Enhanced Axon Sparing In Glaucoma Through Augmentation Of EphB/ephrin B Signaling

通过增强 EphB/ephrin B 信号传导增强青光眼中的轴突保护

• 批准号: 8515411
• 负责人: DAVID W SRETAVAN
• 金额: $ 37.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515411
• 关键词: Affect; Age; Alleles; Animals; Area; Astrocytes; Axon; Blindness; Breeding; CMV promoter; Cell Death; Cells; Clinical; Cloning; Complementary DNA; Country; Data; Diet; Disease; Disease model; Disorder by Site; Doxycycline; Drainage procedure; EphB2 Receptor; Ephrin B Receptor; Ephrin-B2; Ephrins; Extracellular Domain; Eye diseases; Family; Gene Deletion; Genetic; Glaucoma; Glial Fibrillary Acidic Protein; Growth; Human; Immunohistochemistry; Incidence; Individual; Injury; Laboratories; Lasers; Lead; Length; Ligands; Link; Mediating; Medical; Microinjections; Modeling; Molecular; Mus; Optic Disk; Optic Nerve; Optic Nerve Injuries; Optics; Partner in relationship; Pathology; Patients; Pattern; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Population; Primates; Process; Production; Protein Fragment; Protein Tyrosine Kinase; Proteins; Randomized; Receptor Protein-Tyrosine Kinases; Research; Retinal; Retinal Ganglion Cells; Risk Factors; Rodent; SHFM1 gene; Scotoma; Signal Pathway; Signal Transduction; Site; Spinal Cord; Testing; Tetanus Helper Peptide; Therapeutic; Tissue Model; Tissues; Trans-Activators; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; Vision; Work; base; disability; expression vector; in vivo; laser photocoagulation; loss of function; mouse model; mutant; new therapeutic target; novel therapeutics; offspring; pressure; prevent; promoter; protein B; response; vector

DESCRIPTION (provided by applicant): Glaucoma is a major debilitating eye disease affecting some 3 million individuals in this country. Of these, an estimated 100,000 patients each year lose some vision despite medical treatment for the normalization of intraocular pressure. As the incidence of glaucoma for the 65 yo.+ population segment is as high as 1 in 20, there is a great need to better understand disease mechanisms underlying optic nerve axon loss and to identify potential therapeutic strategies. A rapidly progressing area of research is th disease-linked up-regulation of intercellular signaling involving the EphB family of receptor tyrosine kinases and their ligands the ephrin-B proteins. Up-regulation of EphB/ephrin-B signaling occurs specificaly at the optic nerve head, an unmyelinated region of the optic nerve that clinical observations and experimental data both point to as a major site contributing to disease. In addition, increased activation of EphB/ephrin-B signaling occurs in two separate mouse models of glaucoma, in primates with experimental glaucoma, and in ONH tissues/cells from human patients, thereby implicating this signaling pathway as a potential key component of pathology. Recent work from our laboratory utilizing animals with genetic deletions and mutant alleles of specific EphB proteins has further demonstrated that animals with deficient EphB/ephrin-B signaling have more severe optic nerve axon loss compared to their wild-type littermates, indicating that EphB and ephrin-B proteins participate in an endogenous axon protective mechanism triggered by as yet incompletely characterized signals at the ONH. The up-regulation of EphB/ephrin-B signaling as an endogenous response in glaucoma is reminiscent of previous work implicating this signaling pathway in modulating axon survival and re-growth after spinal cord and optic nerve injury. Endogenous mechanisms that act to limit axon loss in glaucoma present intriguing targets for therapy. The current proposed research is based on preliminary evidence that the augmentation of EphB/ephrin-B signaling triggered by the application of biologically active EphB2 protein fragments results in a moderation of optic axon loss in an ex vivo tissue model of glaucomatous disease. Here we seek to build upon this finding and determine whether increased EphB and ephrin-B forward as well as reverse signaling in vivo can salvage optic axon loss in a laser-induced mouse model of glaucoma. Augmentation of EphB and B- ephrin signaling will be accomplished using an inducible Tet-on strategy in laser treated mice and optic nerve axon survival compared between animals receiving Doxycycline and those that do not. The results from this work potentially provide support for a novel therapeutic target and encourage additional discovery efforts.

描述（由申请人提供）：青光眼是一种严重的眼部疾病，影响着该国约 300 万人。其中，估计每年有 100,000 名患者尽管接受了眼压正常化的治疗，但仍丧失了部分视力。由于 65 岁以上人群青光眼的发病率高达二十分之一，因此非常需要更好地了解视神经轴突损失的疾病机制并确定潜在的治疗策略。一个快速进展的研究领域是与疾病相关的细胞间信号传导上调，涉及受体酪氨酸激酶 EphB 家族及其配体肝配蛋白 B 蛋白。 EphB/ephrin-B 信号传导的上调特别发生在视神经乳头，视神经乳头是视神经的无髓鞘区域，临床观察和实验数据均表明该区域是导致疾病的主要部位。此外，在两种不同的青光眼小鼠模型、患有实验性青光眼的灵长类动物以及来自人类患者的 ONH 组织/细胞中，EphB/ephrin-B 信号传导的激活增加，从而表明该信号传导途径是病理学的潜在关键组成部分。我们实验室最近利用具有特定 EphB 蛋白基因缺失和突变等位基因的动物进行的研究进一步证明，与野生型同窝动物相比，EphB/ephrin-B 信号传导缺陷的动物具有更严重的视神经轴突损失，表明 EphB 和 ephrin-B 蛋白参与了由尚未完全表征的信号触发的内源性轴突保护机制。 恩。 EphB/ephrin-B 信号传导作为青光眼中的内源性反应的上调让人想起之前的研究，该研究表明该信号传导途径在脊髓和视神经损伤后调节轴突存活和再生长。限制青光眼轴突损失的内源性机制提出了令人感兴趣的治疗目标。目前提出的研究基于初步证据，即通过应用生物活性 EphB2 蛋白片段触发 EphB/ephrin-B 信号增强，导致青光眼疾病离体组织模型中视轴突损失的减轻。在这里，我们试图在这一发现的基础上，确定体内 EphB 和 ephrin-B 正向和反向信号传导的增加是否可以挽救激光诱导的青光眼小鼠模型中的视轴突损失。在激光治疗的小鼠中，使用诱导型 Tet-on 策略可以增强 EphB 和 B-肝配蛋白信号传导，并与接受多西环素的动物和未接受强力霉素的动物相比，视神经轴突的存活率得到增强。这项工作的结果可能为新的治疗靶点提供支持，并鼓励更多的发现工作。