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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY021342-01A1
Application #
8105940
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (05))
Program Officer
Agarwal, Neeraj
Project Start
2011-01-01
Project End
2014-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
1
Fiscal Year
2011
Total Cost
$430,834
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Belin, Stephane; Nawabi, Homaira; Wang, Chen et al. (2015) Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics. Neuron 86:1000-1014
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; 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
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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