New Treatments of Ocular Neovascularization and Macular Edema

项目摘要/摘要 视网膜和脉络膜血管疾病，包括与年龄相关的新生血管 黄斑变性(NVAMD)、糖尿病视网膜病变(DR)和视网膜静脉 闭塞(RVO)是目前为止中、重度最常见的原因 在美国的视力丧失。在过去的赠款期间，我们的实验室帮助识别和 验证血管内皮生长因子(VEGF)作为关键刺激因子的作用。血管内皮生长因子 拮抗剂现在已经成为NVAMD和黄斑水肿的标准护理，原因是 DR或RVO。这为大量患者提供了巨大的好处，但 人们担心血管内皮生长因子拮抗剂会导致视网膜损伤。在.期间 在过去的授权期内，我们证明了血管内皮生长因子拮抗剂不会损害正常 视网膜，但它们仍有可能使视网膜更容易受到 压力造成的损害。在第一个目标中，将彻底调查这一假说。 虽然血管内皮生长因子拮抗剂为患有 以上病程中，仍有大量患者 回答不完整或很少，需要更多的东西。其他刺激物已经被 一种策略是在它们的每一个上添加拮抗剂，从而产生多个 药物联合治疗。然而，血管内皮生长因子和其他刺激物都是 由缺氧诱导因子-1(HIF-1)上调，在第二个目标中，我们将 探讨利用HIF-1拮抗剂实现单一药物治疗的策略 “联合疗法。”Tie2是一种内皮细胞受体，当受到刺激时 使血管对血管内皮生长因子和其他刺激物无反应，因此 阻断新生血管和过度渗漏。在第三个目标中，我们将探索一个 保留Tie2获得单一药物“联合疗法”的第二个新途径 在具有特定Tie2磷酸酶拮抗剂的激活状态下，人 蛋白酪氨酸磷酸酶-b(HPTP-b)。这项提议的潜在影响是 高，因为它将提供有关阻塞效果的重要信息 视网膜中的血管内皮生长因子，这是一种快速增长的治疗多种视网膜疾病的药物。 此外，该提案使用了新的策略来同时抑制其他 除血管内皮生长因子外的刺激物，并确定是否有任何好处和/或 这样做会带来不利的后果。基于过去的成功，合理的做法是 预测这项提案的结果将导致新的临床试验。

Project Summary/Abstract Retinal and choroidal vascular diseases, which include neovascular age-related macular degeneration (NVAMD), diabetic retinopathy (DR), and retinal vein occlusions (RVO), are by far the most prevalent causes of moderate and severe vision loss in the US. During past grant periods, our laboratory helped to identify and validate vascular endothelial growth factor (VEGF) as a critical stimulator. VEGF antagonists have now become standard care for NVAMD and macular edema due to DR or RVO. This has provided tremendous benefit to large numbers of patients, but concern has been raised that VEGF antagonists cause retinal damage. During the past grant period, we demonstrated that VEGF antagonists do not damage normal retina, but it is still possible that they may make the retina more susceptible to damage from stress. In the first aim, this hypothesis will be thoroughly investigated. While VEGF antagonists have provided tremendous benefit for patients with the above disease processes, there are still a large number of patients who have incomplete or little response and need something more. Other stimulators have been identified and one strategy is to add antagonists to each of them resulting in multi- drug combination therapy. However, VEGF and the other stimulators are all upregulated by hypoxia-inducible factor-1 (HIF-1) and in the second aim we will investigate the strategy of using HIF-1 antagonists to achieve single drug "combination therapy." Tie2 is an endothelial cell receptor that when stimulated makes blood vessels unresponsive to VEGF and the other stimulators and hence blocks neovascularization and excessive leakage. In the third aim, we will explore a second novel approach to obtain single drug "combination therapy" by keeping Tie2 in an activated state with an antagonist to a specific Tie2 phosphatase, human protein tyrosine phosphatase-b (HPTP-b). The potential impact of this proposal is high because it will provide important information regarding the effects of blocking VEGF in the retina, which is a rapidly growing treatment for several retinal diseases. In addition, the proposal uses novel strategies to simultaneously suppress additional stimulators in addition to VEGF and determine if there are any benefits and/or adverse consequences for doing so. Based upon past successes, it is reasonable to predict that findings from this proposal will lead to new clinical trials.