Mechanisms underlying endothelin mediated neurodegeneration in glaucoma

内皮素介导的青光眼神经变性的机制

• 批准号: 10299362
• 负责人: RAGHU R KRISHNAMOORTHY
• 金额: $ 37万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299362
• 关键词: Address; Amino Acids; Animal Model; Applications Grants; Aqueous Humor; Attenuated; Autophagocytosis; Axon; Binding; Bioenergetics; Blood Circulation; Blood Vessels; Cell Death; Cells; Confocal Microscopy; Data; Development; Endothelin; Endothelin B Receptor; Endothelin Receptor; Endothelin Receptor Antagonist; Endothelin-1; Endothelin-2; Endothelin-3; Event; Eye; FDA approved; G-Protein-Coupled Receptors; Glaucoma; Impairment; Injections; Intervention; Knock-out; LAMP-1; Laboratories; LysoTracker; Mediating; Metabolic; Methods; Microspheres; Mitochondria; Molecular; Nerve Degeneration; Neurons; Optic Nerve; Oral; Organelles; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Process; Publications; Quality Control; Rattus; Rattus norvegicus; Receptor Activation; Regulation; Reporting; Resolution; Retina; Retinal Ganglion Cells; Rodent; Rodent Model; Saline; Signal Transduction; System; Testing; Transgenic Mice; Up-Regulation; Vision; Visual impairment; axon injury; axonal degeneration; bench to bedside; central retinal artery; defined contribution; drug repurposing; high resolution imaging; imaging study; improved; innovation; intravitreal injection; neuroprotection; novel; parkin gene/protein; pressure; receptor; two-photon; vasoconstriction

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.

项目概要： 血管活性肽（包括ET-1、ET-2和ET-3）及其G蛋白的内皮素（ET）系统 已经发现偶联受体（ETA和ETB受体）在青光眼的动物模型中升高。 来自几个实验室的确证性发现表明，ET-1通过血管和 细胞机制在青光眼中产生神经变性作用。ET-1通过以下途径介导这些作用： ETA和ETB受体的激活，导致视神经变性和视网膜神经节细胞死亡。这些 这些发现提出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，内皮素受体激活导致青光眼神经变性的机制 是很难理解的。本申请中包含的初步数据表明，线粒体自噬的减少是 在Brown Norway大鼠的IOP升高期间以及用ET-1处理RGC后发生的事件。 ET-1介导的自噬下降中涉及的新机制将在该提案中得到解决， 具体目标1：确定内皮素-1（ET-1）通过其受体起作用是否减少 视网膜神经节细胞的线粒体自噬。具体目标2：阐明导致线粒体自噬减少的机制 啮齿动物IOP升高后视网膜神经节细胞中的变化。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介导的自噬和高水平的 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 在青光眼中受损的线粒体自噬（线粒体的质量控制机制）的动力学。的 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RGCs及其轴突的神经保护。应用程序的一大亮点是开发 使用马昔腾坦的神经保护策略，马昔腾坦是一种FDA批准的药物，有可能迅速 从实验室到床边的青光眼治疗这将极大地促进 开发青光眼的神经保护治疗，这是非常需要的，以减缓进展 尽管积极降低眼压，但在一些青光眼患者中仍会发生视力损害。