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Contact Lens Wear, Bacteria, and Corneal Homeostasis

隐形眼镜佩戴、细菌和角膜稳态

基本信息

批准号：
10610842
负责人：
Suzanne MJ FLEISZIG
金额：
$ 39.25万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610842
关键词：
Aging Automobile Driving Bacteria C57BL/6 Mouse Cell membrane Cells Coin Contact Lenses Contralateral Cornea Corneal Stroma Corynebacterium Custom Data Dendritic Cells Disease Epithelium Event Exposure to Eye Homeostasis Human Hydrogels IL17 gene IL1R1 gene Image Imiquimod Immunohistochemistry Infection Infiltration Inflammasome Inflammation Inflammatory Response Keratitis Knockout Mice Licensing Ligands Liquid substance Location Lung Maintenance Manufacturer Mechanical Stress Microbe Modeling Morphology Mus Myopia Nerve Neutrophil Infiltration Nociceptors Osmolar Concentration Pathology Persons Play Predisposition Prevention Pseudomonas aeruginosa Publishing Reperfusion Injury Research Resolution Risk Role Signal Transduction Silicones Skin Stress Surgical sutures TNFRSF1A gene TRPV1 gene Technology Temperature Testing Thick Tissues Vision cell motility cofactor commensal microbes conjunctiva cytokine human subject in vivo Model infection risk interleukin-23 lens lens induction microbial microbiome mouse model neutrophil preservation recruit response tissue stress tool trafficking

项目摘要

Summary: Worn by >40 million people in the USA alone, contact lenses are associated with a risk of sight-threatening infection. With increasing use for myopia prevention and efforts to develop lenses for technological purposes, a surge in lens usage (extended wear specifically) is predicted. Unfortunately, research related to lens-related complications has been hindered by lack of an in vivo model amenable to the many research tools available only for mice. Following a 25-year effort, we have developed a mouse contact lens wear model. This utilizes silicone hydrogel lenses custom made by a contact lens manufacturer to fit mouse eyes, and does not require lid suturing. The lenses enable corneal infection when contaminated with P. aeruginosa, the most common causative agent of contact lens-related keratitis in people. Foundational to understanding contact lens related infection is knowing how a lens impacts the cornea without bacterial inoculation. Preliminary data show the mouse model replicates multiple events occurring during human lens wear, including colonization of the lens with commensal-type bacteria, and a dendritic cell (DC) response within 24 h. Moving beyond what is feasible using human subjects, high resolution time-lapse imaging of mice with fluorescent cell membranes revealed normally not present motile cells resembling neutrophils in the stroma after 6 days of wear. Immunohistochemistry confirmed infiltration of Ly6G+ cells (neutrophil marker). This DC/Ly6G+ response without pathology fits the definition of parainflammation as “a low-grade inflammatory response at an intermediate state between tissue homeostasis and classic inflammation which can be induced by persistent tissue stress…” The three aims of this project will explore; 1) triggers of parainflammation during contact lens wear, 2) how the signal is transduced within the cornea to drive the Ly6G+ cell response, and 3) its significance during microbe challenge. The hypothesis, based on published and preliminary data, is that parainflammation during contact lens wear in mice can be triggered by microbes colonizing the lens, initiating a sequence of events not otherwise occurring in the normally microbiome-free cornea that function to protect it against commensal-type bacteria, but which primes the cornea to respond overly-aggressively to P. aeruginosa. !

总结：仅在美国就有超过4000万人佩戴隐形眼镜，隐形眼镜与视力威胁风险有关。感染随着越来越多地用于预防近视和努力开发用于技术目的的镜片，预计透镜使用（特别是长期佩戴）会激增。不幸的是，与镜片相关的研究由于缺乏适用于许多可用研究工具的体内模型，只有老鼠。经过25年的努力，我们已经开发出一个鼠标接触透镜磨损模型。这利用由接触透镜制造商定制的硅水凝胶镜片，以适应小鼠眼睛，并且不需要盖子 - 是的当被铜绿假单胞菌污染时，这种镜片会导致角膜感染，人接触镜相关角膜炎的病原体。了解接触透镜相关感染的基础是了解透镜如何影响角膜，而不细菌接种初步数据显示，小鼠模型复制了人透镜配戴，包括用细菌型细菌和树突状细胞（DC）定殖所述透镜 24小时内回复超越了使用人类受试者的可行性，高分辨率延时摄影具有荧光细胞膜的小鼠的成像显示正常情况下不存在类似于在佩戴6天后，基质中的中性粒细胞。免疫组织化学证实Ly6G+细胞浸润（中性粒细胞标志物）。这种无病理的DC/Ly6G+反应符合副炎症的定义，即"一种处于组织稳态和经典状态之间的中间状态的低度炎症反应持续的组织压力会引发炎症" 本项目的三个目标将探讨：1）接触透镜佩戴期间副炎症的触发因素，2）信号在角膜内转导以驱动Ly6G+细胞应答，以及3）其在微生物培养期间的意义挑战.根据已发表的和初步的数据，小鼠的透镜磨损可由定植在透镜上的微生物触发，引发一系列事件，而不是其他情况发生在正常无微生物群的角膜中，其功能是保护角膜免受角膜型细菌的侵害，但这会使角膜对铜绿假单胞菌产生过度积极的反应。 !