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

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 Firstly, I thank God for giving me the strength to persevere and successfully complete this chapter of my life.I would like to express my sincerest gratitude to many people for their support and encouragement throughout my studies. I would like to start by thanking and expressing my immeasurable amount of gratitude to my supervisor, Dr. Patrice D. Smith. Anytime I was uncertain how to proceed, her door was always open; she always answered every question with a smile. Her guidance and support helped me build confidence in myself and made me a better researcher. It was a privilege to work under Dr. Smith's guidance and the completion of this thesis is a testament to her endless patience and constant encouragement. I would like to thank my thesis committee members, Dr. Hayley and Dr.Hildebrand, for their time, insight into my thesis and for their continued support. I would like to express my sincere appreciation to Dr.