Lens capsule and secondary cataract

晶状体囊和继发性白内障

• 批准号: 8437864
• 负责人: Ram H Nagaraj
• 金额: $ 39.47万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437864
• 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

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）：囊外白内障手术使透镜囊基本完整，允许植入眼内透镜（IOL）。该过程通常在剩余的前囊和赤道囊中留下上皮细胞，其及时增殖并迁移到后囊膜。上皮细胞的这种异常生长，连同转分化成间充质表型（EMT），导致后囊膜混浊（PCO）。PCO损害视力，需要激光治疗才能解决。随着更新和更精细的IOL的出现，PCO的发生率有所下降;然而，大量白内障患者返回接受PCO治疗。由于上皮细胞屏障的降低，越来越多地使用人工晶状体可能导致返回患者的数量增加。尽管多年的研究，PCO的生化机制还没有得到很好的理解。糖基化是细胞外基质蛋白的主要化学修饰剂。反应发生在蛋白质氨基和羰基化合物之间，并导致在蛋白质上形成稳定的加合物，统称为晚期糖基化终产物（AGEs）。透镜囊是上皮细胞分泌的基底膜，与其他基底膜一样，它随着年龄的增长而积累AGEs。基于我们的初步数据，我们假设，AGEs在胶囊蛋白阻碍上皮细胞的粘附和迁移，并诱导其转分化为间充质细胞类型。在这个建议中，我们计划调查的生化和分子机制，AGEs发挥作用的PCO有三个目标。在目的1中，我们将确定白内障与人透镜囊中AGE含量之间的关系。在目标2中，我们将定义囊AGEs影响上皮细胞粘附、增殖和迁移的生化途径，然后研究导致透镜上皮细胞异常行为的细胞信号转导的改变。目的3：研究囊膜AGEs对透镜上皮细胞EMT的影响，并探讨通过阻断AGEs与透镜上皮细胞受体的相互作用来抑制PCO的可能性。这些目标的实现将揭示PCO的发病机制，并将为开发更有效的治疗方法以预防PCO提供基础。