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

• 批准号: 9563983
• 负责人: MICHAEL H ELLIOTT
• 金额: $ 36.03万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9563983
• 关键词: Ablation; Address; Adverse effects; Age related macular degeneration; Anti-inflammatory; Biological Response Modifiers; Blindness; Blood Vessels; Blood-Retinal Barrier; CAV1 gene; Cardiovascular Physiology; Caveolae; Cells; Complex; Development; Diabetic Retinopathy; Disease; Eye diseases; Functional disorder; Genes; Glaucoma; Goals; Homeostasis; Immune signaling; Immunologic Receptors; Inflammation; Inflammatory; Inflammatory Response; Ions; Isoflavones; Knockout Mice; Link; Maintenance; Mediating; Membrane; Modeling; Nerve Degeneration; Neuroglia; Pathologic; Pharmacology; Physiology; Play; Preclinical Testing; Primary Open Angle Glaucoma; Production; Property; Proteins; Regulation; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Risk; Role; Signal Transduction; Steroids; TLR4 gene; TNF receptor-associated factor 3; TNFRSF5 gene; Testing; Tissues; Toll-like receptors; Treatment Efficacy; Ubiquitination; autoimmune uveitis; base; caveolin 1; cytokine; daidzein; immune activation; in vivo; neurovascular; neurovascular unit; new therapeutic target; novel; pathogen; retinal damage; targeted treatment; therapeutic evaluation

Project Summary/Abstract Caveolin-1 (Cav-1), the signature protein of caveolae membrane domains, 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, ion homeostasis, and retinal function. More recently, we have found that Cav-1 promotes the activation of Toll-like Receptor-4 (TLR4) propagating TLR4-induced cytokine production and inflammatory BRB breakdown. As Cav-1 is upregulated in several retinal inflammatory conditions, our 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 resulting from pathogens as well as from endogenous damage that occurs during retinal degenerative diseases. However, as Cav-1 plays several important roles in retinal homeostasis and cardiovascular function, we must carefully evaluate the cell and tissue-intrinsic roles of this protein to determine the potential of suppressing Cav-1 function locally in the 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 neurodegeneration induced by inflammation. We will test a novel mechanism whereby Cav-1 modulates the stability of TNF Receptor Associated Factor 3 (TRAF3) a downstream signaling component of innate immune receptors such as TLR4. TRAF3 is abundantly expressed in the retina but has yet to be rigorously studied as a local regulator of immune signaling. The goals of this proposal are to determine the mechanism(s) by which Cav-1 modulates retinal inflammatory signaling, BRB breakdown, and neurodegeneration induced by both pathogen- and damage-derived immune activation. We will also examine the mechanism by which Cav-1 controls retinal TRAF3 levels. These goals have clear

项目摘要/摘要 小窝蛋白-1(Cav-1)是小窝膜结构域的标志性蛋白，与多种眼/视网膜相关 疾病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。我们有 发现Cav-1和Caveolae在血视网膜屏障(BRB)的完整性、离子稳态、 和视网膜功能。最近，我们发现Cav-1促进Toll样受体-4的激活 (TLR4)传播TLR4诱导的细胞因子的产生和炎性BRB的破坏。和CAV-1一样 我们的结果表明，在几种视网膜炎症条件下，Cav-1功能的局部中断 提出了一种可行的治疗方法来抑制视网膜炎症。鉴于目前以类固醇为基础的疗法 对于视网膜炎症性疾病并不是完全有效的，而且充满了潜在的严重副作用，我们 假设Cav-1和小凹结构域代表抑制视网膜的新治疗靶点 由病原体引起的炎症以及在视网膜期间发生的内源性损害 退行性疾病。然而，由于Cav-1在视网膜动态平衡和 心血管功能，我们必须仔细评估这种蛋白质在细胞和组织中的内在作用，以 确定视网膜局部抑制Cav-1功能的可能性，了解 这些复杂的细胞固有属性的机制。在本提案中，我们将使用细胞特异性Cav-1 基因敲除小鼠测试细胞固有的Cav-1功能，希望验证Cav-1作为新的治疗靶点 用于视网膜炎症、BRB分解，以及炎症引起的神经变性。我们将测试一部小说 Cav-1调节肿瘤坏死因子受体相关因子3(TRAF3)a稳定性的机制 天然免疫受体的下游信号成分，如TLR4。TRAF3基因大量表达 在视网膜中，但作为免疫信号的局部调节因子尚未得到严格的研究。这样做的目的是 建议确定Cav-1调节视网膜炎症信号的机制(S) 由病原体和损伤引发的免疫激活所导致的崩溃和神经变性。我们 还将研究Cav-1控制视网膜TRAF3水平的机制。这些目标有明确的