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The potential of elevating Epac2 to modulate glial activation and promote motor neuron regeneration in Amyotrophic Lateral Sclerosis


Project Description

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterised by the selective degeneration and death of motor neurons. Despite several decades of intensive research it remains incurable, and its underlying disease mechanisms are still poorly understood. Medical treatment is mostly limited to alleviation of symptoms and palliative care. It is clear that novel approaches are required to confer effective treatments to this debilitating disease. In addition to motor neuron involvement, recent evidence suggests that there is a complex interplay between motor neurons and neighbouring non-neuronal cells in ALS, such as astrocytes, which have been shown to be critically involved in the survival and demise of motor neurons. Recent work from Dr Huang’s lab has shown that elevation of the second messenger Epac2 not only promotes cortical neuron outgrowth in vitro and enhances axonal regrowth in an ex vivo model of spinal cord injury, but also attenuates in vitro and ex vivo astrocyte activation. Hence, the proposed project will explore the potential of Epac2 activation to modulate astrocyte activation and thereby promote motor neuron survival as a novel approach to treating ALS.

The project will exploit state-of-the-art human cell co-culture techniques, with human induced pluripotent stem cells (iPSCs) from ALS patients, astrocytes from human bone marrow-derived mesenchymal stem cells (MSCs), microfluidic chip culture systems which allow the tripartite divided co-culture of motor neurons, muscle cells and astrocytes, pharmacological and genetic elevation of Epac2, and flow cytometry.

Dr Huang has an internationally recognised track record in studying neuroprotection for traumatic spinal cord injury and peripheral nerve injury (Brain 2007,130:3004-19; Exp Neurol 2013,239:13-27; J Neurosci 2012,32:563-71), as well as in using novel biomaterials and molecules to promote spinal cord repair (Biomaterials 2012,33:59-71; Scientific Reports 2017,7:1-10; J Neurosci 2019,39:8330-46). Dr Bewick is a world-leading expert in neuromuscular research, with >30 years’ experience. His interests centre on understanding how appropriate nerve-muscle connections are established and maintained, both in motor and sensory systems, and has published significantly in this area (Science, 255:200-203; Neuron, 9:805-813; J Neurosci, 23:9340-9348; PNAS, 107:13515-13519; Inter J Mol Sci, 19:1936; Nature Comm, 7:1-15; J Anatomy, 227:194-213; Phil Trans R Soc B, 373:20170327).

APPLICATION PROCEDURE:
This project is advertised in relation to the research areas of MEDICAL SCIENCES. 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. Applicants are limited to applying for a maximum of 3 applications for funded projects. Any further applications received will be automatically withdrawn.


Funding Notes

This project is funded by a University of Aberdeen Elphinstone Scholarship. An Elphinstone Scholarship covers the cost of tuition fees only, whether home, EU or overseas.

For details of fees: View Website

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

• Yamanaka and Komine, 2018, Neurosci Res 126:31-38.

• Guijarro Belmar et al., 2019, J Neurosci 39:8330-46.

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