Optic nerve damage and regeneration failure are major features of trauma, glaucoma, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. We recently made a set of exciting discoveries showing that conditional deletion of PTEN (phosphatase and tensin homolog) or TSC1 (tuberous sclerosis 1) in adult retinal ganglion cells (RGCs) enabled robust long-distance axon regeneration after optic nerve injury (1), thereby establishing the first genetically defined mouse models with reproducible and robust optic nerve regeneration in the adult. The objectives of this proposed study are two-fold: to further explore the underlying mechanisms permitting axon regeneration in PTEN/TSC1 deleted neurons and to determine whether the regenerating axons could re-form synaptic connections and restore lost functions. We expect that the knowledge obtained from these studies can be translated into novel therapeutic strategies to promote functional recovery in patients with optic nerve injury, glaucoma and other types of eye diseases.
Our recent findings that PTEN or TSC1 knockout promotes robust optic nerve regeneration provide an unprecedented opportunity to study the cellular and molecular mechanisms enabling adult RGC axons to regenerate. Furthermore, the availability of these genetically defined models allows us, for the first time, to explore post-regeneration events such as axon pathfinding, targeting, synaptic reconnection and behavioral recovery in vivo. These studies should provide much needed insights into developing therapeutic strategies to promote axon regeneration and vision restoration after head trauma, glaucoma and other eye-related diseases.
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|Duan, Xin; Qiao, Mu; Bei, Fengfeng et al. (2015) Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 85:1244-56|
|Belin, Stephane; Nawabi, Homaira; Wang, Chen et al. (2015) Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics. Neuron 86:1000-1014|
|Belin, Stephane; Norsworthy, Michael; He, Zhigang (2014) Independent control of aging and axon regeneration. Cell Metab 19:354-6|
|Lu, Yi; Belin, Stéphane; He, Zhigang (2014) Signaling regulations of neuronal regenerative ability. Curr Opin Neurobiol 27:135-42|
|O'Donovan, Kevin J; Ma, Kaijie; Guo, Hengchang et al. (2014) B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS. J Exp Med 211:801-14|
|Hu, Yang; Park, Kevin K; Yang, Liu et al. (2012) Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron 73:445-52|
|Sun, Fang; Park, Kevin K; Belin, Stephane et al. (2011) Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480:372-5|