Novel Therapies to Prevent Blindness Caused by Proliferative Vitreoretinopathy

项目总结/摘要 视网膜脱离和严重眼外伤后发生的玻璃体视网膜病变（PVR） 视网膜前和视网膜下瘢痕形成，这是治疗效果差的主要决定因素之一， 这些病人。重要的是，PVR可在超过50%的穿孔伤患者中发现 视网膜脱离患者的发病率高达10%。尽管PVR的病理生理学机制并不完全清楚， 据了解，目前的证据涉及各种细胞类型，包括视网膜色素上皮（RPE） 异常的伤口愈合反应这项工作的长期目标是开发一种新的 有效预防或治疗这种反应的策略，以降低失明或 PVR导致的永久性视力丧失。这项建议的健康相关性是成功的， 这项工作的完成可能会导致受影响个人的视力得到保护。 最近的研究支持了控制EMP 2（上皮膜蛋白2）或其 下游信号通路，可能会改变RPE细胞的生物反应，并预防或治疗 PVR。在这个拨款申请中提出的具体目标将测试这一假设，即下调 EMP 2或其信号转导通路在体外对PVR的预防或治疗均有效 以及在疾病的体内动物模型中。将在动物模型中使用三种不同的方法 包括一种目前用于癌症治疗的抑制剂，一种在我们的研究中开发的设计抗体， 实验室，和生化途径的小分子抑制剂。顺利完成工作 本基金申请中提出的建议将确定预防或早期治疗的最佳策略， PVR。重要的是，这项工作还将确定动物模型中的眼部安全性特征，以便进行 临床前研究是考虑未来人类疾病临床试验所必需的。 这项工作的重大影响将是确定潜在的治疗策略，以预防PVR 通过在视网膜脱离或穿孔性眼损伤的初始修复时进行治疗，或作为 治疗已确诊的PVR的药物。预计， 本补助金申请中提出的研究将构成科学证据的基础， 可以很快用于人类疾病的临床试验。临床试验超出了 目前提交的材料，可能会导致新的治疗方法，并导致视力恢复或预防 眼外伤或视网膜脱离导致失明的原因。这项工作有潜力， 推进研究领域，并最终改变受影响个体的护理标准， 与通过跨学科研究改善医疗保健的战略目标保持一致。

Project Summary/Abstract Proliferative vitreoretinopathy (PVR) occurs after retinal detachment and severe ocular trauma and leads to both pre-retinal and subretinal scar formation, one of the major determinants of poor outcomes for these patients. Importantly, PVR may be found in greater than 50% of patients with perforating injuries and in up to 10% of retinal detachment patients. Although the pathophysiology of PVR is not completely understood, current evidence implicates various cell types including the retinal pigment epithelium (RPE) in an aberrant wound healing response. The long term objectives of this work is to develop a new strategy to effectively prevent or treat this response in order to decrease the risk of blindness or permanent loss of vision from PVR. The health relatedness of this proposal is that successful completion of this work could lead to preservation of vision in affected individuals. Recent studies support the hypothesis that control EMP2 (epithelial membrane protein 2), or its downstream signaling pathway, may change the biologic response of RPE cells and prevent or treat PVR. The specific aims proposed in this grant submission will test the hypothesis that downregulation of EMP2 or its signal transduction pathway could be effective in prevention or therapy of PVR both in vitro and in an in vivo animal model of disease. Three different approaches will be used in the animal models including an inhibitor that is used currently in cancer therapy, a designer antibody developed in our laboratory, and a small molecule inhibitor of a biochemical pathway. Successful completion of the work proposed in this grant submission will identify the optimum strategy for prevention or early therapy for PVR. Importantly this work will also define the ocular safety profile in an animal model in order to perform the preclinical studies necessary to contemplate future clinical trials in human disease. The significant impact of this work will be to identify potential therapeutic strategies for prevention of PVR through treatment at the time of initial repair of retinal detachment or perforating ocular injury or as an adjunctive agent in treatment of established PVR. It is anticipated that successful completion of the studies proposed in this grant application would form the basis of the scientific evidence that could quickly lead to clinical trials in human disease. The clinical trials, beyond the scope of the present submission, could potentially lead to new therapies and result in restoration of sight or prevention of blindness following penetrating ocular trauma or retinal detachment. This work has potential to both advance the field of research and to ultimately change the standard of care for affected individuals and is aligned with the strategic goals of improving healthcare through interdisciplinary research.