New strategies for prevention of posterior capsule opacification

预防后囊膜混浊的新策略

基本信息

批准号：
10334418
负责人：
LINDA S MUSIL
金额：
$ 37.35万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2018-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334418
关键词：
Abnormal Cell Actins Adverse effects Animal Model Animals Anterior Cataract Cataract Extraction Cell Culture System Cell Culture Techniques Cell Density Cell Differentiation process Cell Proliferation Cell physiology Cells Chick Clinical Collaborations Complication Cytoskeleton Development Disease Dose Drug Targeting EGF gene Environment Epithelial Cells Excision FDA approved Family Fibrosis Gene Expression Genetic Transcription Goals Growth Factor Hour Human Intervention Intraocular lens implant device Investigation Lens Fiber Ligands Malignant Neoplasms Mediating Modeling Molecular Myofibroblast National Center for Advancing Translational Sciences National Eye Institute Oncogenes Operative Surgical Procedures Oryctolagus cuniculus Pathway interactions Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacology Population Prevention strategy Preventive treatment Process Proliferating Property Publications Rattus Research Priority Retina Role Serum Signal Transduction Small Interfering RNA Structure System Testing Therapeutic Time Tissues Toxicology Transfection Transforming Growth Factor beta Translating Translations United States National Institutes of Health Vision authority capsule cell motility cell type clinical application combat cost density drug development drug repurposing epithelial to mesenchymal transition experience fiber cell fighting in vivo inhibitor intravitreal injection kinase inhibitor lapatinib lens lens capsule leukemia light transmission mechanotransduction migration novel novel strategies operation pre-clinical pre-clinical assessment preservation prevent programs receptor small molecule small molecule inhibitor therapeutic evaluation

项目摘要

PROJECT SUMMARY Posterior capsule opacification (PCO) is the most common and costly vision-disrupting complication of cataract surgery. A stated major research priority of the Lens and Cataract Program at NEI is "to study the mechanism of TGFβ−mediated lens fibrosis in order to develop effective means of preventing PCO." During the past 25 years, we have perfected a serum-free primary chick lens cell culture system (DCDMLs) that has been validated as an appropriate model for the mammalian lens. Using this system, we found that TGFβ can induce not only lens cell fibrosis (i.e., epithelial-mesenchymal transition to myofibroblasts; EMyT), but also lens fiber cell differentiation. The latter is a major cause of clinically deleterious PCO. In this application, we propose three novel strategies to prevent PCO that target different pathways. Each has the potential to block the development of fibrotic and/or lens fiber-type PCO without increasing the time, complexity, or cost of current standard cataract surgery. They also provide new clinical applications for approved or investigational human therapeutics, a goal of another NIH program (the drug repurposing/rescue initiative at NCATS). (1) We have made the unprecedented discovery that a small molecule multikinase inhibitor FDA-approved in 2012 to fight leukemia blocks TGFβ-induced EMyT and lens fiber cell differentiation in DCDMLs, as well as two other processes essential for the development of PCO (lens cell proliferation and migration). Effective levels of this drug can be loaded into, and be released within an hour from, a standard human intraocular lens (IOL), and were non-toxic in rabbits after either intracameral or intravitreal injection. Aim #1 is to assess the ability of such drug-releasing IOLs to prevent PCO in the most commonly used and accepted preclinical animal model for PCO, namely rabbits subjected to mock cataract surgery. These studies will be conduced in collaboration with Dr. Liliana Werner, a worldwide authority on PCO and its preclinical assessment in rabbits. (2) We have recently discovered that 10/10 small molecule inhibitors of ErbB (EGF) family receptors block TGFβ from inducing EMyT in DCDMLs. To our knowledge, these studies are the first to reveal an obligatory cooperation between the TGFβ and ErbB pathways in fibrosis in lens cells. Aim #2 is to identify the ErbB receptors and ligands required for this process, the essential first step in elucidating the molecular mechanisms of this interaction. We will also test if an FDA-approved ErbB R inhibitor can be delivered via IOL. (3) An obvious but underappreciated consequence of cataract surgery is that the surviving anterior lens epithelial cells loose almost all of their cell-cell contacts. In non-lens systems, two types of druggable transcriptional effectors have been shown to regulate TGFβ-induced fibrosis in a cell density-dependent manner. On the basis of preliminary evidence presented in this application, we propose to carry out the first molecular investigation of the role of MRTF-A (Aim #3A) and YAP/TAZ (Aim #3B) in low density-induced, TGFβ-dependent fibrosis in lens cells.

项目摘要后胶囊不透明（PCO）是最常见，最昂贵的视力中断的并发症白内障手术。 NEI的镜头和白内障计划的主要研究优先级是“研究 TGFβ介导的透镜纤维化的机制，以开发有效的PCO手段。” 在过去的25年中，我们完善了具有无血清的初级鸡透镜细胞培养系统（DCDML）被证实为哺乳动物镜头的合适模型。使用此系统，我们发现TGFβ可以不仅诱导晶状体细胞纤维化（即上皮 - 间质转变为肌纤维细胞； EMYT），还诱导镜头纤维细胞分化。后者是临床上删除的PCO的主要原因。在此应用程序中，我们建议防止针对不同途径的PCO的三种新型策略。每个都有可能阻止开发纤维化和/或镜头纤维型PCO，而不会增加当前的时间，复杂性或成本标准白内障手术。他们还为批准或研究人员提供新的临床应用 Therapeutics，是另一个NIH计划的目标（NCATS的药物重新调整/救援计划）。（1）我们已经做出了前所未有的发现，即一个小分子多次激酶抑制剂FDA批准 2012年，与白血病作斗争，阻止了TGFβ诱导的DCDML中的EMYT和透镜纤维细胞分化，以及 PCO开发至关重要的两个过程（镜头细胞增殖和迁移）。有效的该药物的水平可以加载到标准人眼内镜头一个小时内，并在一个小时内释放（IOL），腔内或玻璃体内注射后的兔子无毒。目标＃1是评估这种释放IOL的能力预防最常用和接受的临床前动物中PCO PCO的模型，即接受模拟白内障手术的兔子。这些研究将在与PCO的全球权威及其在兔子中的临床前评估与Liliana Werner博士合作。（2）我们最近发现ERBB（EGF）家族受体阻滞的10/10小分子抑制剂 DCDML中诱导的EMYT的TGFβ。据我们所知，这些研究是第一个揭示强制性的研究晶状体细胞中纤维化中TGFβ和ERBB途径之间的合作。目标＃2是识别ERBB 此过程所需的接收器和配体，这是阐明分子机制的重要第一步这种相互作用。我们还将测试是否可以通过IOL传递FDA批准的ERBB R抑制剂。（3）白内障手术的明显但不足的后果是幸存的前晶状体上皮细胞几乎松散了其所有细胞 - 细胞接触。在非镜头系统中，两种类型的吸毒已证明转录效应可以调节细胞密度依赖性TGFβ诱导的纤维化方式。根据本申请中提供的初步证据，我们建议执行第一个 MRTF-A（AIM＃3A）和YAP/TAZ（AIM＃3B）在低密度诱导的，透镜细胞中TGFβ依赖性纤维化。