Induction of the blood-retinal barrier

血视网膜屏障的诱导

• 批准号: 7747982
• 负责人: David Antonetti
• 金额: $ 13.57万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747982
• 关键词: Address; Advanced Development; Adverse effects; Age related macular degeneration; Applications Grants; Area; Astrocytes; Basal Cell; Be++ element; Beryllium; Binding; Biotin; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood-Retinal Barrier; Brain; Cell membrane; Cells; Data; Development; Dexamethasone; Diabetic Retinopathy; Disease; Edema; Electrophoretic Mobility Shift Assay; Elements; Endothelial Cells; Enhancers; Epithelial; Family; Functional disorder; Future; Gene Deletion; Gene Expression; Genes; Genetic Enhancer Element; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; In Vitro; Indium; Investigation; Laboratories; Lead; Link; Luciferases; MALDI-TOF Mass Spectrometry; Molecular; Mutation; Neural Retina; Neuroglia; Nucleotides; Pathologic Neovascularization; Pattern; Pericytes; Permeability; Phosphorylation; Physiological; Point Mutation; Process; Property; Protein Isoforms; Proteins; Publishing; Regulation; Reporter; Research; Response Elements; Retina; Retinal; Retinal Diseases; Retinal Vein Occlusion; Retinopathy of Prematurity; Reverse Transcriptase Polymerase Chain Reaction; Role; Scanning; Signal Transduction; Steroids; Structure of retinal pigment epithelium; Techniques; Testing; Therapeutic; Tight Junctions; Tissues; Trans-Activators; Transcriptional Regulation; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Western Blotting; cadherin 5; capillary; chromatin immunoprecipitation; fluid flow; in vivo; innovation; insight; loss of function; member; mutant; novel; occludin; promoter; public health relevance; relating to nervous system; response; solute; transcription factor

DESCRIPTION (provided by applicant): The blood-retinal barrier is essential for normal retinal function and loss of this barrier contributes to the pathophysiology of retinopathy of prematurity, diabetic retinopathy, age related macular degeneration and other retinal diseases. Further, pathological angiogenesis produces highly permeable vessels that lack a proper blood-retinal barrier. The blood vessels of the retina and the retinal pigment epithelium possess well-developed tight junctions that control the flow of fluids and blood-borne solutes into the retina. Induction of the vascular component of the blood-retinal barrier occurs through endothelial interaction with glia and pericytes in vivo and may be induced pharmacologically with glucocorticoids. However, the molecular mechanisms that control tight junction gene expression in the blood-retinal barrier remain largely unexplored. Our overall goal is to understand the process of barrier induction so that novel therapies may be developed to restore the blood-retinal barrier in retinal diseases with limited adverse side effects. The claudins and occludin are transmembrane tight junction proteins necessary for proper formation and regulation of the blood-retinal barrier. Claudin-5 is particularly important to the blood-retinal barrier since this claudin is largely restricted to the vasculature and gene deletion studies have demonstrated claudin-5 is an essential component of the blood-brain and blood-retinal barrier. Occludin content correlates well with barrier integrity, whereas occludin phosphorylation is associated with increased permeability. Our previous studies have demonstrated that glucocorticoids induce gene expression of claudin-5 and occludin and promote barrier integrity. Further, a novel cis-element termed the occludin enhancer element or OEE controls glucocorticoid induction of occludin gene expression. In this proposal we hypothesize that a novel trans-acting transcription factor interacts with the OEE to induce the endothelial cell barrier. These studies will determine the contribution of the OEE element to glucocorticoid control of claudin-5 gene expression, investigate the contribution of the OEE element to RPE expression of tight junction genes and, most importantly, identify the trans-acting factor that controls tight junction gene expression through the OEE. These studies will lead to future investigations that will elucidate the mechanisms of barrier induction during development and advance novel therapies to restore the blood-retinal barrier in disease states. PUBLIC HEALTH RELEVANCE: The blood-retinal barrier is essential for normal retinal function and loss of this barrier contributes to the pathophysiology of retinopathy of prematurity, diabetic retinopathy, age related macular degeneration and other retinal diseases. Further, pathological angiogenesis leads to highly permeable vessels that lack a proper blood-retinal barrier. In this application, we propose a novel molecular mechanism exists to control induction of the blood retinal-barrier. Understanding this mechanism will lead to new therapies to restore the blood-retinal barrier in retinal vascular diseases, with limited side effects.

描述（由申请人提供）：血-视网膜屏障对正常视网膜功能至关重要，该屏障的丧失有助于早产儿视网膜病变、糖尿病视网膜病变、年龄相关性黄斑变性和其他视网膜疾病的病理生理学。此外，病理性血管生成产生缺乏适当的血液-视网膜屏障的高度渗透性血管。视网膜的血管和视网膜色素上皮具有发育良好的紧密连接，其控制流体和血液传播的溶质流入视网膜。血-视网膜屏障的血管成分的诱导通过体内内皮与神经胶质细胞和周细胞的相互作用发生，并且可以用糖皮质激素诱导。然而，控制血视网膜屏障中紧密连接基因表达的分子机制在很大程度上仍未被探索。我们的总体目标是了解屏障诱导的过程，以便开发新的治疗方法，以恢复视网膜疾病中的血视网膜屏障，并减少不良副作用。claudin和occludin是血-视网膜屏障的适当形成和调节所必需的跨膜紧密连接蛋白。紧密连接蛋白-5对血-视网膜屏障特别重要，因为这种紧密连接蛋白主要限于脉管系统，并且基因缺失研究已经证明紧密连接蛋白-5是血-脑和血-视网膜屏障的重要组分。封闭蛋白含量与屏障完整性密切相关，而封闭蛋白磷酸化与渗透性增加相关。我们以前的研究表明，糖皮质激素诱导基因表达的claudin-5和occludin和促进屏障的完整性。此外，一种新的顺式元件称为occludin增强子元件或OEE控制糖皮质激素诱导occludin基因表达。在这个建议中，我们假设一个新的反式作用转录因子与OEE相互作用，诱导内皮细胞屏障。这些研究将确定OEE元件对糖皮质激素控制紧密连接蛋白-5基因表达的贡献，研究OEE元件对紧密连接基因的RPE表达的贡献，最重要的是，鉴定通过OEE控制紧密连接基因表达的反式作用因子。这些研究将导致未来的研究，将阐明屏障诱导在发展过程中的机制，并推进新的治疗方法，以恢复疾病状态下的血视网膜屏障。公共卫生相关性：血-视网膜屏障对于正常视网膜功能是必不可少的，并且该屏障的丧失有助于早产儿视网膜病变、糖尿病视网膜病变、年龄相关性黄斑变性和其他视网膜疾病的病理生理学。此外，病理性血管生成导致缺乏适当的血液-视网膜屏障的高度渗透性血管。在这个应用中，我们提出了一种新的分子机制存在，以控制诱导的血液视网膜屏障。了解这一机制将导致新的治疗方法，以恢复视网膜血管疾病的血视网膜屏障，副作用有限。