Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2022 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).
This 4-year PhD studentship is offered in Dr Michael Devine's Group based at the Francis Crick Institute (the Crick).
Fundamental to the success of complex multicellular life has been the evolution of the nervous system, because this enables organisms to respond to stimuli in a rapid and coordinated manner. However, nervous systems are expensive: the human brain comprises just 2% of the body's mass, but utilises 20% of the body's energy. This energy is needed to power synapses, where neurons communicate with each other. In order to process information, synaptic activity varies from one moment to another. Therefore, neuronal energy usage varies across individual neurons, and at individual synapses over time. Additionally, neurotransmitter release at synapses is triggered by a rapid influx of Ca2+ ions in response to incoming action potentials, so synapses must quickly clear Ca2+ to stop neurotransmission and prepare for future release events. A key question in the field is how do neurons meet such spatiotemporally diverse energy and Ca2+ buffering requirements?
Mitochondria are ideally suited to help, because they are a potent source of ATP (via oxidative phosphorylation) and they avidly take up local Ca2+ via the mitochondrial calcium uniporter. Crucially, they are also mobile: they move within neurons to where they are most needed. They frequently localise to presynapses where they support sustained synaptic transmission via provision of ATP [1]. But recently we and others have shown that presynaptic mitochondria can lower neurotransmission via buffering local Ca2+ [2]. So mitochondria play a dual role in shaping synaptic activity, which has potentially far reaching implications for diseases featuring a mismatch between energy demand and supply (such as stroke and epilepsy), and our recent studies suggest that this delicate balance of Ca2+ regulation and ATP provision breaks down in models of Parkinson's disease — a neurodegenerative disorder that currently has no cure.
The goal of the lab is to unpick the molecular mechanisms by which mitochondria govern synaptic transmission, and how this changes in neurological and psychiatric disease, with the aim of opening up new therapeutic avenues for these disorders.
We are also interested in whether all mitochondria within a neuron are identical, or whether specific subtypes of mitochondria exist in different subcellular locations. If the latter, are certain mitochondrial subtypes susceptible to disease? To tackle this, we have been using a novel nanotweezer to directly ‘biopsy’ and then compare individual mitochondria from different locations within live neurons, enabling us to study single mitochondria in unprecedented detail [3].
Potential projects in the lab include but are not limited to:
(1) establishing the role of presynaptic mitchondria in regulating synapses in midbrain dopaminergic neurons (the neurons most vulnerable in Parkinson’s) and whether they could contribute to the ‘silencing’ of these synapses [4],
(2) how mitochondria localise and anchor at presynapses in order to appropriately buffer Ca2+,
(3) how presynaptic mitochondria interact with local endoplasmic reticulum or lysosomes, which can also buffer Ca2+ thereby tuning synaptic activity [5],
(4) uncovering mechanisms enabling mitochondrial transfer between neurons and astrocytes,
(5) studying subcellular mitochondrial heterogeneity within neurons via single mitochondrial biopsy.
Techniques include primary neuronal and slice culture, iPSC culture and neuronal differentiation, live synaptic imaging, 3D electron and superresolution microscopy, microfluidics, genomic and transcriptomic analysis, and nanobiopsy. We also collaborate widely with other labs at the Crick and UCL, King's and Imperial to adopt new approaches to address research questions.
Candidate background
Candidates would benefit from joining a recently established lab, and so can receive as much hands-on supervision as required. The specific project would be co-developed in discussion with the supervisor, dependent upon the candidate’s interests and background. Experience of cell biology and live cell imaging are useful, but are not essential since ample training opportunities are available. The main attributes would be a willingness to learn, and curiosity for the problems that we are working on. Please feel free to contact me to discuss any of the above.
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.
APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘INSTITUTION WEBSITE’ LINK ABOVE) BY 12:00 (NOON) 11 November 2021. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.