The damage or degeneration of the axons derived from the retinal ganglion cells (RGCs) in the optic nerve accounts for the visual functional defects after traumatic injury or degenerative diseases such as glaucoma. Thus, the logical repair strategy is to promote injured optic nerve axons to regenerate across the lesion and reconnect with their targets. In the previous funding period, we have made significant progress in optimizing regeneration-promoting strategies. We first discovered that co-deletion of PTEN and SOCS3 resulted in robust axon regeneration. Our further studies showed that over-expression of osteopontin (OPN) and IGF1 and CNTF could mimic the effects of co-deletion of PTEN and SOSC3, leading to similar extents of axon regeneration. However, such regenerated axons fail to re-myelinate preventing recovery of vision unless potassium channel blocker is acutely administered to allow axonal conduction of neuronal signal. Since OPN/IGF1/CNTF are all extracellular proteins and recombinant proteins can be produced, this combination may be the most promising treatment for stimulating RGC axon regeneration and vision function recovery. To further develop this into an effective therapeutic strategy, we need to address the following issues: can OPN/IGF1/CNTF combination stimulate all types of RGCs to regenerate axons? Do regenerated axons project to correct targets? How can re-myelination be induced? Using the optic nerve and optic tract regenerative animal model, we will address each of these questions, in a hope to reveal key cellular and molecular regulators these processes. We expect that the obtained results might provide insights into develop more effective and safe therapeutic strategies of promoting vision restoration.

Public Health Relevance

This proposed study is aimed to identify key players in several critical steps from optic nerve regeneration to functional restoration. We hope that the obtained results will provide unique insights into developing effective and safe strategies of promoting axon regeneration and vision restoration.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY021526-06
Application #
9239819
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Liberman, Ellen S
Project Start
2011-05-01
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
6
Fiscal Year
2017
Total Cost
$442,500
Indirect Cost
$192,500
Name
Boston Children's Hospital
Department
Type
Independent Hospitals
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Norsworthy, Michael W; Bei, Fengfeng; Kawaguchi, Riki et al. (2017) Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others. Neuron 94:1112-1120.e4
Cartoni, Romain; Norsworthy, Michael W; Bei, Fengfeng et al. (2016) The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration. Neuron 92:1294-1307
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
Nawabi, Homaira; Zukor, Katherine; He, Zhigang (2012) No simpler than mammals: axon and dendrite regeneration in Drosophila. Genes Dev 26:1509-14
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