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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要 RPE 充当血液外视网膜屏障，将营养物质从脉络膜循环输送到邻近的视网膜。 RPE 上的光感受器顶端微绒毛对于与光感受器外部的交叉相互作用至关重要。 RPE 的基底膜分化为严重折叠的质膜系统。形成一种特殊的细胞器，称为基底内折，这些内折极大地增加了表面积。增强溶质、因子、营养物质和代谢物的扩散和转运辅助通量。我们在初步结果中证明了它与 RPE 生物学的潜在相关性。这种内折叠是由与 N- 和 P-钙粘蛋白/α-连环蛋白以及细胞质 β- 复合物中的 β-连环蛋白介导的连环蛋白对于基底膜折叠的完整性是必需的，我们发现表面的增加。膜内折叠产生的面积对于有效的营养物质运输至关重要。增加血脑屏障、肠腔和肾小管的表面积，充当血液小鼠 -连环蛋白突变体显示出与营养运输的功能性抑制一致的尿屏障。相邻光感受器外节的缩短，这取决于营养物质通过光感受器的运输 RPE。在本提案中，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。用于维持基础内折叠完整性并确保营养物质和代谢物的有效运输 RPE 屏障的代谢支持不足与年龄相关的几个方面有关。黄斑变性，P-钙粘蛋白和 α-连环蛋白有突变，因此，β-连环蛋白有条件。基因敲除小鼠是研究 RPE 营养不良的病因和发病机制的重要模型。我们的研究将为 RPE 基底内皱及其完整性提供一种新的机制。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。