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Cell growth signalling in space: How does mTOR kinase communicate with diverse cellular compartments?


School of Medicine, Medical Sciences & Nutrition

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Dr Riko Hatakeyama , Prof A Donaldson No more applications being accepted Funded PhD Project (UK Students Only)
Aberdeen United Kingdom Biochemistry Bioinformatics Cell Biology Genetics Microbiology Molecular Biology

About the Project

This 4-year PhD project addresses the fundamental question of how individual cells sense and respond to environmental changes. A particular focus is on the signalling mechanisms to orchestrate various biological processes occurring at diverse subcellular locations/compartments (“organelles”). Because improper cellular responses cause serious diseases including cancer, diabetes and Alzheimer’s, understanding the signalling process will contribute to develop therapeutic strategies against these diseases.

OBJECTIVES

This project will address how the Target of Rapamycin Complex 1 (TORC1, or mTORC1) kinase, the central regulator of cell growth, receives signals from, and sends signals to, diverse organelles. TORC1 enables cells to properly adapt to the changing environment (nutrient availability, growth factor signals, cellular stresses etc) by tuning numerous biological processes such as DNA transcription, protein synthesis, trafficking and degradation (“autophagy”), and lipid metabolism. The remarkable prevalence of TORC1’s function can be explained by the division of labour between its multiple pools, which we recently demonstrated using budding yeast model (Hatakeyama et al., 2019, Molecular Cell). Specifically, there exist one TORC1 pool localizing to the organelle called endosomes (E-TORC1) while the other to lysosomes (L-TORC1). Each of them regulates distinct processes via phosphorylating distinct proteins. Based on this finding, the PhD project aims to address the following questions:

1. How are E- and L-TORC1 regulated?

2. How does TORC1 signal beyond endosomes and lysosomes?

A long-term goal is to apply the knowledge to better treat cancer, diabetes and neurodegenerative diseases by selectively targeting desired subsets of TORC1 functions.

APPROACHES

This project combines a broad range of techniques in genetics (e.g. genome editing), biochemistry (e.g. protein purification, kinase assay, proteomics), cell biology (e.g. microscopy) and bioinformatics. Our lab uses two model systems: budding yeast and mammalian cultured cells. The yeast system allows swift acquisition of solid data leading to fundamental discoveries. The translational potential of the discoveries will be immediately tested using mammalian cells. Unique to our lab is the molecular tools to specifically measure or manipulate E- and L-TORC1 activities, which allows us to study the two pools separately. Using these experimental tools and bioinformatic approaches, we have identified novel factors (proteins and chemicals) that regulate, or are regulated by, TORC1 at endosomes, lysosomes or other organelles. The underlying molecular mechanisms will be investigated in this project.

ENVIRONMENT

Our lab is situated in the Institute of Medical Sciences (IMS) of the University of Aberdeen. The student will benefit from IMS’s excellent core facilities including various fluorescence and confocal microscopes and mass spectrometers with technical supports. The student will be trained through a close supervision by the freshly appointed group leader. The student will frequently communicate with neighbouring labs in IMS through regular joint lab meetings and learn a broad range of subjects in cell biology, genetics, and cancer biology. In addition, there will be opportunities to discuss the translational aspect of the project with experts in cancer, diabetes and neurological research across IMS. Moreover, the student will have chances to interact with national and international collaborators in Europe (including UK, Switzerland, Germany, Belgium and Spain), USA and Japan, to expand his/her professional network for future career development.

APPLICATION PROCEDURE:

Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.


Funding Notes

This project is part of a competition funded by the School of Medicine, Medical Sciences and Nutrition for a 4 year PhD programme. Full funding is available to UK candidates only. All other candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £16,625 per annum).
Candidates should have (or expect to achieve) a minimum of a First Class Honours degree in a relevant subject. Applicants with a minimum of a 2:1 Honours degree may be considered provided they have a Distinction at Masters level.

References

Hatakeyama R, Péli-Gulli MP, Hu Z, Jaquenoud M, Garcia Osuna GM, Sardu A, Dengjel J, De Virgilio C. (2019) Spatially distinct pools of TORC1 balance protein homeostasis. Molecular Cell. 73:325-338.
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