Bcl-2 and ocular neovascularization

描述（由申请人提供）：视网膜新生血管和脉络膜新生血管（CNV）发生在早产儿视网膜病变（ROP）和年龄相关性黄斑变性（AMD）中，是失明的主要原因。促血管内皮生长因子（VEGF）在这些疾病中起着重要的作用。因此，玻璃体内给药抗vegf已被广泛用于治疗渗出性AMD和ROP。然而，玻璃体内给药抗VEGF进入全身循环，导致VEGF的长期抑制，这可能导致脱靶效应，包括肾血栓性微血管病变、心肌梗死和中风。Bcl-2是下游事件响应的关键介质，包括促和抗血管生成因子，包括VEGF和血栓反应蛋白-1 （TSP1）。由于Bcl-2具有选择性破坏肿瘤血管和诱导细胞凋亡的能力，它已成为癌症治疗方案的靶点。我们的假设是抑制bcl-2的表达和/或活性将阻止脉络膜和视网膜新生血管。我们的研究表明，vegf驱动的视网膜新生血管需要bcl-2的表达，这一假设得到了支持。此外，去除bc-2的单个等位基因足以减弱CNV。在本研究中，我们采用创新的方法，将bcl-2拮抗剂与组蛋白去乙酰化酶（HDAC）抑制剂联合使用，选择性地阻止眼部新生血管的形成。确定bcl-2的表达是否在内皮细胞和/或血管周围支持细胞中对脉络膜和视网膜新生血管形成至关重要，将使我们进一步了解这两种类型的新生血管形成是否依赖于相似的途径。这些研究结合起来将给我们一个独特的视角来确定最有效的治疗策略，以抑制视网膜和脉络膜新生血管，避免脱靶全身效应。

DESCRIPTION (provided by applicant): Retinal neovascularization and choroidal neovascularization (CNV), as occur in retinopathy of prematurity (ROP) and age-related macular degeneration (AMD), are major causes of blindness. A significant role for the proangiogenic vascular endothelial growth factor (VEGF) has been established in these diseases. Therefore, intravitreal administration of anti-VEGF has been greatly pursued as treatment for exudative AMD and ROP. However, intravitreal administration of anti-VEGF enters the general circulation resulting in prolonged inhibition of VEGF, which may cause off-target effects including renal thrombotic microangiopathy, myocardial infarction and stroke. Bcl-2 is a key mediator of downstream events in response to both pro- and anti-angiogenic factors, including VEGF and thrombospondin-1 (TSP1). Bcl-2 has been a target of cancer therapeutic regimens due to its ability to selectively disrupt tumor blood vessels and induce apoptosis. Our hypothesis is that inhibition of bcl-2 expression and/or activity will prevent choroidal and retina neovascularization. This hypothesis is supported by our studies showing that VEGF-driven retinal neovascularization requires bcl-2 expression. In addition, removal of a single allele of bc-2 is sufficient to attenuate CNV. In this proposal we take the innovative approach of using bcl-2 antagonists in concert with histone deacetylase (HDAC) inhibitors to selectively prevent ocular neovascularization. Identification of whether bcl-2 expression is essential in endothelial cells and/or perivascular supporting cells for choroidal and retinal neovascularization will give us further insight as to whether both types of neovascularization rely on similar pathways. These studies in combination will give us a unique perspective to identify the most effective treatment strategies to inhibit retinal and choroidal neovascularization and avoid off-target systemic effects.