Neural Stability after Retinal Detachment

视网膜脱离后的神经稳定性

• 批准号: 8609037
• 负责人: ELLEN S TOWNES-ANDERSON
• 金额: $ 38.96万
• 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/8609037
• 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.

项目摘要/摘要 维修视网膜支队修复后的视觉恢复通常令人失望 报告视力低落的患者。视网膜神经元在 脱离包括杆轴突的缩回，圆锥端子的圆形以及双极和发芽 水平细胞。这些变化中的一些发生在视网膜模型的视网膜损伤后数小时内发生。它一直 建议这种突触重塑导致视觉恢复不良。在视网膜细胞培养物中 Rhoa-Rho激酶（岩石）信号级联的激活主要负责杆轴突 撤回。因此，该申请检验了以下假设 视网膜手术可以通过防止脱离视网膜修复后可显着改善视觉结果 或降低突触可塑性。该假设将在成年猪上进行检验，其眼睛类似于人类 眼睛，关注以下特定目的：1）测试Rhoa拮抗剂是否抑制活性 Rhoa，Rock或它们的底物的结构突触变化会导致分离引起的结构突触变化 包括杆轴突缩回，杆双极突触溶解，锥末端形态变化和 双极细胞发芽。还将检查对神经胶质细胞反应性的影响； 2）确定是否 可分离后可以使用与RhoA相关的药物，更具治疗性相关的情况，如果是的，则可以使用 受伤后多长时间； 3）确定是否确实是用Rhoa相关药物处理的分离的视网膜 在重新锻炼手术后帮助视觉结构和功能恢复。形态学将由 免疫组织化学，图像分析和共聚焦激光扫描和电子显微镜。水平 RHO信号传导的活动和时间顺序将通过多种生化测定确定 包括RhoA活化和肌球蛋白轻链磷酸化的成分。视网膜功能之后 重新计算将通过电视图评估。一些将要测试的药物（CT-04和 Fasudil）已经被批准用于人类使用。我们希望建立大约剂量和 如果Rhoa拮抗剂被证明是手术的有用辅助手术，则需要在患者中进行测试的应用模式 重新观察。