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-1β 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.