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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. !

概括：仅在美国就有超过 4000 万人佩戴隐形眼镜，其存在视力受到威胁的风险感染。随着近视预防用途的增加以及出于技术目的开发镜片的努力，预计镜片使用量将激增（特别是长时间佩戴）。不幸的是，与镜头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，并发症的发生受到阻碍只适用于老鼠。经过25年的努力，我们开发出了小鼠隐形眼镜佩戴模型。这利用了隐形眼镜制造商定制的硅水凝胶镜片适合小鼠眼睛，不需要盖子缝合。当镜片被铜绿假单胞菌（最常见的细菌）污染时，会导致角膜感染。人类隐形眼镜相关性角膜炎的病原体。了解隐形眼镜相关感染的基础是了解镜片如何影响角膜，而无需细菌接种。初步数据显示，小鼠模型复制了期间发生的多个事件人类镜片佩戴，包括共生型细菌和树突状细胞（DC）在镜片上的定植 24小时内回复。超越人类受试者的可行性，高分辨率延时摄影对带有荧光细胞膜的小鼠进行成像显示，通常不存在类似的运动细胞佩戴 6 天后基质中出现中性粒细胞。免疫组织化学证实 Ly6G+ 细胞浸润（中性粒细胞标记）。这种没有病理学的 DC/Ly6G+ 反应符合副炎症的定义：“ 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可能引起炎症……” 该项目将探讨三个目标： 1) 佩戴隐形眼镜期间副炎症的触发因素，2) 信号在角膜内转导以驱动 Ly6G+ 细胞反应，3) 其在微生物过程中的重要性挑战。根据已发表的初步数据，该假设是接触过程中的副炎症小鼠的镜片佩戴可能是由镜片上的微生物触发的，从而引发一系列原本不会发生的事件发生在通常不含微生物组的角膜中，其功能是保护其免受共生型细菌的侵害，但这会导致角膜对铜绿假单胞菌过度反应。！