Ocular disease and vision loss is a major medical problem in the US and worldwide. Glaucoma is the second leading cause of blindness due to damage to Retinal Ganglion Cells (RGCs) and the optic nerve. The optic nerve does not naturally regenerate, which results in permanent disability. Our long-term goal focuses on developing therapies to induce RGC regeneration to restore sight. Our approach is to analyze the normal development of RGC axons and the optic nerve during the time when nerve growth occurs naturally in order to obtain clues for regenerative therapy. Toward this goal, we are investigating the molecules that guide RGC axons to their correct targets. Specifically, we are analyzing the role of a novel class of signaling molecules, the lysophospholipids, specifically lysophosphatidic acid (LPA). We postulate that LPA, acting through the cognate receptor LPA4, is a guidance molecule for retinal ganglion cell (RGC) axons during development. We propose to test this hypothesis through three specific aims: (1) by determining the spatial and temporal expression of LPA4 receptors in retinal development, (2) by determining the role of LPA4 receptors in mediating axon guidance in vitro through siRNA knockdown, and (3) by determining the role of LPA and LPA4 receptors in mediating RGC axon guidance in vivo in the developing chick. Furthermore, this investigation will be used as a tool to mentor undergraduate students at Winthrop University, developing the next generation of scientists while teaching analytical skills and an understanding of the scientific process.
Visual impairment is a significant unmet medical need. Damage to the optic nerve from injury or disease, such as glaucoma, is permanent and regrowth does not normally occur;however, during development, vibrant growth does occur. We are using development to understand how the optic nerve grows and connects normally to find therapies that will induce regeneration after disease or damage.