Lens capsule and secondary cataract

晶状体囊和继发性白内障

基本信息

批准号：
8600277
负责人：
Ram H Nagaraj
金额：
$ 38.83万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2014-10-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8600277
关键词：
Accounting Adhesions Adult Advanced Glycosylation End Products Affect Age Aging Anterior Arginine Basement membrane Behavior Binding Biochemical Biochemical Pathway Blindness Cataract Cataract Extraction Cell Adhesion Cell Adhesion Inhibition Cell Culture Techniques Cell Proliferation Cell physiology Cell-Cell Adhesion Cells Chemical Modifier Chemicals Collagen Collagen Type IV Data Development Epithelial Cells Excision Extracapsular Extracellular Matrix Extracellular Matrix Proteins Fibronectins Fibrosis Focal Adhesion Kinase 1 Foundations Glucose Growth Growth Factor Half-Life Human Immigration Incidence Integrin Binding Integrins Intraocular Lens Implantation Intraocular lens implant device Kidney Laminin Lasers Lead Life Lysine Mediating Mesenchymal Methods Modification Molecular Myofibroblast Outcome Pathogenesis Pathway interactions Patients Peptides Phenotype Play Post-Translational Protein Processing Preventive Procedures Proliferating Proteins Pyruvaldehyde Reaction Research Resolution Role Senile Cataract Signal Transduction Smooth Muscle Actin Staining Method Testing Time Tubular formation Vision Visual impairment adduct amino group ascorbate base capsule carbonyl compound cell motility cell transformation cell type diabetic effective therapy epithelial to mesenchymal transition glycation heparin proteoglycan human tissue lens lens capsule migration novel prevent public health relevance receptor receptor for advanced glycation endproducts response sugar transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Extracapsular cataract surgery leaves the lens capsule mostly intact, which permits implantation of an intraocular lens (IOL). This procedure often leaves behind epithelial cells in the remaining anterior and equatorial capsule, which in time, proliferate and migrate to the posterior capsule. This aberrant growth of epithelial cells, together with transdifferentiation into a mesenchymal phenotype (EMT), leads to posterior capsule opacification (PCO). PCO impairs vision and requires laser treatment for resolution. With the advent of newer and more refined IOLs, the incidence of PCO has decreased; however, a significant number of cataract patients return for PCO treatment. The increasing use of accommodative IOLs could cause the number of returning patients to increase because of the reduced barrier for epithelial cells. Despite many years of research, the biochemical mechanisms of PCO are not well understood. Glycation is a major chemical modifier of extracellular matrix proteins. The reaction occurs between protein amino groups and carbonyl compounds and leads to the formation of stable adducts on proteins, collectively known as Advanced Glycation Endproducts (AGEs). The lens capsule is a basement membrane secreted by epithelial cells, and like other basement membranes, it accumulates AGEs with age. Based on our preliminary data, we hypothesize that AGEs in capsule proteins hinder the adhesion and migration of epithelial cells and induce their transdifferentiation to a mesenchymal cell type. In this proposal, we plan to investigate the biochemical and molecular mechanisms by which AGEs play a role in PCO with three aims. In Aim 1, we will determine the relationship between cataract and AGE content in human lens capsules. In Aim 2, we will define the biochemical pathways by which capsule AGEs influence epithelial cell adhesion, proliferation, and migration, and then investigate alterations in cell signaling that are responsible for the aberrant behavior o lens epithelial cells. In Aim 3, we will determine the effect of capsule AGEs on EMT in lens epithelial cells and explore the possibility of inhibiting PCO by blocking the interaction of AGE with its receptor on lens epithelial cells. Completion of these aims will uncover a mechanism of PCO, and will provide a foundation for the development of more effective therapies to prevent PCO.

描述（由申请人提供）：囊外性白内障手术使镜头胶囊大多完好无损，该镜头允许植入眼内透镜（IOL）。该过程通常留在其余前和赤道囊中的上皮细胞后面，它们随着时间的流逝而增殖并迁移到后囊。上皮细胞的异常生长，以及转分化为间充质表型（EMT）的生长，导致后囊胶体无缝隙（PCO）。 PCO会损害视力，需要激光治疗以解决。随着较新，更精致的IOL的出现，PCO的发病率下降了。但是，大量白内障患者返回PCO治疗。适应性IOL的使用日益增加可能导致返回患者的数量增加，因为上皮细胞的屏障降低。尽管进行了多年的研究，但PCO的生化机制尚未得到很好的了解。糖基化是细胞外基质蛋白的主要化学修饰剂。该反应发生在蛋白质氨基和羰基化合物之间，并导致蛋白质稳定加合物的形成，蛋白质统称为晚期糖基化终产物（年龄）。镜头胶囊是由上皮细胞分泌的地下膜，与其他基底膜一样，它会随着年龄的增长而积累。基于我们的初步数据，我们假设胶囊蛋白的年龄阻碍了上皮细胞的粘附和迁移，并诱导其转差向间充质细胞类型。在此提案中，我们计划研究年龄在具有三个目标的PCO中发挥作用的生化和分子机制。在AIM 1中，我们将确定人透镜胶囊中白内障与年龄含量之间的关系。在AIM 2中，我们将定义胶囊年龄影响上皮细胞粘附，增殖和迁移的生化途径，然后研究细胞信号传导的改变，这些细胞信号传导导致了异常行为的上皮细胞。在AIM 3中，我们将确定胶囊年龄对透镜上皮细胞中EMT的影响，并通过阻止年龄与其受体在晶状体上皮细胞上的年龄相互作用来探索抑制PCO的可能性。这些目标的完成将揭示PCO的机制，并将为开发更有效的疗法提供预防PCO的基础。