Emp2: Potential Control Of Pathology In Retinal Pigment Epithelium

描述(由申请人提供)： 这项拟议工作的长期目标是为临床护理开发新的治疗方法，以预防创伤或视网膜脱离后的增殖性玻璃体视网膜病变，这两种疾病都是导致退伍军人丧失视力的主要原因。导致视力丧失的原因之一是眼睛创伤，这是现代战争中不幸的一种常见致病原因。增生性玻璃体视网膜病变(PVR)见于30%以上的眼球穿孔伤患者，是导致这些患者预后不良的主要决定因素之一。最近的研究支持一种假说，阻断一种特定的蛋白质，上皮膜蛋白2(EMP2)或其下游信号通路，可能控制RPE细胞的生物反应，降低PVR的可能性。重要的是，如果这一假设得到证实，那么这项工作就为开发治疗或预防这些致盲疾病的新疗法铺平了道路。为了检验这一假设，这一提议有三个具体目标。1)研究EMP2对体外培养的视网膜色素上皮细胞(RPE)功能的影响。在这一目标中，建立的RPE细胞株将用于研究EMP2阻断对细胞存活的影响，细胞信号转导机制，以及收缩胶原胶原凝胶的能力。此外，这一目标验证了通过联合靶向EMP2和FAK/Src通路可以实现剂量协同和降低毒性的预测。2)探讨EMP2及其信号通路与人PVR及其他增生性视网膜疾病的关系。这一目标的潜在和可检验的假设是，EMP2及其相关的信号通路在人PVR的RPE的病理生理行为中起关键作用。3)通过阻断EMP2或其信号转导通路预防PVR的体内实验。这项建议的最终目标是完成临床前研究，以确定在PVR的实验性兔模型中，使用特定的工程抗EMP2抗体阻断EMP2或使用小分子抑制剂FAK/Src磷酸化是否可以在将毒性降至最低的同时消除实验诱导的PVR。预计这项申请中建议的研究的成功完成将很快导致人类疾病的临床试验。这些临床试验超出了本报告的范围，可能会导致新的治疗方法，并导致穿透性眼外伤或视网膜脱离后恢复视力或预防失明。这项工作既有可能推动研究领域的发展，也有可能最终改变受影响个人的护理标准。 公共卫生相关性： 拟议的研究与退伍军人健康和/或医疗保健问题的相关性。视力丧失是退伍军人发病的主要原因，是糖尿病或老年性黄斑变性等慢性或退行性疾病以及创伤或自发性视网膜脱离的结果。增殖性玻璃体视网膜病变(PVR)是导致眼外伤或视网膜脱离后失明的主要原因之一。开发一种预防或治疗PVR的特定疗法，这是本提案的目标，与退伍军人事务部任务的健康相关性直接相关。预计成功完成这项赠款申请中提出的研究将很快导致人类疾病的临床试验。这些临床试验超出了本报告的范围，可能会导致新的治疗方法，并导致穿透性眼外伤或视网膜脱离后恢复视力或预防失明。

DESCRIPTION (provided by applicant): The long term objectives of the proposed work is to develop new therapeutic approaches for clinical care in prevention of proliferative vitreoretinopathy following trauma or retinal detachment, both major causes for loss of vision in veterans. One cause for vision loss is ocular trauma, an unfortunately common cause of morbidity in modern warfare. Proliferative vitreoretinopathy (PVR) is found in greater than 30% of patients with perforating injuries of the eye, and is one of the major determinants of poor outcomes for these patients. Recent studies support the hypothesis that blockade of a specific protein, epithelial membrane protein 2 (EMP2), or its downstream signaling pathway, may control the biologic response of RPE cells and decrease the potential for PVR. Importantly, if this hypothesis is confirmed then this work paves the way towards developing new therapies to treat or prevent these blinding diseases. In order to test the hypothesis there are three specific aims of this proposal. 1) Characterize consequences of EMP2 blockade on retinal pigment epithelial cell (RPE) functions in vitro. In this aim established RPE cell lines will be used to study the effect of EMP2 blockade on cell survival, cell signal transduction mechanisms, and ability to contract collagen gels. In addition, this aim tests the prediction that dose synergy with reduced toxicity could be achieved through combined targeting of EMP2 and the FAK/Src pathway. 2) Evaluate the association of EMP2 and its signaling pathways in human PVR and other scarring retinal diseases. The underlying and testable hypothesis of this aim is that EMP2 and its associated signaling pathways are key players in the pathophysiologic behavior of RPE in human PVR. 3) Test prevention of PVR through blockade of EMP2 or its signaling pathways in vivo. The ultimate goal of this proposal is to complete preclinical studies to define whether, in an experimental rabbit model of PVR, blockade of EMP2 using a specific engineered anti-EMP2 antibody or FAK/Src phosphorylation using a small molecule inhibitor will abrogate experimentally-induced PVR while minimizing toxicity. It is anticipated that successful completion of the studies proposed in this application could quickly lead to clinical trials in human disease. The clinical trials, which are 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 the potential to both advance the field of research and to ultimately change the standard of care for affected individuals. PUBLIC HEALTH RELEVANCE: Relevance of the proposed research to Veterans health and/or healthcare issues. Vision loss is a major cause of morbidity among veterans and results from chronic or degenerative diseases such as diabetes mellitus or age-related macular degeneration as well as trauma or spontaneous retinal detachments. One major cause of blindness after ocular trauma or retinal detachment is proliferative vitreoretinopathy (PVR). Development of a specific therapy to either prevent or treat PVR, the goal of this proposal, is directly relevant to the health relatedness of the VA mission. It is anticipated that successful completion of the studies proposed in this grant application could quickly lead to clinical trials in human disease. The clinical trials, which are 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.