Sigma-1 Receptor Provides Neuroprotection Against Optic Neuropathy

Sigma-1 受体提供针对视神经病变的神经保护作用

• 批准号: 10334443
• 负责人: Kathryn Bollinger
• 金额: $ 37.35万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334443
• 关键词: Address; Affect; Age; Agonist; Amyotrophic Lateral Sclerosis; Astrocytes; Axon; Biochemical Pathway; Blindness; Brain; Brain-Derived Neurotrophic Factor; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Coculture Techniques; Complex; Cytoprotection; Data; Disease; Equilibrium; Experimental Models; Genes; Glaucoma; Goals; Health; Histologic; In Vitro; Injury; Integral Membrane Protein; Knowledge; Ligands; Mediating; Mitochondria; Modeling; Molecular; Molecular Chaperones; Nerve Degeneration; Neuroglia; Neuronal Injury; Neuronal Plasticity; Neurons; Ocular Hypertension; Optic Disk; Optic Nerve; Outcome Measure; Pathogenesis; Pathogenicity; Pathway interactions; Persons; Pharmacology; Physiologic Intraocular Pressure; Play; Primary Open Angle Glaucoma; Publishing; Rattus; Reactive Oxygen Species; Receptor Activation; Regulation; Retina; Retinal Ganglion Cells; Risk Factors; Role; Site; Stress; Supporting Cell; Testing; Vision; Visual system structure; axon injury; base; cell injury; cell type; endoplasmic reticulum stress; excitotoxicity; genetic approach; in vivo; nerve damage; neuroinflammation; neuroprotection; neurotoxic; neurotrophic factor; novel therapeutics; optic nerve disorder; prevent; receptor; retinal damage; retinal ganglion cell degeneration; sigma-1 receptor; treatment strategy; visual information

The goal of this project is to evaluate the effects of sigma-1 receptor (S1R) activation on RGCs and optic nerve head astrocytes (ONHAs) under glaucomatous conditions. Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by the progressive degeneration of retinal ganglion cells (RGCs). The major risk factor for glaucoma is increased intraocular pressure (IOP), and lowering IOP is currently the only treatment strategy for this disease. However, in many cases, decreasing IOP does not effectively prevent glaucomatous vision loss. Thus, novel therapies are needed. Activation of the multifunctional sigma 1 receptor (S1R) is a promising pluripotent target for glaucoma treatment. S1R stimulation provides robust RGC protection, both in vitro and in vivo, but it has not been tested in glaucoma. In addition, the mechanisms of S1R-mediated neuroprotection are not well understood. S1R is a ligand-operated, transmembrane protein that is expressed in RGCs and astrocytes throughout the visual system. A major deficit in our understanding of S1R is knowledge of its direct effects on glia cells and how these effects mediate glia-neuronal interactions. Astrocytes are the major glial constituent of the optic nerve head (ONH), which is the site of initial glaucomatous injury. At the ONH, astrocytes play a critical role in maintaining the health of RGC axons. Our preliminary data indicates that agonists of S1R can protect RGCs through cell autonomous effects on RGCs themselves and through non-cell autonomous effects on optic nerve head astrocytes (ONHAs). We find evidence that activation of S1R in ONHAs suppresses astrocyte reactivity and increases release of brain derived neurotrophic factor (BDNF). In addition, previous studies show that S1R agonists not only protect neurons from injury, but also enhance neuronal plasticity and restore neuronal function. In this proposal, we will test the hypothesis that S1R agonists shift the balance of ONHA-mediated support functions in favor of RGC protection. Thus, treatment of ocular hypertensive rats with S1R agonists is proposed to prevent and restore structural and functional deficits in experimental glaucoma. To test our central hypothesis we propose three specific aims: Aim 1: Test the hypothesis that S1R agonists slow progression and rescue structural and functional deficits in experimental glaucoma. Aim 2: Test the hypothesis that S1R directly mediates ONHA reactivity and trophic factor secretion. Aim 3: Test the hypothesis that S1R activation in ONHAs provides neuroprotection for RGCs. .

本研究的目的是探讨sigma-1受体（sigma-1 receptor，S1 R）激活对视网膜节细胞（RGCs）和视神经的影响 头部星形胶质细胞（ONHAs）。青光眼是导致青光眼的主要原因。 在全世界范围内失明，其特征在于视网膜神经节细胞（RGC）的进行性变性。 青光眼的主要危险因素是眼内压（IOP）升高，降低IOP是目前治疗青光眼的主要方法。 唯一的治疗策略。然而，在许多情况下，降低IOP并不能有效地防止 昏迷性视力丧失。因此，需要新的疗法。多功能sigma 1受体的激活 (S1R)是青光眼治疗的有希望的多能靶点。S1 R刺激提供稳健的RGC 在体外和体内都有保护作用，但尚未在青光眼中进行测试。此外， S1 R介导的神经保护作用尚未得到很好的理解。S1 R是一种配体操纵的跨膜蛋白， 在整个视觉系统的RGC和星形胶质细胞中表达。我们对S1 R的理解存在重大缺陷 它对神经胶质细胞的直接影响以及这些影响如何介导神经胶质-神经元相互作用的知识。 星形胶质细胞是视神经乳头（ONH）的主要胶质细胞成分，其是最初的视神经乳头（ONH）的部位。 昏迷性损伤。在ONH中，星形胶质细胞在维持RGC轴突的健康方面起着关键作用。我们 初步数据表明，S1 R激动剂可通过对RGCs的细胞自主作用来保护RGCs 自身和通过非细胞自主作用于视神经头星形胶质细胞（ONHAs）。我们发现 ONHA中S1 R的激活抑制星形胶质细胞的反应性并增加脑释放的证据 衍生神经营养因子（BDNF）。此外，以前的研究表明，S1 R激动剂不仅保护 神经元损伤，而且还增强神经元可塑性和恢复神经元功能。在本提案中，我们 将检验S1 R激动剂改变ONHA介导的支持功能的平衡， RGC保护。因此，建议用S1 R激动剂治疗高眼压大鼠以预防和治疗高眼压。 恢复实验性青光眼的结构和功能缺陷。为了验证我们的核心假设，我们提出 三个具体目标： 目的1：检验S1 R激动剂减缓疾病进展并挽救结构和功能缺陷的假设。 实验性青光眼 目的2：验证S1 R直接介导ONHA反应性和营养因子分泌的假设。 目的3：检验ONHA中S1 R激活为RGC提供神经保护的假设。 .

项目成果

Relationship between Sigma-1 receptor and BDNF in the visual system.

• DOI: 10.1016/j.exer.2017.10.012
• 发表时间: 2018-03
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Mysona BA;Zhao J;Smith S;Bollinger KE
• 通讯作者: Bollinger KE

Sigma 1 receptor: A novel therapeutic target in retinal disease.

• DOI: 10.1016/j.preteyeres.2018.07.003
• 发表时间: 2018-11
• 期刊: Progress in retinal and eye research
• 影响因子: 17.8
• 作者: Smith SB;Wang J;Cui X;Mysona BA;Zhao J;Bollinger KE
• 通讯作者: Bollinger KE

QuPath Automated Analysis of Optic Nerve Degeneration in Brown Norway Rats.

QuPath 自动分析棕色挪威大鼠视神经变性。

• DOI: 10.1167/tvst.9.3.22
• 发表时间: 2020
• 期刊: Translational vision science & technology
• 影响因子: 3
• 作者: Mysona,BarbaraA;Segar,Sharmila;Hernandez,Cecilia;Kim,Christian;Zhao,Jing;Mysona,David;Bollinger,KathrynE
• 通讯作者: Bollinger,KathrynE