The mechanisms underlying posterior capsular opacification

后囊膜混浊的机制

• 批准号: 9595854
• 负责人: MELINDA K DUNCAN
• 金额: $ 34.36万
• 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/9595854
• 关键词: Address; Adult; Adverse effects; 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; 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.

白内障囊外手术大大减轻了全球白内障相关疾病的负担 失明虽然这种手术非常有效，但大多数患者会出现严重的眼部症状。 白内障手术后的炎症，这可能会损害视力，而其治疗与 有效的抗炎药物对患者来说是不愉快的，并且可能引起副作用。而 白内障手术激活的一些炎性途径是已知的，这些尚未被 它们的综合特征和途径诱导机制尚不清楚。此外，本发明还 替换眼内透镜的最佳植入需要保留大部分透镜 囊，即包围透镜的基底膜。由于透镜上皮细胞（LEC）是 由于晶状体上皮细胞与透镜囊紧密相连，因此在白内障手术中并非所有晶状体上皮细胞都能被摘除， 这些细胞倾向于经历强有力的伤口愈合反应。由此产生的扩散， 迁移、转分化为肌成纤维细胞和形成异常的透镜纤维通常 导致白内障手术后视轴中形成不透明斑块， 后囊膜混浊（PCO）是白内障手术的常见副作用。虽然 已知PCO中肌成纤维细胞的形成需要TGFβ/SMAD通路的激活 手术后，手术时间和TGFβ通路激活之间存在滞后，可能 由于需要激活潜在的TGFβ，并使LEC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通路知之甚少 这导致体内形成纤维化PCO所必需TGFβ信号传导的强烈激活。这 应用程序试图通过调查发生的分子变化来填补这些知识空白 在两个特定目的中，在TGFβ途径强烈激活之前在LEC中进行。第一个目标 研究调节白内障后眼部炎症的分子机制， 手术和随后发生的促纤维化基因表达的LEC中， 在手术后研究这种透镜上皮细胞的重塑 转录组受“立即早期基因”（IEG）调控。第二个目标是测试 白内障后第一天上调的经典Wnt信号转导假说 手术在PCO的发病机制中起着重要的作用， IEGs.这项研究将填补目前有关分子生物学知识的空白。 在手术时间和TGFβ通路激活之间发生的变化， PCO是现代白内障手术的主要副作用。