The mechanisms underlying posterior capsular opacification

后囊膜混浊的机制

• 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
• 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

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.

囊外白内障手术大大减轻了全球白内障相关负担 失明。虽然这种手术非常有效，但大多数患者会出现明显的眼部不适。 白内障手术后的炎症会损害视力，而用以下药物治疗 强效抗炎药物会让患者感到不舒服，并且会引起副作用。尽管 白内障手术激活的一些炎症途径是已知的，但这些途径尚未被研究 全面的概况及其途径诱导机制尚不清楚。更远， 置换人工晶状体的最佳植入需要保留大部分晶状体 囊，晶状体周围的基底膜。由于晶状体上皮细胞 (LEC) 紧密附着在晶状体囊上，并非所有的LEC都可以在白内障手术期间去除，并且 这些细胞往往会经历强烈的伤口愈合反应。由此产生的扩散， 迁移、转分化为肌成纤维细胞以及异常晶状体纤维的形成 导致白内障术后视轴形成不透明斑块，从而导致 后囊膜混浊（PCO），白内障手术的常见副作用。虽然它是 已知 PCO 中肌成纤维细胞的形成需要 TGFβ/SMAD 途径的激活 手术后，手术时间和 TGFβ 通路激活之间可能存在滞后 因为需要激活潜在的 TGFβ，并启动 LEC 来有效地对此做出反应 发信号。然而，人们对手术后立即触发的途径知之甚少 导致 TGFβ 信号的强烈激活，这是体内形成纤维化 PCO 所必需的。这 应用程序试图通过研究发生的分子变化来填补这些知识空白 在 LEC 中，在 TGFβ 通路强烈激活之前，有两个特定目标。第一个目标 研究白内障后调节眼部炎症的分子机制 手术以及随后残留的 LEC 中促纤维化基因表达的开始 手术后，同时研究晶状体上皮细胞如何重塑 转录组受“立即早期基因”（IEG）调节。第二个目标测试 假设白内障后第一天经典 Wnt 信号上调 手术在 PCO 的发病机制中具有重要的功能，并通过以下方式研究其调节： IEG。这项研究将填补目前分子生物学知识的空白。 手术期间和 TGFβ 通路强烈激活之间发生的变化导致 PCO，现代白内障手术的一个主要副作用。