Neural Stability after Retinal Detachment

视网膜脱离后的神经稳定性

基本信息

批准号：
8238663
负责人：
ELLEN S TOWNES-ANDERSON
金额：
$ 37.27万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
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/8238663
关键词：
Adult Animal Model Axon Biochemical Biological Assay Brain Injuries Cell Culture Techniques Cells 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&apos 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 Cone 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 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

Adult Animal Model Axon Biochemical Biological Assay Brain Injuries Cell Culture Techniques Cells 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&apos 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 Cone 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 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

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项目摘要

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. PUBLIC HEALTH RELEVANCE: Visual outcomes after repair of retinal detachment remain disappointing even years after successful reattachment surgery. Based on the effectiveness of preventing deleterious photoreceptor synaptic change, in vitro, a new therapy is proposed for retinal detachment. The therapy consists of intraocular application of RhoA antagonists combined with relatively rapid retinal reattachment.

描述（由申请人提供）：维修视网膜脱离后的视觉恢复通常令人失望，其中一半以上的患者报告低于正常视力。视网膜神经元在脱离后会经历戏剧性的结构可塑性，包括回缩杆轴突，圆锥末端的圆形以及双极和水平细胞发芽。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。已经提出，这种突触重塑有助于视觉恢复不良。在视网膜细胞培养物中，Rhoa-Rho激酶（岩石）信号级联反应的激活主要负责ROD轴突缩回。因此，该应用检验了以下假设：Rhoa抗逆邦剂和视网膜手术的联合治疗可以通过预防或降低突触可塑性来修复分离的视网膜后的视觉结果。该假设将在成年猪上进行检验，其眼睛与人眼相似，重点是以下特定目的：1）测试RhoA拮抗剂是否抑制Rhoa，Rock或其底物的活性是否会防止由杆子撤回，包括杆 - 双极式突触溶解，锥形术语，CORNINAL MERPHOLICT和BIPART和BIPART和BIPART和BIPART和BIPART和BIPARTIAN和BIPARTIAL COLLATIT cONTICAL-BORD轴突撤回，包括脱离的结构突触变化。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与RhoA相关的药物，更具治疗性相关的情况，如果是这样，受伤后多长时间； 3）确定用RhoA相关药物处理的分离的视网膜是否确实有助于重新手术后的视觉结构和功能恢复。形态将通过免疫组织化学，图像分析和共聚焦激光扫描和电子显微镜进行评估。 RHO信号传导的活性水平和时间顺序将由多种组分（包括RhoA激活和肌球蛋白轻链磷酸化）的生化测定确定。重新计算后的视网膜功能将通过电视图评估。一些将要测试的药物（CT-04和Fasudil）已经被批准用于人类使用。如果Rhoa拮抗剂被证明是手术重新检查的有用辅助手术，我们希望建立在患者中测试的近似剂量和应用方式。公共卫生相关性：维修视网膜超脱后的视觉结局，即使在成功进行手术手术后的几年后，视觉上仍然令人失望。基于预防有害光感受器突触变化的有效性，在体外，提出了一种新的治疗视网膜脱离疗法。该疗法由RhoA拮抗剂的眼内应用，结合了相对较快的视网膜重新连接。