Paradigms of Wound Healing and Fibrosis in the Eye

眼睛伤口愈合和纤维化的范例

基本信息

批准号：
9127959
负责人：
A. Sue Menko
金额：
$ 43.36万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127959
关键词：
Adolescent Adult Anterior Apoptosis Blindness Cataract Cataract Extraction Cell Line Cell physiology Cells Cicatrix Collagen Complex Cornea Corneal Injury Data Deposition Disease Disease model Elements Embryo Epithelial Epithelial Cells Epithelium Etiology Eye Fibronectins Fibrosis Funding Goals Health Homeostasis Image Immune Immunologic Surveillance Impaired wound healing Infectious Agent Injury Integrins Knowledge Lens Fiber Lens development Leukocytes Life Light Liver Macular Hole Mediating Membrane Mesenchymal Mesenchymal Stem Cells Mesoderm Cell Modeling Movement Mus Myofibroblast PTPRC gene Phenotype Play Population Process Property Protein Isoforms Publishing Quality of life Recruitment Activity Resolution Retina Role Scleroderma Shapes Signal Transduction Source Stratified Squamous Epithelium Surface Surface Ectoderm Tenascin Time Tissues Vision Visual impairment Water Wound Healing capsule cell motility cell type corneal scar cytokine fiber cell injured integrin alpha9 lens lens capsule lens transparency leukocyte activation migration novel prevent repaired response response to injury tissue regeneration tissue repair wound

项目摘要

DESCRIPTION (provided by applicant): Fibrosis reduces the quality of life for millions and negatively impacts vision in the cornea by causing haze and scarring, in the lens by causing Posterior Capsular Opacification (PCO), and in the retina by causing fibrovascular membrane contraction leading to macular holes. During the previous funding period we showed that in the mouse and chick lens, as in the cornea, there is an innate population of mesodermal cells that are CD45+ and that these cells go to the leading edge of an injured lens epithelium to regulate migration of the epithelium to repair the wound in a mock cataract surgery model. This same population can be induced to express α-SMA, acquiring a myofibroblast phenotype associated with causing PCO. The fact that these innate repair cells express CD45 suggests they are leukocytes. Because the lens was believed to consist exclusively of ectodermally derived cells, these data change our fundamental understanding of the lens and how it is formed and maintained. In this proposal, we propose to: 1) Establish that the lens contains a diverse resident population of mesodermally derived leukocytes with tissue specific properties, by identifying the leukocyte type(s) present in the lens and cornea that modulate the repair process following injury to ocular epithelia, examining how leukocytes impact the rate of epithelial sheet movement and the reestablishment of a normal epithelium following wounding of the lens and cornea, assessing the ability of injury-induced cytokines to mediate lens leukocyte activation, determining whether immune surveillance is induced in the lens following injury to other ocular tissues, and investigating the hypothesis that lens leukocyte activation in response to injury can recruit leukocytes from the outside the lens. 2) Establish that integrin-matrix signaling converts resident immune cells in the lens and cornea to myofibroblasts by investigating the role played by tenascin-C in the provisional matrix needed for FN(EDA+) expression and assembly, examining the mechanism by which FN(EDA+) signals myofibroblast differentiation, determining the mechanism by which α9 integrin mediates myofibroblast differentiation, investigating whether collagen assembly and stiffening modulate persistence of the myofibroblast phenotype in the lens. Leukocyte integrins are known to mediate immune cell migration after injury and leukocytes can convert into α-SMA expressing myofibroblasts. The proposed studies use well-characterized lens and cornea models to study myofibroblast formation and persistence from innate leukocytes with the goal of developing new treatments that induce myofibroblasts to revert into non-pathologic cells and or to undergo apoptosis to reduce the burden of scarring diseases in vision.

描述（由申请人提供）：纤维化降低了数百万人的生活质量，并通过导致角膜混浊和疤痕对视力产生负面影响，通过引起后囊膜混浊（PCO）对晶状体产生负面影响，通过引起纤维血管膜收缩对视网膜产生负面影响在之前的资助期间，我们发现在小鼠和小鸡的晶状体中，就像在角膜中一样，存在先天的 CD45+ 中胚层细胞群，并且这些细胞进入受损晶状体上皮的前缘，调节上皮的迁移，以修复模拟白内障手术模型中的伤口。可以诱导相同的细胞群表达 α-SMA，获得与引起 PCO 相关的肌成纤维细胞表型。这些先天修复细胞表达 CD45 的事实表明它们是白细胞，因为人们认为晶状体完全由外胚层衍生的细胞组成，这些数据改变了我们对晶状体及其形成和维持方式的基本理解。提案中，我们建议：1）确定镜头包含多样化的通过识别晶状体和角膜中存在的白细胞类型来调节眼上皮损伤后的修复过程，研究白细胞如何影响上皮片运动的速率和重建晶状体和角膜的正常上皮伤口，评估损伤诱导的细胞因子介导晶状体白细胞活化的能力，确定其他损伤后晶状体中是否诱导免疫监视眼组织，并研究晶状体白细胞因损伤而激活可以从晶状体外部募集白细胞的假设。 2) 通过研究生腱蛋白所起的作用，确定整合素基质信号将晶状体和角膜中的常驻免疫细胞转化为肌成纤维细胞。 -C 在 FN(EDA+) 表达和组装所需的临时基质中，检查 FN(EDA+) 向肌成纤维细胞分化发出信号的机制，确定 α9 的机制整合素介导肌成纤维细胞分化，研究胶原蛋白组装和硬化是否调节晶状体中肌成纤维细胞表型的持久性。众所周知，白细胞整合素可介导损伤后的免疫细胞迁移，并且白细胞可以转化为表达α-SMA的肌成纤维细胞。晶状体和角膜模型来研究先天白细胞的肌成纤维细胞形成和持久性，目的是开发诱导肌成纤维细胞恢复为肌成纤维细胞的新疗法非病理性细胞和/或发生细胞凋亡，以减轻视力疤痕疾病的负担。