权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8867236
负责人：
DAVID W SRETAVAN
金额：
$ 38.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8867236
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 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 axon injury base disability expression vector in vivo laser photocoagulation loss of function mouse model mutant neurotransmission new therapeutic target novel therapeutics offspring pressure prevent promoter protein B response targeted treatment vector

项目摘要

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）：青光眼是一种主要的使人衰弱的眼病，影响着美国约300万人。其中，估计每年有100，000名患者尽管接受了眼内压正常化的药物治疗，但仍会失去一些视力。青光眼的发病率为65岁以上。由于视神经轴突缺失的患病率高达1/20，因此非常需要更好地了解视神经轴突缺失的疾病机制并确定潜在的治疗策略。一个快速发展的研究领域是与疾病相关的细胞间信号传导的上调，涉及受体酪氨酸激酶的EphB家族及其配体肝配蛋白-B蛋白。EphB/肝配蛋白-B信号传导的上调特异性地发生在视神经头，视神经的无髓鞘区域，临床观察和实验数据都指出其是导致疾病的主要部位。此外，EphB/肝配蛋白-B信号传导的增加的激活发生在两个单独的青光眼小鼠模型中，在患有实验性青光眼的灵长类动物中，以及在来自人类患者的ONH组织/细胞中，从而暗示该信号传导途径是病理学的潜在关键组分。我们实验室最近利用具有特定EphB蛋白的遗传缺失和突变等位基因的动物的工作进一步证明，具有缺陷EphB/肝配蛋白-B信号传导的动物与其野生型同窝仔相比具有更严重的视神经轴突损失，表明EphB和肝配蛋白-B蛋白参与由ONH处尚未完全表征的信号触发的内源性轴突保护机制。EphB/肝配蛋白-B信号传导作为青光眼中的内源性反应的上调使人想起先前的工作，该工作涉及在脊髓和视神经损伤后调节轴突存活和再生长的信号传导途径。限制青光眼轴突丢失的内源性机制为治疗提供了有趣的靶点。目前提出的研究是基于初步证据，即通过应用生物活性EphB 2蛋白片段触发的EphB/肝配蛋白-B信号传导的增强导致在肿瘤疾病的离体组织模型中视神经轴突损失的缓和。在这里，我们试图建立在这一发现，并确定是否增加EphB和ephrin-B正向以及反向信号在体内可以挽救视神经轴突损失激光诱导的小鼠模型青光眼。EphB和B-肝配蛋白信号传导的增强将在激光处理的小鼠中使用可诱导的Tet-on策略来实现，并且在接受多西环素的动物和不接受多西环素的动物之间比较视神经轴突存活。这项工作的结果可能为新的治疗靶点提供支持，并鼓励更多的发现努力。