A 3.5-year PhD studentship is available to study the molecular mechanism of mTORC1 signalling in autophagy, cellular ageing and age-related diseases through an interdisciplinary approach of biochemistry, biophysics, X-ray crystallography and cellular biology. It will be based in my lab and will include an extended rotation period with Dr Viktor Korolchuk, in Newcastle. The details of the project are as follows:
The molecular mechanism of mTORC1 signalling in autophagy, cellular ageing and age-related diseases through biochemistry, structural biology and cellular biology
The mammalian ‘Target of Rapamycin Complex’ (mTORC1) controls cellular growth and proliferation in response to nutrient availability. This fundamental cellular signalling mechanism permits growth of cells when sufficient nutrients (particularly amino acids) are present, and is thereby essential for the growth of our cells and tissues (Bar-Peled and Sabatini 2014, Trends Cell Biol). However, this same mechanism can become detrimental during ageing, when TORC1 signalling contributes to organismal decline and age-related diseases such as Alzheimer’s disease, heart disease and cancer (Laplante and Sabatini 2012, Cell). Indeed, the relevance of mTORC1 signalling to ageing has been highlighted by interventions such as calorie restriction or rapamycin treatment, which suppress this pathway and have been shown to extend life-span and prevent age-related illnesses. In such cases, nutrient starvation or direct inhibition trigger autophagy, a process of self-degradation in which damaged cellular material is removed and recycled to allow the repair of tissues.
This PhD project aims to understand how amino acids are recognised by the mTORC1 machinery and how this results in activation of the pathway. We have identified a novel mechanism of mTORC1 activation by amino acids which act by blocking the inhibition of master mTORC1 activator Rheb by negative regulator TSC2 (Carroll et al 2016, eLife). This simple signalling pathway has numerous possibilities for exploitation in the new therapeutics that may slow or delay the development of age-related diseases, and so this PhD project aims to uncover the precise molecular mechanism whereby this process is achieved. We will use a combination of biochemical, structural biology and cellular biology methods to determine the atomic resolution structure of the TSC2-Rheb complex, the basis of its inhibition by amino acids, and the molecular mechanism whereby Rheb activates mTORC1 within the cell.
This interdisciplinary PhD project will be based in the laboratories of Dr Owen Davies and Dr Viktor Korolchuk in the Institute of Cell and Molecular Biosciences, Newcastle University, and will provide an unprecedented level of training
in a wide variety of techniques. These will include molecular cloning, recombinant protein _expression_ and purification, biophysical methods (including SEC-MALS, SEC-SAXS, ITC, MST, CD and EM) and X-ray crystallography, in addition to mammalian cell culture,
genetic modification of cell lines, immunofluorescence and flow cytometry.
This project will provide a crucial step towards being able to manipulate mTORC1 and its deregulation in ageing. We envisage that this will catalyse future translational research into therapeutic targeting of age-related disease, which will have clear and fundamental implications for medicine.
MRC DiMeN DTP studentships are funded for 3.5 years and include:
Tax-free maintenance grant set at the UK Research Council's national rate.
Full payment of tuition fees at the Home/EU rate.
A Research Training Support Grant to support your research studies.
Successful Home students will receive a full studentship. EU students will be considered for a full studentship/fees only support depending on the excellence of their qualifications and their employment/residency status.
For more information about the PhD programme and to apply please visit the DiMeN website:
Closing date for applications
6th January 2017
Please also feel free to contact me directly with any further queries.
Dr Owen Davies
Wellcome Trust and Royal Society Sir Henry Dale Fellow
Institute for Cell and Molecular Biosciences
Faculty of Medical Sciences
Telephone: +44 (0)191 208 7371