Neural Stability after Retinal Detachment

视网膜脱离后的神经稳定性

• 批准号: 8928267
• 负责人: ELLEN S TOWNES-ANDERSON
• 金额: $ 4.22万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928267
• 关键词: Adult; Animal Model; Axon; Biochemical; Biological Assay; Brain Injuries; Cell Culture Techniques; Cells; Cone; Data; Degenerative Disorder; Effectiveness; Electron Microscopy; Electrons; Electroretinography; Elements; Eye; Family suidae; Glial Fibrillary Acidic Protein; Goals; Guanosine Triphosphate Phosphohydrolases; Hour; Human; Image Analysis; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Injury; LIM Domain Kinase 1; Lasers; Light; Microscopic; Modification; Morphology; Muller' s cell; Myosin Light Chain Kinase; Myosin Light Chains; Neuraxis; Neuroglia; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Photoreceptors; Presynaptic Terminals; Prevention; Publishing; Recovery; Recovery of Function; Reporting; Retina; Retinal; Retinal Detachment; Rho-associated kinase; Scanning Electron Microscopy; Signal Pathway; Signal Transduction; Site; Spinal cord injury; Structure; Synapses; Synaptic plasticity; Testing; Time; Up-Regulation; Vision; Visual; Visual Acuity; Visual system structure; Western Blotting; abstracting; base; central nervous system injury; cytotoxicity; density; design; dosage; drug testing; fasudil; horizontal cell; immunocytochemistry; improved; in vivo Model; light microscopy; prevent; relating to nervous system; repaired; research study; response to injury; retinal neuron; retinal rods; rho; therapeutic target

Project Summary/Abstract Visual recovery after repair of a retinal detachment is often disappointing with more than half of treated patients reporting below normal visual acuity. Retinal neurons undergo dramatic structural plasticity after detachment including retraction of rod axons, rounding of cone terminals, and sprouting by bipolar and horizontal cells. Some of these changes occur within hours after retinal injury in animal models. It has been suggested that this synaptic remodeling contributes to poor visual recovery. In retinal cell cultures, activation of the RhoA-Rho kinase (ROCK) signaling cascade is primarily responsible for rod axon retraction. Thus, this application tests the hypothesis that a combined therapy of RhoA-antagonists and retinal surgery may significantly improve the visual outcome after repair of a detached retina by preventing or reducing synaptic plasticity. This hypothesis will be tested on adult pigs, whose eyes are similar to human eyes, focusing on the following specific aims: 1) To test whether RhoA antagonists which inhibit the activity of RhoA, ROCK, or their substrates will prevent the structural synaptic changes caused by detachment including rod axon retraction, rod-bipolar synaptic dissolution, cone terminal morphological change, and bipolar cell sprouting. The effect on glial cell reactivity will also be examined; 2) To determine whether RhoA-related drugs can be applied after a detachment, a more therapeutically relevant scenario, and if so, how long after the injury; and 3) To determine if detached retinas treated with RhoA-related drugs indeed help visual structural and functional recovery after reattachment surgery. Morphology will be assessed by immunohistochemistry, image analysis and confocal laser scanning and electron microscopy. Levels of activity and the time-course of Rho signaling will be determined by biochemical assays for multiple components including RhoA activation and myosin light chain phosphorylation. Retinal function after reattachment will be assessed by electroretinograms. Some of the drugs that will be tested (Ct-04 and fasudil) have already been approved for human use. We hope to establish the approximate dosage and mode of application to be tested in patients, if RhoA antagonists prove to be a useful adjunct to surgical reattachment.

项目概要/摘要 视网膜脱离修复后的视力恢复往往令人失望，超过一半的接受治疗的患者 报告视力低于正常水平的患者。视网膜神经元经历戏剧性的结构可塑性 分离包括杆状轴突的回缩、锥体末端的变圆以及双极和发芽 水平单元格。在动物模型中，其中一些变化在视网膜损伤后数小时内发生。它一直 表明这种突触重塑会导致视力恢复不良。在视网膜细胞培养中， RhoA-Rho 激酶 (ROCK) 信号级联的激活主要负责杆状轴突 撤回。因此，本申请测试了 RhoA 拮抗剂和 RhoA 拮抗剂的联合疗法的假设 视网膜手术可以通过预防视网膜脱落来显着改善修复脱离视网膜后的视力结果 或降低突触可塑性。这一假设将在成年猪身上进行测试，它们的眼睛与人类相似 眼睛，重点关注以下具体目标：1）测试RhoA拮抗剂是否抑制活性 RhoA、ROCK 或它们的底物将防止分离引起的结构突触变化 包括杆状轴突回缩、杆状双极突触溶解、锥体末端形态变化，以及 双极细胞出芽。还将检查对神经胶质细胞反应性的影响； 2）判断是否 RhoA相关药物可以在脱离后应用，这是一种更具治疗相关性的情况，如果是这样， 受伤后多久； 3) 确定视网膜脱离是否确实用 RhoA 相关药物治疗 帮助复位手术后视觉结构和功能的恢复。形态学将通过以下方式评估 免疫组织化学、图像分析、共焦激光扫描和电子显微镜。级别 Rho 信号传导的活性和时间进程将通过多种生化测定来确定 包括 RhoA 激活和肌球蛋白轻链磷酸化。术后视网膜功能 重新附着将通过视网膜电图进行评估。一些将被测试的药物（CT-04和 fasudil）已被批准用于人类。我们希望确定大概的剂量和 如果 RhoA 拮抗剂被证明是手术的有用辅助药物，则应在患者中测试应用模式 重新附着。