Enhanced Axon Sparing In Glaucoma Through Augmentation Of EphB/ephrin B Signaling

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DESCRIPTION (provided by applicant): Glaucoma is a major debilitating eye disease affecting some 3 million individuals in this country. Of these, an estimated 100,000 patients each year lose some vision despite medical treatment for the normalization of intraocular pressure. As the incidence of glaucoma for the 65 yo.+ population segment is as high as 1 in 20, there is a great need to better understand disease mechanisms underlying optic nerve axon loss and to identify potential therapeutic strategies. A rapidly progressing area of research is th disease-linked up-regulation of intercellular signaling involving the EphB family of receptor tyrosine kinases and their ligands the ephrin-B proteins. Up-regulation of EphB/ephrin-B signaling occurs specificaly at the optic nerve head, an unmyelinated region of the optic nerve that clinical observations and experimental data both point to as a major site contributing to disease. In addition, increased activation of EphB/ephrin-B signaling occurs in two separate mouse models of glaucoma, in primates with experimental glaucoma, and in ONH tissues/cells from human patients, thereby implicating this signaling pathway as a potential key component of pathology. Recent work from our laboratory utilizing animals with genetic deletions and mutant alleles of specific EphB proteins has further demonstrated that animals with deficient EphB/ephrin-B signaling have more severe optic nerve axon loss compared to their wild-type littermates, indicating that EphB and ephrin-B proteins participate in an endogenous axon protective mechanism triggered by as yet incompletely characterized signals at the ONH. The up-regulation of EphB/ephrin-B signaling as an endogenous response in glaucoma is reminiscent of previous work implicating this signaling pathway in modulating axon survival and re-growth after spinal cord and optic nerve injury. Endogenous mechanisms that act to limit axon loss in glaucoma present intriguing targets for therapy. The current proposed research is based on preliminary evidence that the augmentation of EphB/ephrin-B signaling triggered by the application of biologically active EphB2 protein fragments results in a moderation of optic axon loss in an ex vivo tissue model of glaucomatous disease. Here we seek to build upon this finding and determine whether increased EphB and ephrin-B forward as well as reverse signaling in vivo can salvage optic axon loss in a laser-induced mouse model of glaucoma. Augmentation of EphB and B- ephrin signaling will be accomplished using an inducible Tet-on strategy in laser treated mice and optic nerve axon survival compared between animals receiving Doxycycline and those that do not. The results from this work potentially provide support for a novel therapeutic target and encourage additional discovery efforts.