Mechanisms underlying endothelin mediated neurodegeneration in glaucoma

Project Summary: The endothelin (ET) system of vasoactive peptides (comprising of ET-1, ET-2 and ET-3) and their G protein coupled receptors (ETA and ETB receptors) have been found to be elevated in animal models of glaucoma. Corroborative findings from several laboratories have demonstrated that ET-1 acting through both vascular and cellular mechanisms produces neurodegenerative effects in glaucoma. ET-1 mediates these effect through activation of the ETA and ETB receptors, leading to optic nerve degeneration and retinal ganglion cell death. These findings bring up exciting possibilities for neuroprotection by using agents that block endothelin receptors. However, the mechanisms by which endothelin receptor activation contributes to neurodegeneration in glaucoma is poorly understood. Preliminary data included in this application indicates that a reduction in mitophagy is a key event that occurs during IOP elevation in Brown Norway rats, as well as following treatment of RGCs with ET-1. Novel mechanisms involved in ET-1 mediated decline in autophagy will be addressed in the proposal with the following specific aims: Specific Aim 1: Determine if endothelin-1 (ET-1) acting through its receptors decreases mitophagy in retinal ganglion cells. Specific Aim 2: Elucidate mechanisms contributing to decreased mitophagy in retinal ganglion cells following IOP elevation in rodents. Specific Aim 3: Determine the mitochondrial mechanisms contributing to the neuroprotective effects of endothelin receptor antagonists in IOP elevated rats. The innovative aspects of the project include an in-depth assessment of ET-1 mediated autophagy and high- resolution imaging studies, using super-resolution and 2-photon confocal microscopy, to understand the dynamics of mitophagy (a quality control mechanism for mitochondria) which is compromised in glaucoma. The project will also generate possibilities for pharmacological interventions to block endothelin receptors, thereby promote neuroprotection of RGCs and their axons. A major highlight of the application is the development of neuroprotective strategies using macitentan, a FDA approved drug, which has the potential to be rapidly transitioned from the bench to the bedside for the treatment of glaucoma. This will greatly facilitate the development of a neuroprotective treatment of glaucoma, which is much needed to slow down the progression of visual impairment that occurs in some glaucoma patients, despite aggressively lowering IOP.