Glaucoma affects 70 million people worldwide [1, 2] and is characterized by optic nerve (ON) atrophy and the progressive death of retinal ganglion cell (RGC) [3]. Glaucoma is often associated with elevated intraocular pressure (IOP), and current management aims at lowering IOP [4]. Yet although IOP-lowering treatments slow the development and progression of glaucoma, approximately 10% of people who receive proper treatment continue to experience loss of vision [2]. Therefore, investigation of the underlying mechanisms involved in RGC death is likely to improve our understanding of the disease pathophysiology and lead to novel therapeutic approaches. Effective neuroprotection thus is urgently needed, but unfortunately there are no effective treatments available. Although apoptosis has been shown to be a major form of cell death, interventions based solely on inhibition of this important modality have failed to achieve the desired goal. We recently demonstrated that RIP kinase-mediated necrosis (also known as necroptosis) in addition to caspase-dependent apoptosis is involved in photoreceptor death in a retinal detachment model of retinal degeneration and that effective neuroprotection necessitates combination therapy. We propose to study whether the RIP kinase pathway in combination with caspases can be a novel therapeutic target in animal models of glaucoma. We would like to expand our findings on the redundancy of cell death pathways from our work in photoreceptor degenerations to animal models of glaucoma. We propose to evaluate the neuroprotective and axonal regenerative effects of RIPK and Caspase Inhibition (alone and in combination) after optic nerve injury and examine the effects of RIPK inhibition and RIP3 deletion on autophagy and inflammasomes in RGC degeneration after optic nerve crush.
Glaucoma affects millions of people in the USA and there is need for more effective treatments. Loss and cell death of specialized optic nerve cells (retina ganglion cells) is the major cause of the visual decline seen in this disease. Our work has uncovered novel redundant parallel cell death pathways in animal models of this disease and is identifying molecules to successfully interfere with them. These findings may lead to development of new drugs that can be used to help with neuroprotection and regeneration in patients with glaucoma and other optic nerve diseases.
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