Novel Therapies to Prevent Blindness Caused by Proliferative Vitreoretinopathy

项目摘要/摘要 增殖性玻璃体视网膜病变(PVR)发生在视网膜脱离和严重的眼外伤后 对于视网膜前和视网膜下瘢痕的形成，是预后不良的主要决定因素之一 这些病人。重要的是，超过50%的穿孔伤患者可以发现PVR。 在高达10%的视网膜脱离患者中。尽管PVR的病理生理机制并不完全 了解，目前的证据涉及多种细胞类型，包括视网膜色素上皮(Rpe)。 以一种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，以减少失明或 PVR导致永久性失明。这项与健康相关的建议是成功的 这项工作的完成可能会使受影响的人保持视力。 最近的研究支持这样一种假设，即控制EMP2(上皮膜蛋白2)或其 下游信号通路，可能改变RPE细胞的生物反应，预防或治疗 PVR。这份拨款申请中提出的具体目标将检验这样一个假设，即下调对 EMP2或其信号转导通路在体外均可有效防治PVR 在疾病的活体动物模型中。在动物模型中将使用三种不同的方法 包括目前用于癌症治疗的一种抑制剂，我们开发的一种设计抗体 实验室，以及一种生化途径的小分子抑制物。工程圆满完成 在这份赠款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，这项工作还将在动物模型中定义眼睛安全概况，以便进行 为考虑未来人类疾病的临床试验所必需的临床前研究。 这项工作的重大影响将是确定预防PVR的潜在治疗策略 在视网膜脱离或眼球穿通伤最初修复时通过治疗或作为 辅助剂在治疗已建立的PVR中的作用。预计该项目的顺利完成 这项拨款申请中提出的研究将构成科学证据的基础，即 可能很快导致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 穿透性眼外伤或视网膜脱离后的失明。这项工作对两者都有潜力 推进研究领域，并最终改变对受影响个人和IS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.