VEGF Antagonism and Resistance to Neovascular AMD

项目摘要 新生血管形成是包括年龄相关性黄斑变性（AMD）在内的许多眼部疾病的标志。 AMD是一种进行性和退行性疾病，其影响通常超过60岁的个体，导致 视力丧失VEGF的促血管生成活性有助于新生血管性AMD（nAMD）的发病机制。 因此，nAMD的治疗选择是玻璃体内施用抗VEGF。不幸的是，对于未知的 原因是相当多的患者对抗VEGF治疗nAMD的反应很差或没有反应。以来 抗VEGF治疗会增加治疗负担和视力并发症的风险， 萎缩和眼内炎，识别患者可能响应治疗开始之前是有益的。 我们的假设是Bim，一个促凋亡Bcl-2家族成员，抑制VEGF驱动的炎症 和脉络膜新生血管形成（CNV）。在这项建议中，我们将采取创新的方法， 确定Bim表达的遗传变异是否是nAMD抗VEGF治疗失败的原因。 本文提出的目的将确定Bim表达是否是抗VEGF治疗所必需的， 使内皮细胞渗透性和促血管生成特性正常化。我们将检验一个假设， 表达对于nAMD的抗VEGF治疗的功效是需要的，并且确定Bim单次 核苷酸多态性（SNP）调节抗VEGF治疗的功效。这些研究将 这为我们提供了一个独特的视角，即Bim多态性是否会阻碍抗VEGF治疗的成功， nAMD。因此，生物标志物的开发将减轻治疗负担和潜在的视力风险 如果没有获得有益的结果，则与抗VEGF治疗相关。

PROJECT SUMMARY Neovascularization is a hallmark of many ocular diseases including age-related macular degeneration (AMD). AMD is a progressive and degenerative disease that affects individuals typically over the age of 60 leading to vision loss. The proangiogenic activity of VEGF contributes to the pathogenesis of neovascular AMD (nAMD). Thus, the treatment of choice for nAMD is intravitreal administration of anti-VEGF. Unfortunately, for unknown reasons a significant number of patients have poor to no response with anti-VEGF therapy for nAMD. Since anti-VEGF therapy comes with increased treatment burden and risk of vision complications including retinal atrophy and endophthalmitis, identifying patients likely to respond prior to the onset of treatment is beneficial. Our hypothesis is that Bim, a pro-apoptotic Bcl-2 family member, restrains VEGF-driven inflammation and choroidal neovascularization (CNV). In this proposal we will take the innovative approach of determining whether genetic variation in Bim expression is responsible for anti-VEGF therapy failure for nAMD. The aims proposed here will determine whether Bim expression is required for anti-VEGF treatment to normalize endothelial cell permeability and proangiogenic properties. We will test the hypothesis that Bim expression is needed for the efficacy of anti-VEGF treatment of nAMD and determine whether Bim single nucleotide polymorphisms (SNPs) modulate the efficacy of anti-VEGF treatment. Together these studies will give us a unique perspective as to whether Bim polymorphisms impede the success of anti-VEGF therapy for nAMD. Thus, development of a biomarker will alleviate the treatment burden and potential vision risks associated with anti-VEGF therapy if no beneficial outcome will be obtained.