Project Summary
A major risk factor in glaucoma is elevated intraocular pressure (IOP) and current therapies are aimed at lowering IOP through pressure lowering medications and/or surgical intervention. While these current therapies can slow the disease progression in many patients, other patients continue to progress. Moreover, there are many glaucoma patients that never present with elevated IOPs, indicating that IOP-independent mechanisms also participate in the development of glaucoma. Recent evidence demonstrates that the initial injury in glaucoma occurs in the optic nerve head (ONH), where axon bundles exit the eye, and that activated astrocytes produce mediators that damage these axons and trigger inflammatory cell recruitment. We recently discovered that ONH astrocytes in human and mouse eyes constitutively express a critical regulator of inflammation called the NLRP3 inflammasome. Our preliminary data demonstrate triggering the inflammasome in the ONH activates inflammation that leads to the development of glaucoma.
We hypothesize that activation of the NLRP3 inflammasome in ONH astrocytes initiates inflammation and axonal damage in glaucoma. We are testing this hypothesis in two specific aims: Aim 1- Demonstrate that NLRP3 inflammasome activation is required to initiate and amplify inflammation in the ONH, resulting in the production of proinflammatory cytokines, infiltration of immune cells, production of neurotoxic mediators, axonal damage, and death of RGCs. In these studies we will elevate the IOP in genetically modified mice that do not express the NLRP3 inflammasome to demonstrate that activation of the NLRP3 inflammasome is required for (i) loss of axons and RGCs following elevated IOP, and (ii) the production of proinflammatory cytokines, infiltration of macrophages, and release of neurotoxic mediators is inhibited in NLRP3 KO mice, even in the presence of elevated IOP. Aim 2- Determine whether using a small molecule inhibitor to specifically inhibit NLRP3-driven inflammation prevents development of IOP-induced glaucoma by blocking the initiation and amplification of inflammation in the ONH. In these studies we will use a newly developed small molecule inhibitor of NLRP3, to determine (i) if we can specifically block IOP-induced NLRP3 inflammasome activation in the ONH and prevent axonal damage and death of RGCs, and (ii) how late in disease treatment with this novel inhibitor can be initiated and still provide protection for RGCs and their axons.
Upon completion, this work will provide the first evidence that the NLRP3 inflammasome contributes to the development of glaucoma by initiating inflammation in the ONH. More important, this research will serve as a pre-clinical study demonstrating the ability of this small molecule inhibitor to specifically target and inhibit NLRP3-driven inflammation and prevent the development of glaucoma, even in the presence of elevated IOP.
