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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：
10475582
负责人：
MICHAEL H ELLIOTT
金额：
$ 35.43万
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 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10475582
关键词：
Ablation Adenoviruses Anti-Inflammatory Agents Antiinflammatory Effect Blindness Blood-Retinal Barrier CAV1 gene Caveolae Cell Line Cells Complex Conflict (Psychology)Dependovirus Development Diabetic Retinopathy Disease Dose Eye diseases Functional disorder Gene Transfer Genes Glaucoma Goals Growth Factor Immune In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Injury Lead Link Literature Maintenance Mediating Membrane Modeling Morphology Muller&apos s cell Nerve Crush Nerve Degeneration Neural Retina Neuroglia Neurons Ocular Physiology Optic Nerve Organ PC3 cell line Pharmaceutical Preparations Play Primary Open Angle Glaucoma Proteins Publishing Retina Risk Role Signal Transduction Steroids Stress Structural Protein System Testing Tissues Virus autoimmune uveitis base biological adaptation to stress caveolin 1 cell type chemokine cytokine experimental study genetic variant glial activation human disease in vivo innovation new therapeutic target novel novel therapeutic intervention prostate cancer cell line protein expression protein function public health relevance response reverse genetics scaffold side effect therapeutic target

项目摘要

Project summary Caveolin-1 (Cav1), traditionally viewed as the signature protein of caveolae membrane domains, plays crucial roles in blood-retinal barrier integrity and retinal inflammation. Gene variants in Cav1 are associated with risk of primary open angle glaucoma and Cav1 protein expression is upregulated in uveitic retinas and in models of diabetic retinopathy. We have found that Cav-1 and caveolae play important roles in blood-retinal barrier (BRB) and inflammation-induced cytokine release. Intriguingly, ablation of Cav1 only from the neuroretinal compartment (Müller glia and neurons) suppresses cytokine release and immune cell influx following inflammatory and neurodegenerative insult. As Cav1 is upregulated in several retinal inflammatory conditions, we hypothesize that local manipulation of Cav1 function presents a viable therapy to suppress retinal inflammatory stress. Given that current steroid-based therapies for retinal inflammatory disease are not completely effective and fraught with potentially severe side effects, we hypothesize that Cav1 represents a novel therapeutic target to suppress retinal inflammation. Thus, it is crucial to understand the function of this protein in the context of the retinal stress adaptation response. We have made the exciting observation that Cav1 in Müller glial cells of the neural retina does not reside within traditional, morphologically-identifiable caveolae. This is because differentiated Müller glia do not normally express significant levels of Cavin1 which, via interaction with Cav1, is necessary to form caveolae. In all tissues studied to date, loss of Cavin1 results in coincident loss of Cav1 protein stability. However, in Müller glia, Cav1 is stably expressed (outside of caveolae) in the absence of Cavin1. This provides a unique opportunity to examine the role of non-caveolar Cav1 in an organ in which Cav1 is associated with human disease. We hypothesize that this non-caveolar localization is crucial to Cav1’s ability to promote secretion of cytokines, chemokines, and growth factors. In this proposal, we will test this novel concept in Müller glia in culture and in vivo by inducing the expression of Cavin1 to sequester Cav1 within caveolae. We will also take advantage of the unusually stable expression of Cav1 outside of caveolae to examine the composition of the non-caveolae Cav1 domain (called herein “Cav1 scaffolds”) and to identify the mechanism by which Cav1 is stably expressed without Cavin1. These goals have clear

项目总结