Exploring Novel Molecular Approaches to Promote Repair of the Damaged Nervous System: A Role for Neuronal Pentraxin 2

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Creator: 

Shanmugalingam, Ushananthini

Date: 

2021

Abstract: 

The mammalian central nervous system (CNS) does not spontaneously regenerate, thereby limiting functional recovery following numerous CNS injuries. Neural repair is restricted due to both the inhibitory extracellular environment post-injury and the limited intrinsic capabilities of adult neurons. The visual system, including retinal ganglion cells (RGCs), and their axons, the optic nerve, is widely used as a model to study molecular mechanisms associated with neuroprotection and regeneration following CNS injury. Many potential therapeutic strategies have been discovered using this model with variable success in terms of promoting axon regeneration. Recent work has suggested that modulating neural activity can protect neurons and promote axon regeneration after injury; however, this area of research remains in its infancy. Activity-dependent signalling molecules, such as neuronal pentraxin 2 (NP2), have been suggested as critical modulators of neuroplasticity but have not been previously implicated in CNS neuroprotection or axon regeneration. This thesis examined the role of NP2 in protecting RGCs and promoting axon regeneration, using in vitro, ex vivo and in vivo (optic nerve injury) techniques. Given that previous work has supported the notion that RGCs lose intrinsic capacity for regeneration with age, the developmental expression pattern of NP2 was characterized. Additionally, the impact of NP2 treatment on RGC survival, using an in vitro RGC culture model, was evaluated. Furthermore, the ability of NP2 to enhance RGC neurite outgrowth using both in vitro and ex vivo model systems was examined. To assess the in vivo impact of exogenous NP2 administration on RGC survival and axon regeneration, a well-established optic nerve crush (ONC) model was utilized. The effect of NP2 administration on functional recovery following ONC was also evaluated using electroretinography and visual evoked potentials. Taken together, the results indicated a decline in NP2 protein expression with an increase in age and revealed that treatment with NP2 promotes survival and neurite outgrowth in both embryonic and postnatal RGCs. Furthermore, the data demonstrated that exogenous administration of NP2 promotes RGC survival but does not measurably improve functional outcomes post ONC. Collectively, these results illustrate that NP2 holds potential as a survival-inducing factor.

Subject: 

Neuroscience

Language: 

English

Publisher: 

Carleton University

Thesis Degree Name: 

Doctor of Philosophy: 
Ph.D.

Thesis Degree Level: 

Doctoral

Thesis Degree Discipline: 

Neuroscience

Parent Collection: 

Theses and Dissertations

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