Guidance Molecules in Retinal Axon Disease

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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.