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.

项目总结/摘要 RPE充当血液外视网膜屏障，将营养物从脉络膜循环输送到邻近的视网膜。 光感受器RPE上的顶端微绒毛是与感光细胞外表面相互作用的关键。 片段RPE的基底膜分化成高度折叠的质膜系统， 形成一个特殊的细胞器，称为基底内折叠。这些内折显著增加了表面积， 增强溶质、因子、营养物和代谢物的扩散和转运蛋白辅助通量。如何内折 其与RPE生物学的潜在相关性尚未探索。在初步结果中，我们证明 这种内折叠是由N-和P-钙粘蛋白/β-连环蛋白复合物中的β-连环蛋白介导的，而细胞质中的β-连环蛋白是由N-和P-钙粘蛋白/β-连环蛋白复合物介导的。 连环蛋白是基底膜内折叠完整性所必需的。我们假设地表面积的增加 由膜内折叠产生的面积对于有效的养分运输是关键的。相似膜内折 增加血脑屏障、肠腔和肾小管的表面积， 尿液屏障与营养转运的功能抑制一致，小鼠β-连环蛋白突变体显示， 缩短相邻的光感受器外节，这取决于通过 RPE。在这个提议中，我们将测试β-连环蛋白/钙粘蛋白复合物是否稳定RPE基底内折叠， 用于维持基底内折叠的完整性并确保营养物和代谢物跨膜的有效运输 RPE屏障。来自RPE的代谢支持不足与年龄相关的衰老的几个方面有关。 黄斑变性，如P-钙粘蛋白和α-连环蛋白的突变。因此，β-连环蛋白条件 基因敲除小鼠是研究RPE营养不良病因和发病机制的重要模型， 视网膜变性。我们的研究将为RPE基底内折叠的完整性及其与细胞增殖的关系提供一种新的机制。 与RPE功能的相关性，这可能有助于深入了解RPE营养不良和AMD的发病机制，甚至 一些肾脏疾病。