Induction of the blood-retinal barrier

血视网膜屏障的诱导

基本信息

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
项目类别：
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

项目摘要

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）：血液 - 视网膜屏障对于正常的视网膜功能至关重要，而这种障碍的丧失有助于预性，糖尿病性视网膜病变，与年龄相关的黄斑变性和其他视网膜疾病的病理生理学。此外，病理血管生成会产生高度可渗透的血管，缺乏适当的血视网膜屏障。视网膜和视网膜色素上皮的血管具有发达的紧密连接，可控制流体和血源溶质的流入视网膜。血液 - 视网膜屏障的血管成分的诱导是通过与胶质细胞和周细胞体内的内皮相互作用发生的，并且可以用糖皮质激素在药理学上诱导。然而，控制血视视网膜屏障中紧密连接基因表达的分子机制仍然在很大程度上尚未探索。我们的总体目标是了解屏障诱导的过程，以便可以开发出新的疗法来恢复视网膜疾病的血液 - 视网膜屏障，具有有限的不良副作用。 claudins和occludin是跨膜紧密连接蛋白，需要适当形成和调节血视网膜屏障。 Claudin-5对于血红视网膜屏障尤其重要，因为这种Claudin在很大程度上仅限于脉管系统，而基因缺失研究表明Claudin-5是血脑和血液 - 视网膜屏障的重要组成部分。 occludin含量与屏障完整性息息相关，而occludin磷酸化与渗透率的增加有关。我们以前的研究表明，糖皮质激素会诱导claudin-5和occludin的基因表达并促进屏障完整性。此外，一种称为Occludin增强子元件或OEE的新型顺式元素控制胶囊基因表达的糖皮质激素诱导。在此提案中，我们假设一种新型的跨作用转录因子与OEE相互作用以诱导内皮细胞屏障。这些研究将确定OEE元件对Claudin-5基因表达的糖皮质激素控制的贡献，研究OEE元件对紧密连接基因的RPE表达的贡献，最重要的是，确定了控制紧密连接基因通过OEE的转移因子。这些研究将导致未来的研究，该研究将阐明发育过程中屏障诱导的机制，并推进新的疗法，以恢复疾病状态中的血液视网膜屏障。公共卫生相关性：血液 - 视网膜屏障对于正常的视网膜功能至关重要，并且这种障碍的丧失有助于早产，糖尿病性视网膜病变，与年龄相关的黄斑变性和其他视网膜疾病的视网膜病理生理学。此外，病理血管生成会导致高度渗透的血管缺乏适当的血视网膜屏障。在此应用中，我们提出了一种新型的分子机制来控制血液视网膜屏障的诱导。了解这种机制将导致新的疗法恢复视网膜血管疾病中血液 - 视网膜屏障，副作用有限。