Developing ER Stress Chemical Modulators as Neuroprotectants for Glaucoma

PROJECT SUMMARY Glaucoma, the most common worldwide cause of irreversible blindness, is characterized by progressive dysfunction and death of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON). There is a significant unmet clinical need for neuroprotectants. Our previous studies of ON traumatic injury and glaucoma demonstrated that axon injury induce neuronal endoplasmic reticulum (ER) stress in RGCs. We were able to protect the injured RGC somata and axons if we blocked the detrimental effects of ER stress by manipulating two key downstream molecules in opposite ways: a) deletion of CCAAT/enhancer binding protein homologous protein (CHOP), and/or b) activation of X-box binding protein 1 (XBP-1). Using complimentary cell-based high throughput screening (HTS) of small molecule libraries, we identified multiple series of chemical modulators of ER stress (CHOP inhibitors and XBP-1 activators), which are promising neuroprotectant candidates. We will further optimize these chemical ER stress modulators, determine their in vivo efficacies in clinically relevant mouse glaucoma models, and illustrate their mechanism of action. We expect the results through these studies will identify preclinical drug candidates and provide essential information for clinical application of ER stress modulation, and establish translational strategies for safe and effective clinical management of glaucoma patients.