Cell specific roles of the endothelin system in glaucoma-relevant retinal ganglion cell death

内皮素系统在青光眼相关视网膜神经节细胞死亡中的细胞特异性作用

• 批准号: 9884769
• 负责人: Gareth R Howell
• 金额: $ 51.84万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884769
• 关键词: Affect; Animal Model; Astrocytes; Axonal Transport; Biological; Blindness; Cause of Death; Cell Death; Cells; Cellular Morphology; Cessation of life; Critical Pathways; Data; Disease; Disease Progression; EDN2 gene; Endothelial Cells; Endothelin; Endothelin Receptor; Event; Functional disorder; Gene Expression Profiling; Genes; Genetic; Glaucoma; Goals; Human; Individual; Injury; Intervention; Ischemia; Ligands; Mediating; Microglia; Modeling; Molecular; Morphology; Muller' s cell; Mus; Mutant Strains Mice; Myelogenous; Myeloid Cells; Nature; Nerve Degeneration; Neurons; Ocular Hypertension; Onset of illness; Optic Disk; Optic Nerve; Outcome Measure; Output; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pericytes; Pharmacologic Substance; Pharmacology; Physiological; Play; Predisposition; Prevention; Process; Receptor Cell; Research Design; Retina; Retinal Ganglion Cells; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Study models; System; Testing; Tissues; Up-Regulation; Vascular Smooth Muscle; axonal degeneration; cell type; experimental study; genetic approach; genome-wide; human model; in vivo evaluation; intravitreal injection; macrophage; monocyte; mouse model; neuroinflammation; novel; optic nerve disorder; prevent; receptor; response; retinal damage; transcription factor; transcriptome sequencing; transcriptomics

Glaucoma is an optic neuropathy characterized by retinal ganglion cell (RGC) death and optic nerve degeneration. Unfortunately, there are no current treatments that specifically target neurodegeneration. Identifying the signaling pathways responsible for disease onset and progression will be an important step in developing effective pharmacologic interventions for glaucomatous neurodegeneration. The endothelin (EDN) system is widely expressed throughout the body and participates in both physiological and pathophysiological processes. There is now a large body of evidence implicating the EDN system in human and in animal models of glaucoma. Manipulation of the EDN system significantly lessens RGC loss in a genetic and two inducible models of glaucoma. Also EDN signaling is upregulated in both the retina and optic nerve head prior to any signs of RGC death or dysfunction in an ocular hypertensive model of glaucoma. Despite the potential importance of EDN in glaucomatous neurodegeneration, the molecular mechanisms of EDN-induced RGC death are completely undefined. In particular, the upstream regulators and the downstream effectors of the EDN system are not known. Contributing to the difficulty in understanding how EDN signaling plays a role in glaucomatous neurodegeneration is the fact that EDN receptors, Ednra and Ednrb, are expressed on numerous cell types in the retina and optic nerve head including RGCs, astrocytes, myeloid derived cells (microglia and macrophages), and mural cells (pericytes and smooth muscle vascular cells). Furthermore, EDN is known to affect all of these cells in ways that are consistent with pathological responses observed in glaucoma. Thus, in order to understand EDN signaling in glaucoma the requirement of components of the EDN system, both receptors and ligands, must be systematically tested in the glaucoma-relevant cells they are expressed in. Here, we will test the hypothesis that defining the role of the EDN system in RGC death will identify early, critical signaling pathways that underlie glaucoma pathogenesis. To accomplish this and to define how EDN signaling functions after glaucoma-relevant insults, we will 1) define the mechanisms within RGCs that are required for EDN-induced RGC death, 2) determine the receptor, cell type, and molecular pathway(s) controlling EDN-induced RGC death, and 3) determine which cell types and molecular pathways are responsible for producing pathogenic EDN ligands. Importantly, this application will focus on the role of the EDN system in individual cell types, conditionally removing EDN components and performing transcriptomics on individual cell types. Together, the experiments outlined in the application critically test a long-standing hypothesis about the role of EDN in glaucoma and identify the various cell types and molecular mechanisms controlling glaucoma-relevant pathogenic EDN signaling. Given the early nature and proven role of EDN signaling in glaucomatous neurodegeneration these experiments will identify novel targets for developing neuroprotective treatments for glaucoma at early stages of disease pathogenesis.

青光眼是一种视神经病变，其特征是视网膜神经节细胞 (RGC) 死亡和视神经 退化。不幸的是，目前没有专门针对神经退行性疾病的治疗方法。 确定导致疾病发生和进展的信号通路将是迈出的重要一步 开发针对青光眼神经变性的有效药物干预措施。内皮素 (EDN) 系统广泛表达于全身各处，参与生理和病理生理过程 流程。现在有大量证据表明 EDN 系统存在于人类和动物模型中 青光眼。 EDN 系统的操作显着减少了遗传性和两种诱导性中的 RGC 损失 青光眼模型。此外，视网膜和视神经乳头中的 EDN 信号传导在任何信号发生之前都会上调。 青光眼高眼压模型中 RGC 死亡或功能障碍的迹象。尽管有潜力 EDN 在青光眼神经变性中的重要性、EDN 诱导 RGC 的分子机制 死亡完全没有定义。特别是，上游调节器和下游效应器 EDN 系统未知。导致理解 EDN 信号如何在 青光眼性神经变性是 EDN 受体 Ednra 和 Ednrb 在 视网膜和视神经头中的多种细胞类型，包括 RGC、星形胶质细胞、骨髓衍生细胞 （小胶质细胞和巨噬细胞）和壁细胞（周细胞和平滑肌血管细胞）。此外， 已知 EDN 影响所有这些细胞的方式与观察到的病理反应一致。 青光眼。因此，为了了解青光眼中的 EDN 信号传导，EDN 成分的需求 系统，包括受体和配体，必须在青光眼相关细胞中进行系统测试 在这里，我们将检验以下假设：定义 EDN 系统在 RGC 死亡中的作用将 识别青光眼发病机制的早期关键信号通路。为了实现这一目标并 定义 EDN 信号在青光眼相关损伤后如何发挥作用，我们将 1) 定义其中的机制 EDN 诱导的 RGC 死亡所需的 RGC，2) 确定受体、细胞类型和分子 控制 EDN 诱导的 RGC 死亡的途径，以及 3) 确定哪些细胞类型和分子途径 负责产生致病性 EDN 配体。重要的是，该应用程序将重点关注 单个细胞类型中的 EDN 系统，有条件地去除 EDN 成分并进行转录组学 关于单个细胞类型。总之，应用程序中概述的实验严格测试了长期存在的 关于 EDN 在青光眼中的作用的假设并确定各种细胞类型和分子机制 控制青光眼相关的致病性 EDN 信号传导。鉴于 EDN 的早期性质和经过验证的作用 青光眼神经变性中的信号传导这些实验将确定开发的新靶点 在疾病发病机制的早期阶段对青光眼进行神经保护治疗。