Novel function of beta-catenin in regulation of RPE basal membrane

β-连环蛋白调节 RPE 基底膜的新功能

• 批准号: 9979132
• 负责人: Qingxian Lu
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979132
• 关键词: Active Biological Transport; Adhesions; Adolescent; Adult; Affect; Age related macular degeneration; Aging; Animals; Antibodies; Antibody Specificity; Apical; Area; Basal lamina; Biology; Blood; Blood - brain barrier anatomy; Blood Circulation; Bruch' s basal membrane structure; Butterflies; Cadherins; Cell membrane; Cell-Matrix Junction; Cells; Choroid; Complex; Data; Defect; Diffusion; Disease; Ectodermal Dysplasia; Electron Microscopy; Electroretinography; Ensure; Epithelial Cells; Etiology; Eye diseases; Face; Functional disorder; Glucose; Glucose Transporter; Histologic; Human; Hypotrichosis; Intestines; Iron; Kidney Diseases; Knock-out; Knockout Mice; Lateral; Lead; Link; Liquid substance; Mediating; Membrane; Metabolic; Modeling; Molecular; Morphology; Mus; Mutation; N-Cadherin; Nutrient; Organelles; P-Cadherin; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Photoreceptors; Pigments; Play; Regulation; Renal tubule structure; Retina; Retinal Degeneration; Retinitis Pigmentosa; Role; SHFM1 gene; SLC2A1 gene; Source; Stains; Stratum Basale; Surface; Swelling; Symptoms; Syndrome; System; Testing; Time; Tissues; Urine; Vision; Work; alpha catenin; base; beta catenin; cell type; cellular microvillus; conditional knockout; corneal epithelium; glucose uptake; innovation; insight; macular dystrophy; mutant; novel; null mutation; receptor; recruit; renal epithelium; solute

PROJECT SUMMARY/ABSTRACT The RPE acts as a blood outer retinal barrier transporting nutrients from the choroid circulation to adjacent photoreceptors. Apical microvilli on the RPE are critical for interdigitating interaction with photoreceptor outer segments. The basal membrane of the RPE differentiates into a heavily folded plasma membrane system to form a specialized organelle, called basal infolding. These infoldings dramatically increases the surface area to enhance diffusion and transporter-assisted flux of solutes, factors, nutrients, and metabolites. How the infolding arises and its potential relevance to RPE biology has not been explored. In preliminary results, we demonstrate that this infolding is mediated by -catenin in a complex with N- and P-cadherins/-catenin, and cytoplasmic - catenin is required for the integrity of basal membrane infolding. We hypothesize that the increase in surface area resulting from membrane infolding is critical for efficient nutrient transport. Similar membrane infolding increases surface area at the blood brain barrier, the intestinal lumen and kidney tubules that serve as a blood- urine barrier. Consistent with functional inhibition of nutrient transport, mouse -catenin mutants show shortening of adjacent photoreceptor outer segments, which depend upon nutrients transported through the RPE. In this proposal, we will test whether the -catenin/cadherin complex stabilizes the RPE basal infoldings for maintaining the basal infolding integrity and ensuring efficient transport of nutrients and metabolites across the RPE barrier. Inadequate metabolic support from RPE has been linked to several aspects of age-related macular degeneration, as have mutations in P-cadherin and α-catenin. As such, the β-catenin conditional knockout mouse represents an important model to study the etiology and pathogenesis of RPE dystrophy and retinal degeneration. Our study will provide a novel mechanism for the integrity of RPE basal infoldings and its relevance to RPE function, which may give insight into the pathogenesis of RPE dystrophy and AMD, even some of renal diseases.

项目摘要/摘要 RPE充当血液外视网膜屏障从脉络膜循环到相邻的养分 感受器。 RPE上的顶端微绒毛对于与光感受器外部相互作用至关重要 细分市场。 RPE的基本膜分化为重折叠的质膜系统 形成一个专门的细胞器，称为基本插头。这些不积显着将表面积提高到 增强溶剂，因子，营养物质和代谢物的扩散和转运剂辅助通量。如何插头 尚未探索出现及其与RPE生物学的潜在相关性。在初步结果中，我们证明了 在与N-和P-钙粘着蛋白/-catenin的复合物中介导这种源性的，以及细胞质--- 蛋白链蛋白是基本膜插入的完整性所必需的。我们假设表面增加 膜不造成的区域对于有效的营养运输至关重要。类似的膜插头 增加表面积，在血脑屏障，肠腔和肾小管中，它们充当血液 - 尿液屏障。与营养转运的功能抑制一致，小鼠-catenin突变体显示 缩短相邻的光感受器外部段，取决于通过 RPE。在此提案中，我们将测试-catenin/cadherin复合物是否稳定RPE基本源 维持基本的不构成完整性，并确保养分和代谢物的有效运输 RPE障碍。 RPE的代谢支持不足已与年龄有关的几个方面链接 黄斑变性，P-钙粘着蛋白和α-catenin中的突变也是如此。因此，β-catenin条件 敲除小鼠是研究RPE营养不良和发病机理的重要模型 视网膜变性。我们的研究将为RPE基本插件的完整性及其其完整性提供新的机制 与RPE功能相关，这可能会深入了解RPE营养不良和AMD的发病机理，甚至 一些肾脏疾病。