The long-term objective of our research is to understand the basic mechanisms underlying optic nerve axon response to injury and disease. The overall aim of the current application is to investigate the potential role of EphB2 and EphB3, members of the EphB family of receptor tyrosine kinases, in the development or progression of chronic optic nerve disease such as glaucomatous neuropathy. As a whole, optic neuropathies are a major debilitating disease that affects more than three million individuals in this country, and an estimated seventy million worldwide. An increased understanding of the basic disease mechanisms leading to vision loss is of fundamental importance and is directly relevant to the mission of the National Eye Institute. The proposed studies test the hypothesis that EphB2 and EphB3, molecules previously known for their axon guidance role during development, are functionally involved in the development of axon loss and visual disability in optic neuropathies. The proposal involves in vivo tests of this hypothesis investigating whether the severity of RGC axon loss in mice with laser-induced glaucoma is altered in the absence of EphB2 and EphB3. This is supplemented by similar studies in a second mouse model of glaucoma, the DBAl2J mouse, in order to strengthen the potential relevance of the study results to disease mechanisms. The results from these studies provide inSight into how extrinsic signals can affect the normal health of retinal ganglion cell axons and can lead to the eventual loss of ganglion cells. Given that the mechanisms involved in EphB mediated signaling have been extensively studied, there is an opportunity to utilize our understanding of EphB biology to guide the development of future therapeutic strategies for glaucoma.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Song, Yuanquan; Sretavan, David; Salegio, Ernesto A et al. (2015) Regulation of axon regeneration by the RNA repair and splicing pathway. Nat Neurosci 18:817-25
Fu, Christine T; Sretavan, David (2012) Involvement of EphB/Ephrin-B signaling in axonal survival in mouse experimental glaucoma. Invest Ophthalmol Vis Sci 53:76-84
Fu, Christine T; Sretavan, David W (2012) Ectopic vesicular glutamate release at the optic nerve head and axon loss in mouse experimental glaucoma. J Neurosci 32:15859-76
Du, Juan; Tran, Tony; Fu, Christine et al. (2007) Upregulation of EphB2 and ephrin-B2 at the optic nerve head of DBA/2J glaucomatous mice coincides with axon loss. Invest Ophthalmol Vis Sci 48:5567-81
Goldberg, Jeffrey L; Vargas, Mauricio E; Wang, Jack T et al. (2004) An oligodendrocyte lineage-specific semaphorin, Sema5A, inhibits axon growth by retinal ganglion cells. J Neurosci 24:4989-99
Beggs, Hilary E; Schahin-Reed, Dorreyah; Zang, Keling et al. (2003) FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies. Neuron 40:501-14
Birgbauer, E; Cowan, C A; Sretavan, D W et al. (2000) Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina. Development 127:1231-41
Zhang, F; Lu, C; Severin, C et al. (2000) GAP-43 mediates retinal axon interaction with lateral diencephalon cells during optic tract formation. Development 127:969-80
Marcus, R C; Shimamura, K; Sretavan, D et al. (1999) Domains of regulatory gene expression and the developing optic chiasm: correspondence with retinal axon paths and candidate signaling cells. J Comp Neurol 403:346-58
Deiner, M S; Sretavan, D W (1999) Altered midline axon pathways and ectopic neurons in the developing hypothalamus of netrin-1- and DCC-deficient mice. J Neurosci 19:9900-12

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