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