Lens capsule and secondary cataract

描述（由申请人提供）：白内障囊外手术使晶状体囊基本完整，可植入人工晶状体（IOL）。该手术通常会在剩余的前囊和赤道囊中留下上皮细胞，这些细胞及时增殖并迁移到后囊。上皮细胞的异常生长，以及向间充质表型（EMT）的转分化，导致后囊膜混浊（PCO）。PCO损害视力，需要激光治疗来解决。随着更新和更精细的iol的出现，PCO的发生率已经下降；然而，仍有相当数量的白内障患者再次接受PCO治疗。由于上皮细胞屏障的降低，调节型人工晶状体的使用增加，可能导致复诊患者的数量增加。尽管多年的研究，PCO的生化机制尚不清楚。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，导致蛋白质上形成稳定的加合物，统称为晚期糖基化终产物（AGEs）。晶状体囊是上皮细胞分泌的基底膜，与其他基底膜一样，随着年龄的增长而积累AGEs。根据我们的初步数据，我们假设胶囊蛋白中的AGEs阻碍上皮细胞的粘附和迁移，并诱导其向间充质细胞类型的转分化。在本文中，我们计划从三个方面探讨AGEs在PCO中发挥作用的生化和分子机制。在Aim 1中，我们将确定白内障与人晶状体囊中AGE含量之间的关系。在Aim 2中，我们将定义胶囊AGEs影响上皮细胞粘附、增殖和迁移的生化途径，然后研究导致晶状体上皮细胞异常行为的细胞信号通路的改变。在Aim 3中，我们将确定胶囊AGEs对晶状体上皮细胞EMT的影响，并探索通过阻断AGE与其受体在晶状体上皮细胞上的相互作用来抑制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治疗方法来预防PCO提供基础。

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.