The optic nerve of adult humans shows little potential for regeneration or self-repair, which presents a major challenge to restoring vision in patients with optic nerve injury or diseases, including glaucoma. These patients thus suffer from the pathological consequences and vision loss for the rest of their lives. A regenerative therapy is vital for preserving sight or reversing vision loss. Yet an in depth understanding of the molecular basis that controls optic nerve growth/regeneration remains ambiguous. We here propose to investigate why the optic nerve fails to regenerate and how nerve regeneration can be enhanced to improve neuronal function after injury. Long-standing work from my and other laboratories has shown that optic nerve growth is a programed event during development whose shut-down contributes critically to the failure of optic nerve regeneration. A recent discovery in my laboratory has identified a novel potent regulator, insulin-like growth factor (IGF binding protein like 1 (IGFBPL1) whose presence activates the growth program and regenerative process of retinal ganglion cell (RGC) axons and induces activation of IGF-1 receptor (IGF-1R) and its downstream signals. Administration of exogenous IGFBPL1 promoted optic nerve regeneration and RGC survival in adult mice; whereas, blockade of IGF-1R-induced signals, at least in culture, abolished IGFBPL1-mediated axonal growth or regeneration. This points to a central role for IGFBPL1 functioning through IGF-1R-induced intracellular events to regulate optic nerve regeneration. Importantly, IGFBPL1 as a secretory factor presents a clinically feasible candidate for manipulating nerve regeneration and restoring vision after injury in humans. This proposal thus seeks to further explore the underlying mechanisms through which IGFBPL1, particularly its relation to IGF-1R-mediated signals, promotes RGC axon regeneration. Moreover, it will evaluate the efficacy of IGFBPL1 on promoting optic nerve regeneration in an established animal model of optic nerve injury. Completion of the proposed studies will uncover a previously unknown signaling loop in IGF-1R-mediated cascades in the regulation of RGC axon growth and will advance our understanding of the mechanisms that control optic nerve regeneration and repair. This will accelerate the preclinical development of a novel regenerative therapy for currently untreatable conditions. As the optic nerve has long served as a standard model for the study of CNS injury, results may also have a broad impact on the development of new therapies to treat brain and spinal cord injury or diseases.

Public Health Relevance

This proposal intends to unravel the underlying mechanism of nerve regeneration and to activate the regenerative potential of optic nerve neurons through a newly identified secretory protein and novel potent stimulator of axon growth, thereby eliciting a repairing mechanism of the damaged nerve and neurons in human patients. If proven successful, this can lead to the first therapy for currently untreatable conditions of vision loss and will significantly improve the quality of life of patients suffering from optic nerve damage or diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY025259-02
Application #
9225212
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
073826000
City
Boston
State
MA
Country
United States
Zip Code
02114
Olivares, A M; Jelcick, A S; Reinecke, J et al. (2017) Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina. Sci Rep 7:690
Sehic, Amer; Guo, Shuai; Cho, Kin-Sang et al. (2016) Electrical Stimulation as a Means for Improving Vision. Am J Pathol 186:2783-2797
Yang, Liu; Li, Shaohua; Miao, Linqing et al. (2016) Rescue of Glaucomatous Neurodegeneration by Differentially Modulating Neuronal Endoplasmic Reticulum Stress Molecules. J Neurosci 36:5891-903
Yan, Naihong; Cheng, Lin; Cho, Kinsang et al. (2016) Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1. Sci Rep 6:33887