The mechanisms underlying posterior capsular opacification

后囊膜混浊的机制

• 批准号: 10163512
• 负责人: MELINDA K DUNCAN
• 金额: $ 6.5万
• 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/10163512
• 关键词: Address; Adult; Anti-Inflammatory Agents; Attenuated; Automobile Driving; Basement membrane; Biological Assay; Blindness; Cataract; Cataract Extraction; Cell Proliferation; Cells; Cicatrix; Complication; Data; Detection; Development; Early Gene Transcriptions; Environment; Epithelial; 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; 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; wound healing

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.

白内障囊外手术大大减轻了全球与白内障相关的负担 失明。虽然这种手术非常有效，但大多数患者都会出现明显的眼部症状。 白内障手术后的炎症，这会损害视力，而它的治疗 强效抗炎药对患者来说令人不快，可能会产生副作用。而当 一些由白内障手术激活的炎症通路是已知的，这些尚未被发现。 目前尚不清楚其诱导途径的全面概况和机制。此外， 理想的人工晶状体植入需要保留大部分人工晶状体 囊膜，晶状体周围的基底膜。由于晶状体上皮细胞(LEC) 晶状体囊紧密附着，并不是所有的晶状体上皮细胞都能在白内障手术中被移除，以及 这些细胞往往会经历强大的伤口愈合反应。由此导致的核扩散， 向肌成纤维细胞的迁移、转分化和异常晶状体纤维的形成 结果白内障手术后视轴形成不透明斑块，导致 后囊混浊(PCO)是白内障手术常见的副作用。虽然它是 已知后囊膜增生症中肌成纤维细胞的形成需要转化生长因子β/sMAD通路的激活 术后，在手术时间和转化生长因子β途径激活之间可能有一段时间的滞后。 由于既需要激活潜在的转化生长因子β，又需要启动LEC以有效地响应这一点 发信号。然而，对手术后立即触发的通路知之甚少。 这导致了转化生长因子β信号的强烈激活，这是在体内形成纤维化后囊混浊所必需的。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 在晶状体上皮细胞中，强健的转化生长因子β通路在两个特定的目的下被激活。第一个目标 探讨调节白内障后眼部炎症的分子机制 手术和随后遗留的晶状体上皮细胞中促纤维化基因的表达 手术后，研究晶状体上皮细胞的这种重塑 转录组由“即刻早期基因”(IEGs)调控。第二个目的是测试 假设典型的Wnt信号在白内障后第一天上调 手术在后囊混浊的发病机制中具有重要的作用，并通过以下途径研究其调节 腿。这项研究将填补目前关于分子的认识空白。 在手术时间和强大的转化生长因子β途径激活之间发生的变化导致 后发性白内障，现代白内障手术的主要副作用。