Role and regulation of inflammasome in the intraocular pressure-induced injury of retinal ganglion cells

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PROJECT SUMMARY Glaucoma is the second leading cause of blindness, impacting 79.6 million worldwide 1. This blindness results from the loss of retinal ganglion cells (RGCs) and is primarily linked to chronic ocular hypertension (OHT). Because of gaps in our understanding of the molecular pathways linking OHT with RGC loss, the only current clinical strategy to slow glaucoma progression is to lower intraocular pressure (IOP). This strategy has serious limitations as it does not stop the disease and has a high proportion of non-responders 2. Elevation of IOP varies in magnitude and disrupts RGCs in several ways. High elevation (above systolic blood pressure) causes an acute and severe ischemic injury in these neurons, more common in closed-angle glaucoma, while lower magnitude chronic IOP elevations affect them slowly over time. Acute ischemic injury is similar to a stroke that activates pressure-sensitive calcium channels, induces oxidative and ER stresses, ATP release via activated Panx1/Cx hemichannels, and obstructs axonal transport3. More recent studies have revealed that the activation of the endogenous inflammasome and subsequent formation of GasderminD pores is a primary mechanism in neuronal dysfunction and pyroptotic death in ischemic OHT injury models 4, 5. In contrast, episodes of sub-ischemic low level but chronic IOP elevations can cause glaucoma despite being non- injurious short term6. In addition to these two modalities, rapid IOP elevation “spikes” below ischemic levels have been shown to induce RGC dysfunction and glaucomatous degeneration in both human and rodent eyes7, 8. In people, such pressure spikes can be induced by surgery and drugs and by activities such as eye rubbing, playing wind instruments, head down exercising, heavy weight lifting, and frequent caffeine intake, which have been linked to higher glaucoma risk2. However, the mechanisms causing RGC injury by such relatively low amplitude but rapid and recurring spiking IOP fluctuations are poorly understood. In this project, I utilize a model of sub-ischemic OHT spikes (SIOHS) to investigate early RGC-damaging pathways and their role in glaucomatous RGC degeneration. My main focus is on the mechanism linking mild acute stress by sub-ischemic OHT spikes with the functional deficit and RGC loss. In this project, I will test the hypothesis that overactivation of mechanosensitive channels on the cell surface of RGCs challenged by IOP spikes initiates metabolic stress and eventual loss via the activity of endogenous inflammasome. To examine this, I will determine 1. the role of endogenous neuroinflammation in RGC dysfunction and death following SIOHS, and 2. Test if cell surface TLRPV4 receptor signaling pathway is specifically responsive to SIOHS events.