The mechanisms underlying posterior capsular opacification

后囊膜混浊的机制

基本信息

批准号：
9765330
负责人：
MELINDA K DUNCAN
金额：
$ 34.34万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765330
关键词：
Address Adult Anti-inflammatory Attenuated Automobile Driving Basement membrane Biological Assay Blindness Cataract Cataract Extraction Cell Proliferation Cells Cicatrix Complication Data Detection Development Early Gene Transcriptions Environment Epithelial Cells Epithelium Event Excision Extracapsular Eye Flare Gene Expression Genes Genetic Transcription Growth Hour Immediate-Early Genes Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intraocular lens implant device Investigation Knowledge Lead Lens Fiber Mediating Methods Modeling Modernization Molecular Molecular Target Mus Myofibroblast Operative Surgical Procedures Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Prevention Procedures Regulation Reporter Signal Transduction TCF7L2 gene Testing Time Tissues Transforming Growth Factor beta Up-Regulation Vision Visual WNT Signaling Pathway Work Wound Healing aqueous cell motility cytokine design fiber cell implantation improved in vivo insight lens lens capsule migration novel preservation prevent public health relevance response side effect transcription factor transcriptome transdifferentiation

项目摘要

Extracapsular cataract surgery has greatly reduced the global burden of cataract-related blindness. While this procedure is very effective, most patients develop significant ocular inflammation after cataract surgery, which can compromise vision, while its treatment with potent anti-inflammatory drugs is unpleasant for patients and can cause side effects. While some inflammatory pathways activated by cataract surgery are known, these have not been comprehensively profiled and their mechanisms of pathway induction are not known. Further, optimal implantation of a replacement intraocular lens requires preservation of most of the lens capsule, the basement membrane surrounding the lens. Since lens epithelial cells (LECs) are tightly attached to the lens capsule, not all LECs can be removed during cataract surgery, and these cells tend to undergo robust wound healing responses. The resulting proliferation, migration, transdifferentiation to myofibroblasts, and formation of aberrant lens fibers often results in the formation of opaque plaques in the visual axis post-cataract surgery, resulting in posterior capsular opacification (PCO), a common side effect of cataract surgery. While it is known that myofibroblast formation in PCO requires the activation of TGFβ/SMAD pathways post-surgery, there is a lag between the time of surgery and TGFβ pathway activation, likely due to the need to both activate latent TGFβ, and to prime LECs to efficiently respond to this signaling. However, little is known about the pathways triggered immediately after surgery that lead to robust activation of TGFβ signaling necessary to form fibrotic PCO in vivo. This application seeks to fill these knowledge gaps by investigating the molecular changes that occur in LECs prior to the onset of robust TGFβ pathway activation in two specific aims. The first aim investigates both the molecular mechanisms regulating ocular inflammation post-cataract surgery and the subsequent onset of pro-fibrotic gene expression in the LECs remaining behind after surgery while investigating how this remodeling of the the lens epithelial cell transcriptome is regulated by "immediate early genes“ (IEGs). The second aim tests the hypothesis that the canonical Wnt signaling that upregulates during the first day after cataract surgery is functionally important in the pathogenesis of PCO and investigates its regulation by IEGs. This investigation will fill the current gap in knowledge concerning the molecular changes that occur between the time of surgery and robust TGFβ pathway activation leading to PCO, a major side effect of modern cataract surgery.

囊外性白内障手术大大减轻了白内障相关的全球负担盲目的同时非常有效白内障手术后的炎症，同时可以使视力提高视力，而其治疗有效的抗炎药对患者不愉快，并引起副作用。已知的一些通过白内障手术激活的炎症途径已知，这些途径尚未全面构图和途径指示的机制。替代的人工晶状体的最佳植入需要保存大多数晶状体胶囊，镜头周围的地下膜。紧密连接到镜头胶囊上，并非所有LEC都可以重新进行白内障手术，并且这些细胞倾向于进行稳健的伤口愈合反应。迁移，转变为肌纤维细胞以及通常形成异常镜头纤维导致在视觉轴后手术手术中形成不透明的斑块，重新占据后囊不粘附（PCO），这是白内障手术的常见副作用知道PCO中的肌纤维细胞形成需要TGFβ/SMAD途径的激活手术后，这是手术时间和TGFβ途径激活之间的滞后，可能由于需要同时激活潜在的TGFβ，又需要限制LEC以有效地做出回应信号。但是，关于手术后立即触发的途径这导致TGFROTION的强大激活在体内形成牢固的PCO 应用程序旨在通过研究发生的分子变化来填补知识差距在鲁棒的TGFUST TGWAIN激活开始之前，在两个特定目标中研究两种调节眼部炎症后调节眼部炎症的分子机制手术和随后在留下的LEC中的促纤维化基因表达发作手术后，研究了这种重塑晶状体上皮细胞的重塑转录组由“立即的早期基因”（IEG）定期。假设在白内障后的第一天上调的规范Wnt信号手术在PCO的发病机理中在功能上很重要，研究是由 IEGS。手术时间和强大的TGFWay激活之间发生的变化导致 PCO，现代白内障手术的主要副作用。