Neuroprotection by Inhibition of ER Stress in Glaucoma

Loss of retinal ganglion cells and their axons due to optic nerve injury account for visual function deficits in glaucoma. Dr. Yang Hu’s team hypothesizes that the underlying mechanisms involve stress induced by optic nerve injury to a part of the cell where proteins are made, called the endoplasmic reticulum (ER). Dr. Hu’s team propose to manipulate ER stress proteins to promote neuroprotection and therefore to preserve vision function of glaucoma patients.

Grantee institution at the time of this grant: Temple University

In glaucoma, loss of vision is due to optic nerve (ON) injury, axon degeneration and death of retinal ganglion cells (RGCs), the nerves that are bundled into the ON. A better understanding of the mechanisms underlying RGC and ON degeneration is needed to develop novel neuroprotective treatments. In an ON crush model of glaucoma, which leads to the death of most RGCs in mouse, Dr. Hu’s team demonstrated that axon injury induces endoplasmic reticulum (ER) stress. In addition, modifying ER stress dramatically protected RGCs, suggesting the critical role of ER stress in neuronal survival. Thus, targeting ER stress may have considerable therapeutic neuroprotective potential in glaucoma.

There are three signal transduction pathways downstream of ER stress and multiple molecules in those pathways could potentially play a role in neuronal degeneration. In fact, Dr. Hu’s team has shown that manipulating two key ER stress proteins significantly promote neuroprotection of injured RGCs. Thus, the team will determine whether other molecules in the ER stress pathways also exert potent neuroprotection. In addition, they will determine whether targeting several molecules together will achieve synergistic neuroprotection. The team has identified a potentially new mechanism of neurodegeneration that links the critical stress response with optic nerve injury. New insights into the critical proteins that regulate RGC survival can be translated into novel therapeutic approaches to prevent vision loss in patients with glaucoma. Furthermore, by developing an adeno-associated virus-mediated genetic manipulation of ER stress, Dr. Hu’s team is testing the possibility of a novel gene therapy strategy to maximize neuroprotection and prevent disease progression in glaucoma patients.