Phosphoinositide Signaling and Optic Nerve Regeneration

Veterans Admin Palo Alto Health Care Sys, Palo Alto CA

Investigators

Abstract

ABSTRACT Background and Innovation: Glaucomatous optic neuropathy is a primary cause of irreversible blindness among veterans. Reducing eye pressure remains the only treatment for glaucoma patients experiencing vision loss. The gradual loss of retinal ganglion cells leads to a progressive decline in vision and the potential for permanent blindness. In our previous research phase, we successfully established an innovative mouse model of glaucoma, silicone oil-induced ocular hypertension. Using calcium indicators expressed exclusively in retinal ganglion cells, we also developed methods to detect functional changes in ganglion cells under stress. Preliminary data support the involvement of phosphoinositide metabolism signaling pathways. INPP5K is an inositol 5-phosphatase that dephosphorylates PIP3 and regulates ER structure as well as ER stress. We also have shown that the ER stress pathway is involved in optic nerve regeneration in mouse models of glaucoma. We hypothesize that targeting both phosphoinositide and endoplasmic reticulum stress pathways will enhance protein synthesis, facilitate axon regeneration, and ultimately lead to more significant axon regeneration in the central nervous system. Our proposal aims to investigate whether targeting both INPP5K and ER stress responses will enhance optic nerve regeneration. Significance and Impact to Veterans Healthcare: Glaucoma is a blinding condition that affects over 285,000 Veterans. Currently, all glaucoma treatments can only slow down the disease, with no effective means to regenerate the optic nerve. By determining the therapeutic potential of the phosphoinositide pathways, our research will contribute to developing innovative therapeutic strategies to promote functional recovery. This, in turn, will aid in the discovery of new therapies for open-angle and other forms of glaucoma for our veteran patients. Our proposal addresses the VHA/ORD research priority for increasing the impact of VA research. Ultimately, the knowledge gained from this project will develop novel therapeutic compounds to benefit veterans suffering from vision loss. Path to translation/implementation: The pathway to translation and implementation involves enabling the translation of small molecule-based treatments for optic nerve regeneration from the laboratory setting to clinical use. Initially, these treatments will undergo rigorous evaluation in animal models to assess their efficacy, safety, and potential side effects. Successful candidates will progress towards clinical trials; we aim to bridge the gap between experimental findings and tangible therapeutic interventions, ultimately offering hope to veterans suffering from glaucoma and other forms of optic neuropathies.