LENS CAPSULE AND SECONDARY CATARACT

晶状体囊和继发性白内障

• 批准号: 8999943
• 负责人: Ram H Nagaraj
• 金额: $ 38.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999943
• 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; Health; 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; 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(申请人提供)：囊外白内障手术使晶状体囊基本完好，可以植入人工晶状体(IOL)。这一过程通常会在剩余的前囊和赤道囊中留下上皮细胞，随着时间的推移，这些细胞会增殖并迁移到后囊。这种异常的上皮细胞生长，加上转分化为间充质表型(EMT)，导致后囊混浊(PCO)。PCO损害视力，需要激光治疗才能解决。随着新的、更精细的人工晶状体的出现，后囊混浊的发生率有所下降；然而，相当数量的白内障患者重新接受后囊混浊治疗。由于人工晶状体上皮细胞屏障的减少，调节性人工晶状体的使用增加可能会导致返回患者的数量增加。尽管进行了多年的研究，但对PCO的生化机制还不是很清楚。糖基化是细胞外基质蛋白的主要化学修饰物。蛋白质的氨基和羰基化合物之间发生反应，在蛋白质上形成稳定的加合物，统称为高级糖基化终产物(AGEs)。晶状体囊是由上皮细胞分泌的基底膜，和其他基底膜一样，随着年龄的增长，它会积累年龄。根据我们的初步数据，我们假设被膜蛋白中的AGEs阻碍上皮细胞的黏附和迁移，并诱导它们向间充质细胞类型的转分化。在这项建议中，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。在目标1中，我们将确定白内障与晶状体囊中年龄含量的关系。在目标2中，我们将定义囊膜AGE影响上皮细胞黏附、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变化。在目的3中，我们将研究AGEs胶囊对晶状体上皮细胞EMT的影响，并探讨通过阻断AGE与其受体的相互作用来抑制晶状体上皮细胞PCO的可能性。这些目标的完成将揭示多囊卵巢的发病机制，并将为开发更有效的预防多囊卵巢的治疗方法提供基础。