The mechanisms underlying posterior capsular opacification

后囊膜混浊的机制

• 批准号: 10414847
• 负责人: MELINDA K DUNCAN
• 金额: $ 5.91万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414847
• 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; 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.

囊外性白内障手术大大减少了白内障相关的全球燃烧 失明。尽管此过程非常有效，但大多数患者会出现重要的眼部 白内障手术后的炎症，可以损害视力，而其治疗 有效的抗炎药对于患者来说是不愉快的，可能会引起副作用。尽管 已知的一些通过白内障手术激活的炎症途径，这些途径尚未 尚不清楚完全构图及其途径诱导机制。更远， 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。由于晶状体上皮细胞（LEC）是 紧密连接到镜头胶囊上，在白内障手术期间可以去除所有LEC，并且 这些细胞倾向于经历强大的伤口愈合反应。由此产生的扩散， 迁移，转变为肌纤维细胞以及形成异常的镜片纤维 导致在视觉轴后手术手术中形成不透明的斑块，从而导致 后囊壳不透明（PCO），是白内障手术的常见副作用。虽然是 知道PCO中的肌纤维细胞形成需要TGFβ/SMAD途径的激活 手术后，手术时间和TGFβ途径激活之间存在滞后，可能 由于需要激活潜在的TGFβ，并为LEC提供有效做出反应 信号。但是，关于手术后立即触发的途径知之甚少 这导致在体内形成纤维化PCO所需的TGFβ信号的强大激活。这 申请通过研究发生的分子变化来填补这些知识差距 在鲁棒的TGFβ途径激活之前，在两个特定目标中激活了LEC。第一个目标 研究两种分子机制，用于治疗眼部注射后注射的分子机制 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 转录组受“立即的早期基因”（IEG）的调节。第二个目标测试 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，并通过 IEGS。这项投资将填补有关分子的当前知识差距 手术时间与鲁棒TGFβ途径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。