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Title: A novel method of targeting Epac activation to promote spinal cord repair
Author: Guijarro Belmar, Alba
ISNI:       0000 0004 8498 4923
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2019
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Spinal cord injury is a particularly debilitating affliction as it usually results in permanent loss of sensory and motor function, affecting millions of people globally and there are no effective treatments. The challenges for spinal repair include a lack of intrinsic capacity for adult CNS neurons to regrow post-injury and the inhibitory physical and chemical barriers formed at the lesion site. Elevating cAMP levels promotes CNS neuron growth in the presence of growthinhibiting molecules. cAMP's effects on neuron growth is partly mediated by Epac, a guanine nucleotide exchange factor, which has two isoforms, Epac1 and 2 – the latter is predominantly expressed in postnatal-adult neural tissue. Here, it is hypothesized that Epac2 activation will enhance axonal outgrowth after injury. Using in vitro assays, I demonstrated that Epac2 activation using a specific soluble agonist (S-220) significantly enhanced neurite outgrowth of cortical neurons and markedly overcame inhibitory environments in vitro. I further investigated the potential of Epac2 activation in promoting axonal outgrowth using an ex vivo model of spinal cord injury mimicking the post-injury environment in vivo and by delivering S-220 via a selfassembling Fmoc-based hydrogel that has suitable properties for spinal repair. Results herein demonstrate that S-220 significantly enhanced axonal outgrowth across the lesion gaps in the ex vivo model. Furthermore, Epac2 activation profoundly modulated the lesion environment by reducing astrocyte/microglial activation and transforming astrocytes into an elongated morphology that guided outgrowing axons. Finally, two different in vivo rat models of spinal cord injury were used to further demonstrate that the combined treatment enhanced locomotor recovery, reduced the extent of injury and promoted axonal regrowth four weeks after injury. These results demonstrate a promising therapeutic potential of combining Epac2 elevation with hydrogels to promote axon regrowth, inducing beneficial effects on neurons and glia post-injury to facilitate axonal outgrowth and potentially recover function.
Supervisor: Huang, Wenlong ; Shewan, Derryck Sponsor: International Spinal Research Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Spinal cord