About the Project
We are interested in combining bioengineering, advanced imaging techniques and stem-cell modelling to obtain novel insights into neurodegeneration. By creating novel "neural-circuitry-on-a-chip" platforms we aim to shed light on how the nervous system works in health and disease, and to tackle important questions in the field of neurobiology and neurodegenerative disorders, pushing the edge of what is currently achievable with stem cell modelling. In particular, the questions of length dependent vulnerability of motor neurones (MNs) in amyotrophic lateral sclerosis (ALS), and how specific changes related to extremely long axons can present a molecular bottlenecks for neurons, are important and cannot at present be systematically addressed with current in vitro paradigms.
ALS is an incurable disease that causes death within 3 to 5 years from diagnosis, and that mainly targets MNs. MNs are the longest neurons in our bodies, and are inserted into ordered circuits designed for long range connectivity between the brain and the muscle system. Several lines of evidence point the possibility that this particular characteristic makes MNs particularly vulnerable in ALS. However, current stem cell based modelling cannot recapitulate these characteristics.
This project aims to create a novel bioengineered platform, LAMBDA, in which length-dependent vulnerability and changes in axonal transport and local translation can be investigated directly in vitro using patient-derived stem cells, pushing stem cell modelling efforts for ALS closer to a better understanding of the disease and increasing their translational potential. During the project we will employ micro-fabrication techniques, high-content imaging, optogenetics, genome editing techniques and advanced molecular imaging to engineer a circuit arrangement that closely mimics the spinal cord characteristics and that can better recapitulate how disease like ALS target MNs. The results obtained will shed light how ALS causing mutations affect axonal transport, rate of distal mRNA translation and neuronal activity at different axonal lengths, and they determine vulnerability and response to stressors in both control and patient derived MNs. This is a highly interdisciplinary project that offers opportunities to interact across different labs and institutions. The student will receive training in stem cell culture and directed differentiation, microfabrication and bio-functionalisation of bioengineered substrates, soft-lithography, and advanced microscopy techniques and molecular imaging.
Person specification.
A successful candidate will have (or be expecting) a degree in a biological or medical sciences and a good understanding of the bases neurobiology and cellular biology. Students with an engineering or physical science may also be considered depending on the level of experience with biological systems. A proven track record in hands-on laboratory work and proficiency in cell-culture techniques will be highly beneficial. Experiences with molecular imaging or bioengineering techniques are also desirable. Being able to work in a dynamic, interdisciplinary environment is essential. Most importantly, the applicant must be highly motivated and capable of working well in a multi-disciplinary research environment.
Research training.
iPSC/Stem cell differentiation, optogenetics, bioengineering, microscopy, neurobiology and molecular biology.
Please note: Applicants must include the project reference number (2018/DI/02) in the ’Research proposal’ and ’Funding (point 5)’ sections of the application.
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