postgraduate.study.cam.ac.uk/application-process/applicant-portal-and-self-service-account ) regardless of funding source. Please see the “Applying for a PhD” pages on our website ( https://www.babraham.ac.uk/) for further details of the application process.
We hope to be able to invite short-listed applicants to attend our Institute for a series of interviews shortly after the application deadline. This will give applicants an opportunity to meet their Group Leader and their research group, 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 1st December 2022. Incomplete applications will not be considered.
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