Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity

 描述(申请人提供)：小窝膜微区的标志性蛋白小窝蛋白-1(Cav-1)与几种眼/视网膜疾病有关，包括原发性开角型青光眼、糖尿病视网膜病变和自身免疫性葡萄膜炎。我们发现Cav-1和小窝在血-视网膜屏障(BRB)的完整性、视网膜离子动态平衡和视网膜功能中起着重要作用。最近，我们发现Cav-1在促进视网膜炎症信号转导和炎性BRB分解中起着重要作用。这些结果表明，局部阻断Cav-1功能为抑制视网膜炎性损伤提供了一种可行的治疗方法。鉴于目前基于类固醇的治疗视网膜炎症的方法并不完全有效，并且充满了潜在的严重副作用，我们假设Cav-1和小凹结构域代表着抑制视网膜炎症的新的治疗靶点。为了有效地评估局部抑制视网膜Cav-1功能的治疗潜力，了解这些复杂的细胞固有属性的机制是非常必要的。在这项提案中，我们将使用细胞特异性Cav-1基因敲除小鼠来测试细胞固有的Cav-1功能，希望验证Cav-1作为视网膜炎症、BRB破裂和炎症性血管生成的新治疗靶点。这项建议的具体目的是：1)在体内确定哪些Cav-1表达细胞促进视网膜炎症信号和BRB的破坏；2)在内毒素诱导的葡萄膜炎和急性高眼压两种疾病相关模型中测试Cav-1调节炎症信号和BRB破坏的机制；3)测试临床前治疗策略局部阻断Cav-1依赖的炎症信号和BRB破坏。这些目标有明确的

 DESCRIPTION (provided by applicant): Caveolin-1 (Cav-1), the signature protein of caveolae membrane microdomains, is linked to several ocular/retinal diseases including primary open angle glaucoma, diabetic retinopathy, and autoimmune uveitis. We have found that Cav-1 and caveolae play important roles in blood-retinal barrier (BRB) integrity, retinal ion homeostasis, and retinal function. More recently, we have found that Cav-1 plays a prominent role in promoting retinal inflammatory signaling and inflammatory BRB breakdown. These results imply that local disruption of Cav-1 function presents a viable therapy to suppress retinal inflammatory insults. Given that current steroid- based therapies for retinal inflammatory disease are not completely effective and fraught with potentially severe side effects, we hypothesize that Cav-1 and caveolae domains represent novel therapeutic targets to suppress retinal inflammation. In order to effectively evaluate the therapeutic potential of suppressing Cav-1 function locally in th retina, it is imperative to understand the mechanisms for these complex cell-intrinsic properties. In this proposal we will use cell-specific Cav-1 knockout mice to test cell-intrinsic Cav-1 functions in the hope of validating Cav-1 as a new therapeutic target for retinal inflammation, BRB breakdown, and inflammatory angiogenesis. The specific aims of this proposal are: 1) to determine which Cav-1-expressing cells promote retinal inflammatory signaling and BRB breakdown, in vivo; 2) to test the mechanism by which Cav-1 modulates inflammatory signaling and BRB breakdown in two disease relevant models, endotoxin- induced uveitis and acute ocular hypertension and; 3) to test preclinical therapeutic strategies to locally disrupt Cav-1-dependent inflammatory signaling and BRB breakdown. These goals have clear