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

Caveolin-1 在维持血视网膜屏障完整性中的作用

基本信息

批准号：
8963726
负责人：
MICHAEL H ELLIOTT
金额：
$ 36.78万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2017-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8963726
关键词：
Acute Adverse effects Age related macular degeneration Animal Model Anti-Inflammatory Agents Anti-inflammatory Bioavailable Biological Availability Blood Vessels Blood-Retinal Barrier CAV1 gene Caveolae Cells Complex Diabetes Mellitus Diabetic Retinopathy Disease Endotoxins Enzymes Experimental Diabetes Mellitus Eye diseases Flavonols Funding Genes Glaucoma Goals Homeostasis Hyperactive behavior Immune Immune response Inflammation Inflammatory Inflammatory Response Injury Ions Isoflavones Knockout Mice Link Maintenance Mediating Membrane Microdomains Modeling Natural Immunity Nitric Oxide Ocular Hypertension Outcome Pathology Physiologic Intraocular Pressure Play Positioning Attribute Preclinical Testing Primary Open Angle Glaucoma Production Property Proteins Regulation Reperfusion Injury Reporting Retina Retinal Retinal Diseases Risk Role Signal Transduction Steroids Testing Therapeutic Tissues Treatment Efficacy Uveitis Work acid sphingomyelinase angiogenesis autoimmune uveitis base caveolin 1 cytokine daidzein glycation human NOS3 protein improved in vivo inhibitor/antagonist new therapeutic target novel novel therapeutics pathogen pre-clinical public health relevance response to injury retinal damage toll-like receptor 4 tool

项目摘要

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

描述（由申请人提供）：Caveolin-1 (Cav-1) 是小窝膜微结构域的标志蛋白，与多种眼部/视网膜疾病有关，包括原发性开角型青光眼、糖尿病性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) 完整性、视网膜离子稳态和视网膜功能中发挥重要作用。最近，我们发现 Cav-1 在促进视网膜炎症信号传导和炎症 BRB 分解中发挥着重要作用。这些结果表明，局部破坏 Cav-1 功能是抑制视网膜炎症损伤的可行疗法。鉴于目前基于类固醇的视网膜炎症疗法并不完全有效并且充满潜在的严重副作用，我们假设 Cav-1 和小凹结构域代表了抑制视网膜炎症的新治疗靶点。为了有效评估视网膜局部抑制 Cav-1 功能的治疗潜力，必须了解这些复杂的细胞固有特性的机制。在本提案中，我们将使用细胞特异性 Cav-1 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 破坏和炎症血管生成的新治疗靶点。该提案的具体目标是：1）确定哪些表达 Cav-1 的细胞在体内促进视网膜炎症信号传导和 BRB 分解； 2)测试Cav-1在内毒素诱导的葡萄膜炎和急性高眼压这两种疾病相关模型中调节炎症信号传导和BRB分解的机制； 3) 测试局部破坏 Cav-1 依赖性炎症信号传导和 BRB 分解的临床前治疗策略。这些目标有明确的