OCULAR SURFACE INJURY: INFLAMMATORY CASCADE AND HEALING OF CORNEAL WOUNDS

眼表损伤：炎症级联和角膜伤口的愈合

• 批准号: 7365346
• 负责人: Clifton WAYNE SMITH
• 金额: $ 38.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365346
• 关键词: A Mouse; Adhesions; Animal Model; Area; Bacterial Infections; Blindness; Blood Platelets; C57BL/6 Mouse; Cornea; Corneal Abrasion; Corneal Injury; Corneal Opacity; Corneal Stroma; Data; Defect; Emigrations; Ensure; Epithelial; Epithelium; Event; Excision; Healed; Hour; Inflammation; Inflammatory; Inflammatory Response; Injury; Kinetics; Knockout Mice; Leukocytes; Maintenance; Modeling; Molecular; Operative Surgical Procedures; Paper; Peripheral; Play; Population; Process; Publishing; Reagent; Research; Research Design; Research Personnel; Resolution; Resources; Role; Safety; Surface; T-Lymphocyte; Therapeutic Intervention; Transgenic Organisms; Work; Wound Healing; corneal epithelium; healing; interest; limbal; macrophage; molecular array; mouse model; neovascularization; neutrophil; ocular surface; prevent; response; trafficking; vascular bed

DESCRIPTION (provided by applicant): The inflammatory response and its resolution are necessary for efficient healing of corneal injuries. The inflammation develops as a cascade of sequentially dependent cellular emigrations, and the precise temporal and molecular relationships within this cellular trafficking are critical. There are unique features in the cornea not predictable from studies of other vascular beds, and dysregulation of this cascade diminishes the efficiency of or actively delays corneal wound healing. Research design: The proposed studies are limited to an animal model: corneal epithelial abrasion in C57BL/6 mice. A mouse model provides access to molecular reagents and resources for mechanistic studies (e.g., transgenic and knockout mice). The injury is standardized -- removal of a defined area of epithelium with no or minimal direct stromal injury, and analysis of inflammation at 6 hour intervals over an observation period of 48 hours defines the kinetics of cellular trafficking. The specific aims deal with previously unrecognized aspects of corneal epithelial wound repair -- specifically, the involvement of ?/? T cells and platelets in facilitating healing. Aim 1. Define mechanisms for the accumulation of platelets in limbal vessels and peripheral corneal stroma following central corneal epithelial abrasion. Hypothesis: Platelet accumulation depends on adhesion to leukocytes in limbal vessels and in turn augments leukocyte accumulation. Our published work shows that depletion of circulating platelets significantly reduces corneal healing. Aim 2. Define mechanisms by which ?/? T cells influence the inflammatory response to central corneal epithelial abrasion. Hypothesis: Resident and emigrated ?/? T cells are necessary for efficient epithelial healing through their control of the inflammatory process including the accumulation of platelets. Preliminary data in this application reveal that depletion of ?/? T cells significantly reduces corneal healing and significantly reduces platelet and neutrophil localization in the limbus. Epithelium on the surface of the cornea plays important roles in the maintenance of corneal function and optimal healing, a major concern for efficacy and safety of refractive surgical procedures and the treatment of corneal injury. The proposed research defines mechanisms by which inflammation in response to corneal injury promotes or retards healing, revealing potential targets for therapeutic intervention.

描述（由申请人提供）：炎症反应及其消退是角膜损伤有效愈合所必需的。炎症的发展是一系列顺序依赖的细胞迁移，这种细胞运输中精确的时间和分子关系至关重要。角膜中存在无法从其他血管床的研究中预测的独特特征，并且该级联的失调降低了角膜伤口愈合的效率或主动延迟角膜伤口愈合。研究设计：拟定研究仅限于动物模型：C57 BL/6小鼠角膜上皮擦伤。小鼠模型为机制研究提供了分子试剂和资源（例如，转基因和敲除小鼠）。损伤是标准化的--去除限定区域的上皮，没有或有最小的直接基质损伤，并且在48小时的观察期内以6小时的间隔分析炎症，确定细胞运输的动力学。具体的目标是处理以前未被认识到的角膜上皮伤口修复方面-特别是，参与？/？T细胞和血小板促进愈合。目标1.明确中央角膜上皮擦伤后角膜缘血管和周边角膜基质中血小板聚集的机制。假设：血小板聚集依赖于与角膜缘血管中白细胞的粘附，进而增加白细胞聚集。我们已发表的工作表明，循环血小板的消耗显着减少角膜愈合。目标2.定义用于？/？T细胞影响中央角膜上皮磨损的炎症反应。假设：居民和移民？/？T细胞通过控制炎症过程（包括血小板的积累）对于有效的上皮愈合是必需的。本申请的初步数据表明，消耗？/？T细胞显著减少角膜愈合并显著减少血小板和中性粒细胞在利姆布斯中的定位。 角膜表面的上皮细胞在维持角膜功能和最佳愈合中起着重要作用，这是屈光手术程序和角膜损伤治疗的有效性和安全性的主要关注点。拟议的研究定义了角膜损伤引起的炎症促进或延缓愈合的机制，揭示了治疗干预的潜在靶点。