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

 描述（由申请人提供）：小窝蛋白-1（Cav-1）是小窝膜微结构域的特征蛋白，与几种眼部/视网膜疾病相关，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。我们已经发现Cav-1和小窝在血视网膜屏障（BRB）的完整性、视网膜离子稳态和视网膜功能中起重要作用。最近，我们发现Cav-1在促进视网膜炎症信号传导和炎症性BRB破坏中起着重要作用。这些结果意味着Cav-1功能的局部破坏提供了抑制视网膜炎性损伤的可行疗法。鉴于目前用于视网膜炎性疾病的基于类固醇的疗法不是完全有效的并且充满了潜在的严重副作用，我们假设Cav-1和小窝结构域代表抑制视网膜炎症的新的治疗靶点。为了有效地评估在视网膜中局部抑制Cav-1功能的治疗潜力，有必要了解这些复杂的细胞内在特性的机制。在这项提议中，我们将使用细胞特异性Cav-1敲除小鼠来测试细胞内在Cav-1功能，希望验证Cav-1作为视网膜炎症，BRB分解和炎症性血管生成的新治疗靶点。该建议的具体目的是：1）确定哪些Cav-1表达细胞在体内促进视网膜炎症信号传导和BRB分解; 2）在两种疾病相关模型（内毒素诱导的葡萄膜炎和急性高眼压症）中测试Cav-1调节炎症信号传导和BRB分解的机制; 3）测试临床前治疗策略以局部破坏Cav-1依赖性炎症信号传导和BRB分解。这些目标明确

 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