Mechanisms underlying endothelin mediated neurodegeneration in glaucoma

项目总结： 血管活性多肽(包括ET-1、ET-2和ET-3)及其G蛋白的内皮素系统 已发现偶联受体(ETA和ETB受体)在青光眼动物模型中升高。 来自几个实验室的确证发现表明，ET-1通过血管和 细胞机制在青光眼中产生神经退行性变化。ET-1通过以下途径介导这些效应 ETA和ETB受体激活，导致视神经变性和视网膜神经节细胞死亡。这些 这一发现带来了通过使用阻断内皮素受体的药物来保护神经的令人兴奋的可能性。 然而，内皮素受体激活促进青光眼神经退行性变的机制 人们对此知之甚少。本申请中包含的初步数据表明，减少有丝分裂是一个关键 在棕色挪威大鼠眼压升高期间发生的事件，以及在ET-1治疗视网膜节细胞后发生的事件。 与ET-1介导的自噬减少有关的新机制将在提案中与 以下特定目标：特定目标1：确定通过其受体作用的内皮素-1(ET-1)是否减少 视网膜神经节细胞中的有丝分裂。具体目标2：阐明导致有丝分裂减少的机制 啮齿动物眼压升高后视网膜神经节细胞的变化。具体目标3：确定线粒体 内皮素受体拮抗剂对高眼压大鼠神经保护作用的机制。 该项目的创新方面包括深入评估ET-1介导的自噬和高... 分辨率成像研究，使用超分辨率和双光子共聚焦显微镜，以了解 有丝分裂的动力学(线粒体的一种质量控制机制)在青光眼中受到损害。这个 该项目还将产生药物干预的可能性，以阻断内皮素受体，从而 促进视网膜节细胞及其轴突的神经保护。该应用程序的一大亮点是开发 使用美国食品和药物管理局批准的药物Macitentan的神经保护策略，该药物有可能迅速 从替补席过渡到床边治疗青光眼。这将极大地便利 开发一种治疗青光眼的神经保护疗法，这是减缓青光眼进展的迫切需要 在一些青光眼患者中出现的视力损害，尽管有积极的降低眼压的作用。

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.