In primary glaucoma, ocular hypertension (OHT) stress triggers a neurotoxic cascade leading to selective death of retinal ganglion cells (RGC). However, the molecular mechanism transforming mechanical, non-ischemic stress into RGC dysfunction, injury and death in glaucoma remains highly debated. We discovered that OHT stress of various intensity and duration acutely activates neuronal NLRP1/NLRP3 inflammasomes that release of interleukin-1? cytokine and trigger GasderminD pore formation in RGCs in vivo. This project is premised on our exciting preliminary data where inflammasome blockade suppressed GsdmD activation and prevented dysfunction and loss of OHT-challenged RGCs in both acute OHT and chronic OHT (glaucoma) models. We designed this project to test our new hypothesis that metabolic and physiological dysfunction of RGCs leading to their loss in OHT injury is facilitated by activation of GsdmD pores in mitochondria and plasma membranes. If our hypothesis is correct, modulation of inflammasome pathway in the retina would prevent functional decline and loss of RGC in glaucoma.
This proposal investigated a novel molecular pathway that we recently discovered in the retina, which is implicated in visual disorders resulting from elevated extraocular pressure, such as in glaucoma. We discovered that this pathway causes retinal cell dysfunction via energy depletion in mitochondria, which is the earliest response of retinal cells to elevated intraocular pressure. This project explores how this initial insult subsequently progress to cause neuronal death and ensuing blindness. This grant proposal is designed to test a hypothesis that this inflammation- driven damage to retinal neurons contributes to glaucoma following relatively mild episodes of intraocular pressure elevation.