Clusterin at the Ocular Surface

7.项目摘要/摘要 干眼症是一种常见的眼部疾病，影响着数百万人。干眼症是由 老化、眼部手术或环境暴露，也是戴隐形眼镜的不良影响，并外用 眼科药物。症状包括疼痛、灼热、瘙痒、发红、对光敏感和其他不适。如果 如果不进行治疗，严重的病例可能会因角膜疤痕而导致视力丧失。来自这项研究的新研究 该团队最近发表在NIH支持的《公共科学图书馆·综合》杂志上，提出了一种治疗干燥症的新方法 眼睛。利用一种实验性的小鼠模型，研究人员发现，被称为 聚集素选择性地与干燥应激破坏的眼表屏障结合 这种方式，同时也防止进一步的损害。聚集素的已知性质表明它可能进一步保护 对抗炎症级联激活和随后的鳞状化生的上游效应。这个 拟议的研究将调查这一以前未被认识到的内源性保护机制。这个 计划中的研究利用小鼠实验模型和眼部定量功能测试 表面屏障的破坏，并利用小鼠的遗传学。具体目标是：1)确定 聚集素插入眼表糖萼的分子性质，以及它可能如何与ALL相关。 或-无影响；2)记录聚集素在抗蛋白降解中的作用，蛋白降解对能力的影响 对于聚集素结合，以及蛋白水解性和聚集素途径之间的关系；3)定义 内源性聚集素保护途径及其在维持机体抗炎环境中的作用 眼表。这项研究的影响将是关于眼表的新的基础科学知识 屏障，它在疾病中是如何改变的，以及聚集素的保护机制。这一结果将为 临床创新。

7. PROJECT SUMMARY/ ABSTRACT Dry eye syndrome is a common affliction of the eye that affects millions of people. Dry eye is brought on by aging, eye surgery or environmental exposure and is also an adverse effect of contact lens wear, and topical eye medications. Symptoms include pain, burning, itching, redness, sensitivity to light and other discomfort. If left untreated, severe cases may result in vision loss due to corneal scarring. New research from this research team, recently published in the NIH-supported journal PLOS ONE, suggests a new approach to treating dry eye. Using an experimental mouse model, the researchers found that the natural tear protein known as clusterin selectively binds to the ocular surface barrier disrupted by desiccating stress in an all-or-none manner, while also preventing further damage. Known properties of clusterin suggest it may further protect against the upstream effects of inflammatory cascade activation and subsequent squamous metaplasia. The proposed research will investigate this previously unrecognized, endogenous protective mechanism. The planned studies make use of the mouse experimental model and a quantitative functional assay for ocular surface barrier disruption, and take advantage of mouse genetics. The specific aims are: 1) to determine the molecular nature of clusterin intercalation into the ocular surface glycocalyx, and how it might relate to the all- or-none effect; 2) to document the role of clusterin in anti-proteolysis, the effects of proteolysis on the capacity for clusterin binding, and the relationship between the proteolytic and clusterin pathways; 3) to define the endogenous clusterin protection pathway and its role in maintaining an anti-inflammatory environment at the ocular surface. The impact of this research will be new basic science knowledge about the ocular surface barrier, how it is altered in disease, and mechanisms of protection by clusterin. The results will set the stage for clinical innovation.