Neural Stability after Retinal Detachment

视网膜脱离后的神经稳定性

• 批准号: 8782542
• 负责人: ELLEN S TOWNES-ANDERSON
• 金额: $ 30.21万
• 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/8782542
• 关键词: Neural; Stability; after; Retinal; Detachment

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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。视网膜神经元在脱离后经历显着的结构可塑性，包括杆状轴突的回缩、锥体末端的变圆以及双极和水平细胞的萌芽。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。有人认为这种突触重塑会导致视力恢复不良。在视网膜细胞培养物中，RhoA-Rho 激酶 (ROCK) 信号级联的激活主要负责视杆细胞轴突的收缩。因此，本申请测试了这样的假设：RhoA拮抗剂和视网膜手术的联合治疗可以通过防止或减少突触可塑性来显着改善脱落视网膜修复后的视觉结果。该假设将在成年猪上进行测试，其眼睛与人眼相似，重点关注以下具体目标：1）测试抑制RhoA、ROCK或其底物活性的RhoA拮抗剂是否会阻止由脱离引起的结构性突触变化，包括杆状轴突回缩、杆状双极突触溶解、锥状末端形态变化和双极细胞出芽。还将检查对神经胶质细胞反应性的影响； 2) 确定在脱离后是否可以使用 RhoA 相关药物，这是一种与治疗更相关的情况，如果可以，受伤后需要多长时间； 3) 确定用 RhoA 相关药物治疗的视网膜脱离是否确实有助于复位手术后视觉结构和功能的恢复。将通过免疫组织化学、图像分析、共焦激光扫描和电子显微镜评估形态学。 Rho 信号传导的活性水平和时间进程将通过多种成分的生化测定来确定，包括 RhoA 激活和肌球蛋白轻链磷酸化。重新附着后的视网膜功能将通过视网膜电图进行评估。一些将要测试的药物（Ct-04 和法舒地尔）已被批准用于人类。如果 RhoA 拮抗剂被证明是手术复位的有用辅助手段，我们希望确定在患者中进行测试的大致剂量和应用方式。