July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Modulation of Eph-receptor signaling: implications for neurodegenerative disease and neural regeneration
Author Affiliations & Notes
  • Daniel Pelaez
    Ophthalmology. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
    Biomedical Engineering, University of Miami, Coral Gables, Florida, United States
  • Galina Dvoriantchikova
    Ophthalmology. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
  • Ravi Doddapaneni
    Ophthalmology. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
  • Gabriel S Gaidosh
    Ophthalmology. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
  • Wensi Tao
    Ophthalmology. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
  • Zenith Acosta Torres
    Ophthalmology. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
  • John P Turner
    University of Miami, Miami, Florida, United States
  • Steven Pappas
    University of Miami, Miami, Florida, United States
  • Dmitry V Ivanov
    Ophthalmology. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
  • David T Tse
    Ophthalmology. Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States
  • Footnotes
    Commercial Relationships   Daniel Pelaez, None; Galina Dvoriantchikova, None; Ravi Doddapaneni, None; Gabriel Gaidosh, None; Wensi Tao, None; Zenith Acosta Torres, None; John Turner, None; Steven Pappas, None; Dmitry Ivanov, None; David Tse, None
  • Footnotes
    Support  Dr. Al-Rashid Research Center Endowment, NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted grant
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4552. doi:
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      Daniel Pelaez, Galina Dvoriantchikova, Ravi Doddapaneni, Gabriel S Gaidosh, Wensi Tao, Zenith Acosta Torres, John P Turner, Steven Pappas, Dmitry V Ivanov, David T Tse; Modulation of Eph-receptor signaling: implications for neurodegenerative disease and neural regeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4552.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Eph/Ephrin signaling is critical for proper development of the central nervous system (CNS), and in particular, the coordination of retinotopic projections. However, forward signaling through Eph-receptors is known to be repulsive to outgrowing neurites, responsible for inducing axonal growth cone collapse, restricting of mid-line crossing of axons, and even destabilizing synaptic connections. Recently, involvement of Eph-receptor activation has been associated with the onset of several neurodegenerative diseases of the CNS, including various retinopathies. This study explored the effect of antagonizing Eph-receptor activation using novel molecules on axonal growth dynamics, de novo neurite extension, and axonal regeneration following optic nerve crush

Methods : To test the effect of Eph-receptor masking on retinal ganglion cell (RGC) neurite outgrowth, we used commercially available small molecule specific inhibitors (NVP-BHG712) and peptides (SNEW and KYL), as well as our own library of pan-antagonistic peptides (xEFN) to the Eph-receptor families. We used in-vitro screening of the compounds on isolated mouse RGC, as well as in affinity binding studies between inhibitors and Eph-receptors. We further explored the use of our lead candidates in an animal model of optic nerve crush (ONC) and evaluated regenerative potential of the modulation

Results : We found that concurrently antagonizing the activation of multiple Eph-receptors led to higher number of sprouting neurites per RGC, longer overall neurite extension length, and significantly reduced number of collapsed growth cones when compared to single specific receptor inhibition in-vitro. We further found that antagonizing Eph-receptor activation could desensitize outgrowing neurites to repulsive Ephrin-coated surfaces, and that this repulsion was mediated in RGCs by multiple receptors of the Eph family. In ONC experiments, administration of xEFN antagonizing peptides led to preservation of RGC somas in the retina and axonal regeneration past the injury site

Conclusions : Our findings suggest that modulation of the repulsive cues in the CNS, like Ep-receptor activation can aid in the attenuation of degenerative processes and stimulate some level of regeneration. This modulation can be synergistically combined with attractive/neuroprotective strategies to enhance therapeutic avenues for regeneration

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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