Project Summary/Abstract The proposal is in response to NEI's strategic plan, described recently by NEI in “Vision Research: Needs, Gaps, and Opportunities”, and focuses on our most recent discoveries of a novel neuronal mechanism rooted at the intersection of aging and the biological mechanisms of eye disease identified as a high programmatic priority. The proposed research targets a novel mechanism of neuroprotection utilizing intracellular calcium channels as drug targets to treat neurodegeneration in glaucoma. Specifically, we plan to determine mechanisms of action and to measure preservation of neuronal viability and function in model systems of glaucoma. The proposed research will allow us to generate preclinical data needed for the development of novel neuroprotectants to complement existing therapies targeting intraocular pressure: The intracellular free Ca2+ concentration of retinal ganglion cells like in other neurons of the CNS is highly regulated and subject to dysregulation during aging. For the development of acute and chronic degenerative diseases including glaucoma reducing the viability and function of retinal ganglion cells (RGCs) several studies indicate that both changes in intracellular second messenger concentration and pathological increases in the intracellular Ca2+ concentration promote pathogenesis. The present application will test the hypothesis that Ca2+ signaling of RGCs is functionally regulated by an immediate early gene product upregulated in RGCs after a neurodegenerative insult to generate a cellular defense mechanism. This hypothesis is based on strong preliminary evidence that normal aging of the retina is mechanistically similar to glaucoma disease processes and can be exploited to devise novel treatments for glaucoma. The proposed experiments designed to test this hypothesis will investigate the molecular, cellular and functional mechanisms underlying this interaction under experimentally induced disease conditions in models of glaucoma. The overall goal of the proposed study is to identify a novel mechanism of RGC neuroprotection and determine its potential as a strategy for neuroprotective therapies targeting RGCs. This therapy approach will have the potential to be both preventative and therapeutic in nature and to complement existing treatment designs and rationales.