VEGF Antagonism and Resistance to Neovascular AMD

项目总结 新生血管是许多眼科疾病的标志，包括老年性黄斑变性(AMD)。 AMD是一种进行性和退行性疾病，通常影响60岁以上的人，导致 视力丧失。血管内皮生长因子的促血管生成活性参与了新生血管性AMD的发病过程。 因此，NAMD的首选治疗方法是玻璃体内注射抗血管内皮生长因子。不幸的是，对于未知的 原因相当多的患者对抗血管内皮生长因子治疗NAMD的反应很差或没有反应。自.以来 抗血管内皮生长因子治疗增加了治疗负担，增加了包括视网膜在内的视力并发症的风险 对于萎缩性眼内炎和眼内炎，在治疗开始之前确定可能有反应的患者是有益的。 我们的假设是Bim，一个促凋亡的Bcl-2家族成员，抑制了血管内皮生长因子驱动的炎症 脉络膜新生血管(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抗血管内皮生长因子治疗失败的原因。 这里提出的目标将决定抗血管内皮生长因子治疗是否需要BIM表达 使内皮细胞通透性和促血管生成特性正常化。我们将检验比姆的假设 抗血管内皮生长因子治疗NAMD的疗效需要表达，并决定BIM是否单一 核苷酸多态(SNPs)调节抗血管内皮生长因子治疗的效果。这些研究将结合在一起 为我们提供了一个独特的视角，即BIM基因多态是否阻碍了抗血管内皮生长因子治疗的成功 NAMD。因此，生物标记物的开发将减轻治疗负担和潜在的视力风险。 如果不能获得有益的结果，则联合抗血管内皮生长因子治疗。

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.