Poor regeneration of retinal ganglion cell (RGC) axons is a major obstacle for treating ocular trauma and diseases including glaucoma. There are as yet no therapies to repair optic nerve once the damage is done. We now demonstrate that modulation of PTEN (phosphatase and tensin homolog) expression in adult RGCs using small interference RNAs (siRNA), with elevation of ciliary neurotrophic factor (CNTF) and cyclic AMP (cAMP) promotes robust optic nerve regeneration. Remarkably, some regenerating axons successfully reach a brain target, the suprachiasmatic nucleus (SCN), a master pacemaker for regulating circadian rhythms. The overall goal of this proposal is to determine;i) whether the axons that reach to the SCN form functional connections and induce recovery of circadian rhythm, and ii) develop strategies to further enhance optic nerve regeneration to the central targets. Despite impressive regeneration, not all retinal neurons regenerated their axons over long distances, and many regenerating axons stalled at the optic chiasm.
In Aim 1, we will combine strategies to enhance the intrinsic growth potentials of RGCs to further increase regeneration. Next, we will look for factors that limit axon regeneration into and beyond the optic chiasm. Recently, we found that over-expression of light sensor proteins induces some axon regeneration.
In Aim 2, we will elucidate the molecular mechanisms underlying this form of regeneration. It is unknown whether the regenerated axons in the SCN restore the ability of the SCN to adjust to light dark cycles, a process known as circadian photoentrainment.
In Aim 3, we will determine whether the axons that reach to the SCN form functional connections and induce recovery of circadian photoentrainment. Identifying methods to further increase regeneration to brain and determining whether the regenerated axons restore visual functions represent critical future studies. Results obtained from these studies will provide invaluable information on developing future therapies to repair degenerated optic nerve after glaucoma and traumatic optic neuropathy.
Poor regeneration of retinal ganglion cell axons is a major feature of glaucoma, optic neuritis and traumatic optic neuropathies. There are currently no therapies to repair damaged optic nerve. We now present a novel and therapeutically relevant approach that permits long-distance regeneration of retinal ganglion cell axons after injury. This grant will harness our new methods to further enhance regeneration, and determine whether the regenerating axons restore visual functions.
|Fischer, Dietmar; Harvey, Alan R; Pernet, Vincent et al. (2017) Optic nerve regeneration in mammals: Regenerated or spared axons? Exp Neurol 296:83-88|
|Patel, Amit K; Park, Kevin K; Hackam, Abigail S (2017) Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse. Neuroscience 343:372-383|
|Yungher, Benjamin J; Ribeiro, Márcio; Park, Kevin K (2017) Regenerative Responses and Axon Pathfinding of Retinal Ganglion Cells in Chronically Injured Mice. Invest Ophthalmol Vis Sci 58:1743-1750|
|Bray, Eric R; Noga, Markus; Thakor, Kinjal et al. (2017) 3D Visualization of Individual Regenerating Retinal Ganglion Cell Axons Reveals Surprisingly Complex Growth Paths. eNeuro 4:|
|Mehta, Saloni T; Luo, Xueting; Park, Kevin K et al. (2016) Hyperactivated Stat3 boosts axon regeneration in the CNS. Exp Neurol 280:115-20|
|Dvoriantchikova, Galina; Pappas, Steve; Luo, Xueting et al. (2016) Virally delivered, constitutively active NF?B improves survival of injured retinal ganglion cells. Eur J Neurosci 44:2935-2943|
|Luo, Xueting; Ribeiro, Marcio; Bray, Eric R et al. (2016) Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System. Cell Rep 15:398-410|
|Soderblom, Cynthia; Lee, Do-Hun; Dawood, Abdul et al. (2015) 3D Imaging of Axons in Transparent Spinal Cords from Rodents and Nonhuman Primates eNeuro 2:|
|Yungher, B J; Luo, X; Salgueiro, Y et al. (2015) Viral vector-based improvement of optic nerve regeneration: characterization of individual axons' growth patterns and synaptogenesis in a visual target. Gene Ther 22:811-21|
|Luo, Xueting; Yungher, Benjamin; Park, Kevin K (2014) Application of tissue clearing and light sheet fluorescence microscopy to assess optic nerve regeneration in unsectioned tissues. Methods Mol Biol 1162:209-17|
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