Endothelin Signaling in Glaucomatous Neurodegeneration

青光眼神经变性中的内皮素信号转导

• 批准号: 10163051
• 负责人: Olivia Joyce Marola
• 金额: $ 3.96万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163051
• 关键词: Acute; Affect; Age; Animal Model; Apoptosis; Apoptotic; Aqueous Humor; Astrocytes; Attenuated; Axon; Binding; Blindness; Blood Vessels; Blood flow; Cause of Death; Cell Death; Cells; Cessation of life; Chronic; Clinical; Critical Pathways; Development; EDN2 gene; Endothelin; Endothelin Receptor; Endothelin-1; Event; Eye; Fellowship; Glaucoma; Goals; Human; Hypoxia; In Vitro; Injections; Injury; Intervention; Lead; Ligands; Mediating; Mediator of activation protein; Modeling; Molecular; Muller' s cell; Mus; Myelogenous; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Ocular Hypertension; Optic Disk; Optic Nerve; Output; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Peptides; Pericytes; Physiologic Intraocular Pressure; Plasma; Production; Protein Isoforms; Research; Retina; Retinal Ganglion Cells; Risk Factors; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Source; System; Testing; Thinness; axon injury; cell injury; cell type; constriction; experience; experimental study; genetic manipulation; human model; in vivo; in vivo evaluation; insight; intravitreal injection; jun Oncogene; macroglia; mouse model; prevent; receptor; retinal neuron; transcription factor; vasoconstriction

Glaucoma is a leading cause of blindness that is characterized by the death of retinal ganglion cells (RGCs)— the output neurons of the retina. Ocular hypertension, elevated intraocular pressure (IOP), is an important risk factor for glaucoma. Through unknown mechanisms, chronically elevated IOP leads to RGC axonal injury, ultimately causing RGC death and loss of vision. To date, elevated IOP is the only clinically treatable component of glaucoma, and unfortunately, normalizing IOP does not prevent glaucoma progression or development in many patients. Therefore, identifying the molecular signaling pathways that lead from ocular hypertension to RGC death is critical for understanding the pathobiology of glaucoma. There is growing evidence that the endothelin (EDN) system is an important mediator of glaucomatous neurodegeneration. Components of the EDN system were upregulated in human and animal models of glaucoma. Importantly, EDN ligands (Edn1, Edn2) and receptors (Ednra, Ednrb) were upregulated prior to the onset of glaucomatous neurodegeneration in a mouse model of chronic ocular hypertension (DBA/2J mice). EDN induced RGC death both in vitro and in vivo, and antagonizing EDNRs lessened glaucomatous neurodegeneration in DBA/2J mice. Thus, targeting EDN signaling holds great promise as a neuroprotective treatment for glaucoma. However, it is unknown which retinal and/or optic nerve cell type EDN affects to elicit RGC death. Retinal neurons and macroglia (astrocytes and Müller glia) are the retinal and optic nerve cells known to express EDNRB, and deletion of Ednrb from these cell types did not protect RGCs from intravitreal EDN insult. Therefore, I propose to investigate the role of EDNRA in EDN- induced RGC death. EDNRA is expressed by RGCs and vascular mural cells. The canonical role of EDNRA is to regulate vascular tone, and EDN-activation of EDNRA elicits vasoconstriction. EDN injection caused immediate retinal vasoconstriction and hypoxic RGCs 3hr post-insult. Interestingly, glaucomatous DBA/2J retinas also had hypoxic RGCs, which were not seen in age-matched controls. Therefore, it is possible that EDNRA contributes to glaucoma-relevant EDN-induced RGC death by causing a hypoxic insult to RGCs. To investigate the role of EDNRA in EDN-induced RGC death, I will systematically delete Ednra from glaucoma- relevant cell types, perform intravitreal EDN injections, and assess changes in vasoconstriction, hypoxia, and RGC death. Furthermore, the importance of EDN in ocular hypertension-induced RGC death has not been critically tested in vivo. The Edn2 ligand was robustly upregulated in the optic nerve head and retina (specifically, by RGCs) prior to the onset of glaucomatous neurodegeneration in DBA/2J mice. By deleting Edn from glaucoma-relevant cell types in DBA/2J mice, I will determine the necessity and cellular source of EDN production in glaucomatous neurodegeneration. Identifying the mechanisms controlling EDN-induced RGC death will provide insight into early, critical pathways of glaucomatous neurodegeneration and can identify potential targets for neuroprotective glaucoma treatments.

青光眼是导致失明的主要原因，其特征是视网膜神经节细胞(RGC)死亡。 视网膜的输出神经元。高眼压，即眼压升高，是一个重要的风险。 导致青光眼的因素。通过未知的机制，慢性高眼压导致RGC轴突损伤， 最终导致RGC死亡和失明。到目前为止，高眼压是临床上唯一可以治疗的因素。 而不幸的是，眼压正常化并不能阻止青光眼的进展或发展。 很多病人。因此，确定导致高眼压的分子信号通路 RGC的死亡对于了解青光眼的病理生物学至关重要。越来越多的证据表明， 内皮素(EDN)系统是青光眼神经退行性变的重要介质。EDN的组件 系统在人和动物青光眼模型中表达上调。重要的是，EDN配体(Edn1，Edn2)和 受体(EDNRA、EDNRB)在小鼠青光眼神经变性开始前上调 慢性高眼压模型(DBA/2J小鼠)。EDN在体外和体内均可诱导RGC死亡； 拮抗EDNRs减轻DBA/2J小鼠青光眼神经变性。因此，以EDN信令为目标 作为一种治疗青光眼的神经保护疗法，前景看好。然而，目前尚不清楚哪一种视网膜和/或 视神经细胞型EDN影响引起RGC死亡。视网膜神经元和大胶质细胞(星形胶质细胞和Müler胶质细胞) 是否已知视网膜和视神经细胞表达EDNRB，并且这些细胞类型中的EDNRB缺失确实如此 而不是保护RGC免受玻璃体内EDN的侮辱。因此，我建议研究Ednra在EDN中的作用- 致RGC死亡。Ednra由视网膜节细胞和血管壁细胞表达。Ednra的典型作用是 调节血管张力，EDN激活Ednra引起血管收缩。EDN注入导致 损伤后即刻视网膜血管收缩和缺氧性视网膜节细胞。有趣的是，青光眼DBA/2J 视网膜也有缺氧性RGC，这在年龄匹配的对照组中是看不到的。因此，有可能 Ednra通过对RGC造成缺氧性侮辱，导致与青光眼相关的EDN诱导的RGC死亡。至 研究Ednra在EDN诱导的RGC死亡中的作用，我将系统地从青光眼中删除Ednra- 相关细胞类型，进行玻璃体内EDN注射，并评估血管收缩、缺氧和 RGC死亡。此外，EDN在高眼压诱导的RGC死亡中的重要性尚未得到证实。 在体内进行了严格的测试。Edn2配体在视神经头和视网膜中强烈上调(具体地说， 在DBA/2J小鼠青光眼神经变性开始之前。通过将EDN从 DBA/2J小鼠青光眼相关细胞类型，我将确定EDN的必要性和细胞来源 青光眼神经变性的产生。识别EDN诱导的RGC的控制机制 死亡将为青光眼神经变性的早期关键途径提供洞察，并可以识别 神经保护性青光眼治疗的潜在靶点。